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Genetic Variants Associated with Quantitative Glucose Homeostasis Traits Translate to Type 2
Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics)
Consortium
Running Title: Glucose Homeostasis in the GUARDIAN Consortium
Nicholette D. Palmer1,2,3,4*, Mark O. Goodarzi5,6*, Carl D. Langefeld4,7*, Nan Wang9,41*, Xiuqing
Guo15,16, Kent D. Taylor15,16, Tasha E. Fingerlin11,12, Jill M. Norris11, Thomas A. Buchanan8,13,41,
Anny H. Xiang14, Talin Haritunians6, Julie T. Ziegler4,7, Adrienne H. Williams4,7, Darko
Stefansovski6, Jinrui Cui6, Adrienne W. Mackay9, Leora F. Henkin4,17, Richard N. Bergman10,
Xiaoyi Gao9,28, James Gauderman9,28, Rohit Varma28, Craig L. Hanis21, Nancy J. Cox29, Heather
M. Highland21, Jennifer E. Below21, Amy L. Williams19,30,31, Noel P. Burtt19, Carlos A. AguilarSalinas32, Alicia Huerta-Chagoya32,33, Clicerio Gonzalez-Villalpando34, Lorena Orozco35,
Christopher A. Haiman9, Michael Y. Tsai18, W. Craig Johnson36, Jie Yao15, Laura RasmussenTorvik37, James Pankow38, Beverly Snively7, Rebecca D. Jackson39, Simin Liu40, Jerry L.
Nadler24, Fouad Kandeel25, Yii-Der I. Chen15,16, Donald W. Bowden1,2,3,26 Stephen S. Rich27,
Leslie J. Raffel6, Jerome I. Rotter15,16†, Richard M. Watanabe8,9,41†, Lynne E. Wagenknecht4,17†
*These authors contributed equally to this work
†
These authors jointly directed this work and are co-corresponding authors
1
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA
3
Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA
4
Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA
5
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
6
Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA
7
Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC
8
Department of Physiology and Biophysics, Keck School of Medicine of USC, Los Angeles, CA
9
Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, CA
10
Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, CA
11
Departments of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO
12
Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, CO
13
Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA
14
Research and Evaluation Branch, Kaiser Permanente of Southern California, Pasadena, CA
15
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical
Center, Torrance, CA
16
Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA
17
Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC
18
Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN
19
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA
20
Department of Genetics, Harvard Medical School, Boston, MA
21
Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, TX
22
Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA
23
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
24
Department of Medicine, Eastern Virginia Medical School, Norfolk, VA
25
Department of Diabetes, Endocrinology and Metabolism, City of Hope, Duarte, California
26
Section on Endocrinology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC
27
Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA
28
UIC Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, Chicago, IL
29
Department of Human Genetics, University of Chicago, Chicago, IL
30
Howard Hughes Medical Institute, Chicago, IL
31
Biological Sciences Department, Columbia University, New York, NY
32
Endocrinologia y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
33
Universidad Nacional Autónoma de México, Mexico City, Mexico
34
Centro de Estudios en Diabetes Instituto Nacional de Salud Publica, Mexico
35
Instituto Nacional de Medicina Genómica
36
Collaborative Health Studies Coodinating Center, Department of Biostatistics, University of Washington, Seattle, WA
37
Preventive Medicine-Epidemiology, Northwestern University Feinberg School of Medicine, Evanston, IL
38
Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN
39
Ohio State University Medical Center, Columbus, OH
2
1
Diabetes Publish Ahead of Print, published online December 18, 2014
Diabetes
40
41
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Department of Epidemiology, Brown University, Providence, RI
USC Diabetes and Obesity Research Institute, Keck School of Medicine of USC, Los Angeles, CA
Corresponding Authors:
Jerome I. Rotter
Harbor-UCLA Medical Center
1124 W. Carson Street, Bldg., E-5
Torrance, CA 90502
Phone: 310-974-9501
E-mail: [email protected]
Richard M. Watanabe
Keck School of Medicine of USC
2250 Alcazar Street, Suite 200
Los Angeles, CA 90033
Phone: 323-442-2053
Fax: 323-442-2349
E-Mail: [email protected]
Lynne E. Wagenknecht
Wake Forest School of Medicine
1 Medical Center Blvd.
Winston-Salem, NC 27157, USA
Phone: 336-716-7652
Fax: 336-716-6427
E-mail: [email protected]
Journal: Diabetes
Word Count (max. 4000): 200 (abstract), 4000 (body)
References (max 50): 50
Number of Tables and Figures (max. 8): 6
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ABSTRACT
Insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness exhibit strong
genetic components although few studies have examined their genetic architecture or their
influence on type 2 diabetes (T2D) risk. We hypothesized that loci affecting variation in these
quantitative traits influence T2D. We completed a multi-cohort genome-wide association study
to search for loci influencing T2D-related quantitative traits in 4,176 Mexican Americans.
Quantitative traits were measured by the frequently-sampled intravenous glucose tolerance test
(4 cohorts) or euglycemic clamp (3 cohorts) and random effects models were used to test
association between loci and quantitative traits, adjusting for age, gender, and admixture
proportions (Discovery). Analysis revealed significant (P<5.00x10-8) association at 11q14.3
(MTNR1B) with acute insulin response. Loci with P<0.0001 among the quantitative traits were
examined for translation to T2D risk in 6,463 T2D cases and 9,232 controls of Mexican ancestry
(Translation). Non-parametric meta-analysis of the Discovery and Translation cohorts identified
significant associations at 6p24 (SLC35B3/TFAP2A) with glucose effectiveness/T2D, 11p15
(KCNQ1) with disposition index/T2D, and 6p22 (CDKAL1) and 11q14 (MTNR1B) with acute
insulin response/T2D. These results suggest that T2D and insulin secretion and sensitivity have
both shared and distinct genetic factors, potentially delineating genomic components of these
quantitative traits that drive risk for T2D.
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INTRODUCTION
The pathophysiologic basis of type 2 diabetes (T2D) reflects derangements in both
insulin sensitivity and beta-cell function(1). Alterations in insulin clearance and glucose
effectiveness may also contribute to the development of T2D(2). Genome-wide association
studies (GWAS) of T2D have focused almost entirely on clinical presentation of disease and not
on these underlying pathophysiologic traits. Expanding the focus to include the genetic basis of
insulin sensitivity and beta-cell function has the potential to expand our knowledge of the
pathophysiologic pathways underlying T2D. To date, GWAS of T2D and related traits have been
conducted primarily in European origin populations(3). However, the prevalence of T2D and
related traits vary by ethnicity, suggesting differential genetic architecture will provide important
insight into T2D diathesis.
GWAS in case/control samples of T2D have had a substantial impact on the current
understanding of genetic susceptibility to disease, implicating variants in at least 70
genes/regions that each have relatively small individual effects but are common in the general
population(4). Most identified T2D genes appear to mediate their influence through the beta-cell
and not through insulin resistance. These data contrast with other evidence and the widely
accepted belief that insulin resistance is a major(5; 6) heritable(7-10) component of T2D
susceptibility. This suggests that insulin resistance is a part of the necessary milieu, but is
insufficient to cause frank T2D in isolation.
GWAS of the underlying pathophysiologic traits of insulin sensitivity and beta-cell
function have relied almost entirely on surrogate measures such as homeostasis model
assessment (HOMA) parameters(11). While these fasting measures do not reflect the dynamic
processes of glucose homeostasis, new T2D loci have been identified through GWAS of basic
T2D-related traits such as fasting glucose(11; 12). We have recently documented substantial
heritability of direct measures of insulin resistance and insulin clearance in Mexican
Americans(13), suggesting that genetic factors underlying these traits should be investigated to
identify new loci underlying disease susceptibility. In addition, strong genetic correlation was
observed between these traits, raising the possibility of shared genetic determinants(13).
Only two GWAS(14; 15) of T2D have been conducted in Mexican origin populations, a
group whose disease risk is nearly two times greater than that of European origin
populations(16). The recent SIGMA (Slim Initiative for Genomic Medicine in the Americas)
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T2D Consortium identified a novel risk variant in SLC16A11, which is rare in European and
African individuals, suggesting a possible role for triacylglycerol metabolism in T2D(15). Thus,
the study of detailed physiologic traits in individuals of Mexican ancestry has the potential to
uniquely expand our understanding of T2D.
The Genetics Underlying Diabetes in Hispanics (GUARDIAN) Consortium was designed
to overcome numerous gaps in the field of T2D genetics. GUARDIAN conducted a GWAS in
multiple Mexican-ancestry cohorts with highly detailed glucose homeostasis measures. In the
Discovery phase, measures were obtained using gold-standard protocols, i.e., the euglycemic
clamp and the frequently sampled intravenous glucose tolerance test (FSIGT). Genomic regions
associated with these quantitative traits were carried forward in a Translation phase that
evaluated association with the clinical outcome of T2D. Using this approach, GUARDIAN has
found novel and known risk variants in a Mexican-ancestry population that specifically translate
to T2D. The study identified possible new pathways of disease etiology, and discovered risk
variants for glucose homeostasis traits that do not associate with overt T2D, providing unique
opportunities to understand physiologic regulation of glucose homeostasis traits within the
normal range.
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RESEARCH DESIGN AND METHODS
Study Populations
Discovery Cohorts
Seven cohorts were included in the Discovery: five family-based (IRAS-FS(17),
BetaGene(18), HTN-IR(10), MACAD(19), NIDDM-Athero(20); n=3,925) and two non-family
based studies (IRAS(1), TRIPOD(21); n=411). Cohorts were ascertained on various conditions
including diabetes, gestational diabetes, hypertension, or atherosclerosis (Supplementary Text).
Cohorts included persons without T2D who self-reported Mexican ancestry. Four studies
measured glucose homeostasis traits by FSIGT(22) (IRAS, IRAS-FS, BetaGene, TRIPOD) and
three by euglycemic clamp(23) (MACAD, HTN-IR, NIDDM-Athero). The primary traits of
interest were insulin sensitivity (SI from FSIGT or M from clamp, as well as a meta-analysis
combining these, denoted SI+M), metabolic clearance rate of insulin (MCRI), acute insulin
response (AIRg), disposition index (DI), and glucose effectiveness (SG). All participants provided
written informed consent and institutional review boards at the clinical, laboratory, and
coordinating centers approved the study.
Phenotyping
Glucose homeostasis traits were measured by hyperinsulinemic-euglycemic clamp in
three studies using an identical protocol(23). A priming dose of human insulin (Novolin;
Clayton, NC) was given followed by infusion for 120 minutes at a constant rate (60mU m-2 min1
) to establish steady state hyperinsulinemia. Blood was sampled every 5 minutes and the rate of
20% dextrose co-infused was adjusted to maintain plasma glucose concentrations at 95100mg/dL. The glucose infusion rate (M, mg m-2 min-1) over the last 30 minutes of steady-state
insulin and glucose concentrations reflects glucose uptake by all tissues of the body (primarily
insulin-mediated glucose uptake in muscle) and is therefore directly correlated with tissue insulin
sensitivity(23). The insulin sensitivity index (mg m-2 min-1 µIU-1 mL) was calculated as M/I,
where I is the steady-state insulin level. In this study, to distinguish between insulin sensitivity
and clearance, we relied on M as an approximation for insulin sensitivity because the
calculations of M/I and insulin clearance both use steady-state insulin in the denominator. MCRI
(mL m-2 min-1) was calculated as the insulin infusion rate divided by the steady state plasma
insulin level of the euglycemic clamp (9; 23). DI, a measure of beta-cell compensation for
insulin resistance, was calculated as M/I*delta insulin where delta insulin was calculated as the
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difference between insulin at 30 minutes and insulin at baseline from a 2-hr oral glucose
tolerance test (OGTT).
Glucose homeostasis traits were measured by FSIGT in four studies, with two
modifications. An injection of insulin was used (one study, TRIPOD, injected tolbutamide) to
ensure adequate plasma insulin levels for computation of insulin resistance across a broad range
of glucose tolerance(24). Also, the reduced sampling protocol (which requires 12 rather than 30
plasma samples(25)) was used to facilitate study of large numbers of individuals. A 50% glucose
solution (0.3g/kg) and regular human insulin (0.03units/kg) were injected through an intravenous
line at 0 and 20 minutes, respectively. Blood was collected at −5, 2, 4, 8, 19, 22, 30, 40, 50, 70,
100, and 180 minutes for plasma glucose and insulin concentrations. SI and SG were calculated
by mathematical modeling using the MINMOD program (version 3.0 [1994](22)). AIRg was
calculated as the increase in insulin concentrations at 2–8 minutes above the basal (fasting)
insulin level after the bolus glucose injection at 0-1 minute. DI was calculated as the product of
SI and AIRg. MCRI was calculated as the ratio of the insulin dose over the incremental area
under the curve of insulin from 20 minutes to infinity(26), using the following equation:
Here, Dose is the amount of insulin injected at 20 minutes. Ins(t) is the plasma insulin
concentration in standard units (µU/ml) at each FSIGT sampling point and Ins(0) is the fasting
plasma insulin concentration determined prior to the FSIGT glucose injection.
Genotyping
All samples were genotyped on the Illumina HumanOmniExpress BeadChip and alleles
called using GenomeStudio (Illumina, San Diego, CA)(27; 28). Samples with call rates >0.98
and SNPs with call rates >0.99 and MAF>0.001 passed laboratory quality control following
usual best practices (e.g., sufficient signal and cluster separation with no replicate errors)(29).
Additionally, ~22,000 SNPs were manually reviewed for clustering accuracy.
Statistical Analysis
Quality Control
Samples were removed from analysis if the overall call rate was <0.98, self-reported
ethnicity was inconsistent with genetic data (i.e., admixture proportions) relative to other
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members of the cohort (i.e., a genetic outlier), self-reported gender was inconsistent with
genotype data, the sample exhibited excess or insufficient heterozygosity relative to cohort
expectations, or the genotype data was inconsistent with the genotype data from existing SNP
data (i.e., fingerprinting). The primary inferential SNPs did not exhibit differential missingness
by trait, had a SNP call rate >95% and were consistent with Hardy-Weinberg Expectation
proportions. For family-based studies, pedigree structures were confirmed using standard
procedures (e.g. KING, http://people.virginia.edu/~wc9c/KING/index.html). Each SNP was
examined for Mendelian inconsistencies using PedCheck
(http://watson.hgen.pitt.edu/register/docs/pedcheck.html) and inconsistencies were converted to
missing. A maximum of 693,128 SNPs were meta-analyzed among the Discovery cohorts.
Population Stratification
Population substructure was estimated using ADMIXTURE
(http://www.genetics.ucla.edu/software/admixture/) v1.21 at each study site based on SNPs that
passed quality control (n=117,347 LD-pruned SNPs). Data from the HapMap Project (CEU,
CHB/JPT, YRI, and MEX; n=591) were utilized as reference populations. Depending on the
cohort, up to k=5 subpopulations were identified based on low cross-validation error. In all tests
for association, admixture proportions were included as covariates in the linear or variance
component models such that the covariates were not collinear and tests of association did not
exhibit evidence of inflation.
Association
Variance component models as implemented in GWAF(30) or SOLAR(31) were used to
test for association in family cohorts and linear regression models as implemented in
QSNPGWA (www.phs.wakehealth.edu) in non-family cohorts. All models included age, gender,
study site (in multi-center recruitment studies), and admixture proportions. Conditional analyses
were performed for significant loci with multiple uncorrelated variants by including the most
significant variant as an additional covariate. If necessary, winsorization or transformation was
applied to best approximate the distributional assumptions of conditional normality (conditional
on the covariates) and homogeneity of variance. For traits warranting transformation, the same
transformation was computed across all cohorts and included natural logarithm of the trait plus a
constant (SI), natural logarithm (MCRI derived from FSIGT), and square root (M, AIRg, and DI);
MCRI derived from clamp and SG were not transformed. The primary inference was derived
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from the additive genetic model. However, we also tested for a lack of fit to additivity using the
orthogonal contrast. If that lack of fit was significant (P<0.05), we report the “best” p-value as
the minimum of the three genetic models. It can be shown that this approach has an inflation
factor of 1.3. For robust estimation purposes, the additive and recessive genetic models were not
computed if there were not at least 10 and 20 individuals homozygous for the minor allele,
respectively. In addition to single variant association tests, a genetic risk score was computed,
i.e. risk allele load was determined by the number of previously reported T2D risk alleles
(Supplementary Table 2) carried by each individual, and analyzed for association with the
primary traits of interest (SI+M MCRI, and AIRg). Subsequently, an enrichment analysis was
performed among these variants to determine if an excess of nominally significant values were
observed.
A non-parametric meta-analysis was computed to combine the evidence of association
across cohorts as implemented in METAL (http://www.sph.umich.edu/csg/abecasis/metal/). For
each genetic model and T2D-related quantitative trait, a weighted, fixed effects meta-analysis
was computed weighting by cohort sample size and not by the standard error of the parameter
estimate because the traits were not identical and studies had different designs and ascertainment
criteria.
Power for the association analysis in the Discovery cohorts accounting for the familial
correlations, with stimulation-based estimations resulting in an effective sample size of 92%, was
estimated to be 80% to detect SNP-quantitative trait associations that explain 1% and 0.56% of
the variance at α=5x10-8 and α=1x10-4, respectively.
Translation
Evaluation of T2D-related quantitative traits is a potentially powerful approach to
identify genetic variants contributing to defects in specific underlying pathways leading to T2D;
however, the true impact can be gauged only through direct validation in a population with
clinically defined disease.
Translation Cohorts
Six cohorts were included in the Translation effort: LALES, MESA Family, MESA, Starr
County, WHI, and SIGMA (Supplementary Text). All cohorts were of self-reported Mexican
origin and provided either look-ups of the index SNPs or a pre-selected proxy.
SNP Selection for Translation
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Results from the Discovery GWAS were reviewed to generate the list of SNPs to be
examined for translation to T2D. For each of seven traits (SI+M, SI, M, MCRI, AIRg, DI, and
SG), SNPs associated in the GWAS (P<1.00x10-4) or with both primary traits (SI+M and MCRI;
P<0.05) were included. After removal of correlated SNPs (r2>0.90 within a 500kb window in the
largest set of unrelated samples; n=553 from BetaGene and TRIPOD), this yielded a total of 594
SNPs for translation to T2D.
Meta-analysis of Discovery and Translation Results
Discovery and Translation cohort genotype data were aligned to the positive strand for
compatibility. After alignment, the same non-parametric meta-analysis approach was used to
combine the association statistics. Lower values for the quantitative traits were hypothesized to
be associated with T2D risk(2; 32). Supplementary Figure 1 estimates the power of the
Translation cohort to detect various odds ratios for T2D over a range of minor allele frequencies.
Functional Database Validation
Queries of the Encyclopedia of DNA Elements (ENCODE) data were carried out using
both the UCSC genome browser (http://genome.ucsc.edu) and RegulomeDB
(http://regulome.stanford.edu/). The positions of associated loci were overlaid with DNase I
hypersensitivity hotspots from ENCODE that identified regions of chromatin accessibility and
transcription factor motifs in 125 diverse cell lines and tissues. We utilized the browsers set up
by the Genotype-Tissue Expression (GTEx) project to determine whether any of our association
signals represented expression quantitative trait loci (eQTL), i.e. SNPs associated with mRNA
transcript levels(33).
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RESULTS
The Discovery sample included 4,176 Mexican Americans without T2D (Table 1 and
Supplementary Table 1). Characteristics of the sample have been previously reviewed(13). The
Translation sample was comprised of 6,463 T2D cases and 9,232 controls (Supplementary
Text).
Figure 1 displays associations with T2D-related quantitative traits in the Discovery cohorts
with signals that were significant at P<2.00x10-6 listed in Table 2 (Supplementary Table 2 lists
nominally significant hits). Results were broadly similar with inclusion of BMI as a covariate
(Supplementary Table 3). The top signal (P=5.23x10-12) was association of rs10830963 in
MTNR1B (melatonin receptor 1B gene) with AIRg; this SNP was also associated with DI but not
with SI (Figure 2). Associations with insulin sensitivity (SI, M, or SI+M), MCRI, and SG did not
reach genome-wide significance levels. One signal for M (rs11683087) was located near IRS1, a
locus previously identified for T2D and deemed to act via insulin resistance based on association
with HOMA-IR(34). These variants were not highly correlated (r2=0.04) and the previously
described variant (rs2943641) failed to show evidence of association with M (P=0.63) or reduce
the level of significance at rs11683087 upon conditional analysis (P=1.29x10-6; Supplementary
Table 4).
Within the Discovery cohorts, we evaluated the association of previously reported T2Dsusceptibility variants (n=90; Supplementary Table 5) with seven T2D-related quantitative
traits. Using the reported variant (n=76) or a HapMap MEX proxy (n=14; r2>0.80), the most
profound effects were observed with decreased AIRg for 17 of the SNPs evaluated (P=2.3x10-80.021). The most significant association was at the MTNR1B locus (rs1387153)(35).
Comparatively, SI+M (n=9; P=0.0019-0.041) and MCRI (n=5; P=0.0053-0.050) had markedly
fewer nominal associations. Similarly, the cumulative genetic risk score (P=1.11x10-8) and
enrichment analysis (P<0.00001) were significantly associated with AIRg. Notably, we also
observed an enrichment for previously reported T2D SNPs with insulin sensitivity (SI+M;
P=3.6x10-4) although the significance was attenuated in comparison.
Meta-analysis of the Discovery and Translation cohorts identified multiple SNPs that met or
approached genome-wide significance (Table 3, Supplementary Figure 3; Supplementary
Table 6 for all results) and included novel and established T2D loci. Results were broadly
similar with the additional inclusion of BMI as a covariate (Supplementary Table 7). The most
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significant association observed was at rs2237897 (P=1.24x10-21) in KCNQ1 (potassium voltagegated channel, KQT-like subfamily, member 1 gene). This variant was associated with DI in the
Discovery cohort (P=7.04x10-6) and after conditional analysis for previously associated T2D
variants (rs2237892, P=1.57x10-4; rs231362, P=1.06x10-5; Supplementary Table 8). Three
established T2D genes, motivated by their association with AIRg, remained associated in the
meta-analysis: rs10830963 within MTNR1B (P=5.86x10-9); rs2206734 within CDKAL1 (CDK5
regulatory subunit associated protein 1-like 1 gene; P=1.11x10-8); and rs7018745 near
CDKN2A/B (cyclin-dependent kinase inhibitor 2A and 2B gene cluster; P=7.3x10-8) which is a
strong genetic susceptibility locus for cardiovascular disease (36) and linked to T2D (37).
Four novel associations were observed that reached or approached genome-wide
significance. At 6p24, rs2064197 was associated with SG and the meta-analysis with T2D
reached genome-wide significance (P=2.56x10-8). Other novel associations included rs322394
(M/T2D, P=1.12x10-7) at 5q35; rs7219451 at 17q21 (SI+M/T2D, P=3.97x10-7); and rs4266763
(DI/T2D, P=4.34x10-7) in SNAPC4 (small nuclear RNA activating complex, polypeptide 4 gene).
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DISCUSSION
GUARDIAN conducted a GWAS in seven Mexican-American cohorts of insulin sensitivity,
insulin secretion, insulin clearance, and glucose effectiveness directly quantified by the
euglycemic clamp and the FSIGT. We posited that the measurements of insulin sensitivity and
clearance obtained by detailed physiologic phenotyping procedures are closer to the gene
products and would yield increased statistical power to detect SNPs influencing trait variation.
Establishing these loci in the Mexican-American population will inform diabetes risk in an
ethnicity that experiences a disproportionately high diabetes burden(16) and may explain risk in
other ethnicities either directly or through a deeper understanding of the relevant biological
pathways.
The most significant association observed (rs10830963, P=5.23x10-12; Table 2) which
translated to T2D (P=5.86x10-9; Table 3) was at MTNR1B, which was initially identified as a
locus for fasting glucose(35). Two modestly correlated variants in MTNR1B, rs10830963 and
rs1387153 (r2=0.68), were associated with AIRg (P=5.23x10-12 and 2.21x10-9, respectively).
These variants were also, but less significantly, associated with fasting glucose in the Discovery
cohorts (P=3.92x10-8 and 2.09x10-5, respectively). As suggested by ENCODE, rs10830963
resides in a FOX2A transcription factor binding site and has a lower RegulomeDB Score (3a
versus 5, respectively) which corroborates the stronger evidence of association observed at
rs10830963. MTNR1B is expressed in both rodent and human islets and co-localizes with insulin.
Gene expression increases with each copy of the rs10830963 risk allele in human islets from
non-diabetic individuals. Consistent with this observation, MTNR1B gene expression levels are
higher in human islets from patients with T2D compared to those from individuals without
diabetes. MTNR1B is hypothesized to inhibit glucose-stimulated insulin secretion through
binding of its ligand, melatonin, and decreasing cAMP levels(38), consistent with the direction
of effect observed in our study.
Among novel variants that translated to disease risk was rs2064197 (P=2.56x10-8), which
was also associated with SG in the Discovery cohorts (P=7.23x10-6) and located intergenically on
6p24.3 between the SLC35B3 (solute carrier family 35, member B3) and TFAP2A (transcription
factor AP-2 alpha). SG is the ability of glucose to enhance its own disappearance and suppress its
production at fasting insulin levels(39; 40). The role of SG in the regulation of glucose tolerance
is often ignored, but may be physiologically significant(40; 41). SG varies by both physiologic
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and pathologic state(42) and has been shown to be predictive of conversion to T2D(43). Notably,
this variant resides distally (1.7Mb) to the recently implicated T2D susceptibility locus, RREB1
(ras responsive element binding protein 1), which was not associated with SG in our analysis
(Supplementary Table 4G). Other variants more nominally associated with this phenotype and
translation to T2D included rs1260326, a missense variant located in GCKR (glucokinase
regulator gene). This association is supported biologically, as the ATP-dependent
phosphorylation of glucose, which is catalyzed by glucokinase, is the first and rate-limiting step
in liver glucose metabolism(44). Since this step of glucose metabolism is independent of
dynamic insulin response, it is thought that a large portion of SG results from the ability of the
liver to take up glucose via the glucokinase pathway, independent of insulin.
It is widely accepted that replication of GWAS results in independent samples is critical.
However, we are unaware of additional Mexican-ancestry cohorts with highly detailed glucose
homeostasis phenotypes available in which to directly replicate our findings. Given that these
phenotypes predict the subsequent occurrence of T2D, we have taken a unique approach by
translating our findings to the directly relevant clinical phenotype, T2D. This approach provides
support that these loci are involved in deterioration from impaired glucose homeostasis to T2D.
Not surprisingly, we observed that only some of the quantitative trait loci identified via our
Discovery sample -- as loci associated with regulation of glucose homeostasis -- were associated
with T2D. While likely not attributable to power (we had 80% power to detect modest effect
sizes (OR=1.10-1.15) among common variants (MAF>0.15) at stringent significance levels
(P=5.00x10-8; Supplementary Figure 1)), this observation likely reflects the pleiotropic nature
of quantitative intermediate phenotypes of glucose homeostasis and the common observation that
not all individuals with impaired glucose tolerance transition to overt T2D. Alternatively, a lack
of association with T2D could reflect association of higher values for the quantitative traits with
T2D which conflicts with our underlying hypothesis. While requiring further verification, these
loci are still of substantial interest and have the potential to aid in understanding specific
physiologic pathways that may ultimately lead to disease or phenotypic variation within the
normal range.
GWAS for T2D have identified over 70 susceptibility loci; association studies with
quantitative traits have identified disturbed insulin secretion as the most frequent observation.
The inability to identify insulin resistance loci may be partially explained by the high frequency
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of insulin resistance in non-diabetic controls(45). Furthermore, cohorts included in GWAS for
T2D generally do not have detailed measures of insulin resistance. Fasting insulin and the
closely-related homeostasis model assessment of insulin resistance have been most commonly
used to represent insulin resistance in large-scale genetic studies(11). These traits only partially
reflect insulin resistance(46), and therefore may be inadequate for gene discovery. Other than a
small pilot study(47), the present GWAS is the first to include detailed measures of insulin
resistance.
A few of the previously reported diabetes loci do appear to act via altered insulin
sensitivity (FTO, PPARG, IRS1, KLF14, ADAMTS9, GCKR, RBMS1/ITGB6) (48), suggesting
the likely presence of other as yet undiscovered loci. The discovery of additional such traits was
a major goal of GUARDIAN. However, consistent with prior GWAS, we did not identify any
insulin sensitivity loci at genome-wide significance levels. While none of the more modestly
significant insulin sensitivity loci translated to T2D, rs7219451 and rs322394, nearly reached
genome-wide significance. It is possible that environmental or lifestyle factors have a relatively
greater effect on insulin sensitivity than genetic factors. We do not believe that differences in
phenotyping of this trait (euglycemic clamp or FSIGT) hampered our ability to discover insulin
sensitivity loci, given that these methods produce highly correlated measures(49).
Failure to meet genome-wide significance does not necessarily indicate that the detected
variants are not of importance; such variants have been found to be enriched in enhancer
elements in relevant tissues(50). Whether this is the case for the variants described herein will
require further experimentation. To gain insight on the functional potential of our association
signals, we queried ENCODE and GTEx databases. The linked SNAPC4 SNPs rs3812570 and
rs4266763 (r2=0.85), associated with DI/T2D in the Translational meta-analysis, had
RegulomeDB scores of 1f and 1b, respectively, indicating a high likelihood of functionality
based on eQTL evidence, residence in transcription factor binding sites, and DNAse
hypersensitivity sites. These SNPs are associated in multiple tissues not only with mRNA levels
of SNAPC4, but also the nearby genes INPP5E and CARD9. INPP5E codes for an inositol
polyphosphate-5-phosphatase that has been implicated in Golgi-vesicular trafficking(51),
alterations in which might affect beta-cell insulin granule formation. Of interest, another variant
with a putatively functional RegulomeDB score, rs10870202 (score 1f, associated with
AIRg/T2D in Table 3) is also an eQTL for INPP5E as well as DNLZ, a gene adjacent to CARD9
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and SNAPC4, suggesting this region on chromosome 9 may be key to insulin secretion.
Additionally, SNP rs1978648 was associated with SI (RegulomeDB score 2b) and resides in a
DNAase hypersensitive region harboring multiple transcription factor binding sites in HepG2
cells.
In summary, GUARDIAN has performed the first GWAS to explore the genetic
architecture of T2D-related quantitative phenotypes in a large Mexican-American cohort. As
defects in the maintenance of glucose homeostasis are postulated to contribute to the
development of T2D, a direct translation of our findings was performed to identify possible new
disease pathways and test whether these variants explain T2D risk. Consistent with the literature,
our results suggest a strong contribution for variants that affect insulin secretion pathways as
assessed by AIRg and DI, e.g. CDKAL1, MTNR1B and KCNQ1. Although novel signals of
association with insulin sensitivity traits were observed, they did not translate with statistical
significance to the clinically relevant phenotype of T2D. Notably, a novel association with
glucose effectiveness was observed, adding further to the complex pathophysiology underlying
T2D.
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AUTHOR CONTRIBUTIONS
N.D.P., M.O.G., C.D.L., N.W., R.M.W., L.E.W. wrote the manuscript.
T.A.B., L.F.H., D.W.B., S.S.R., L.J.R., J.I.R., R.M.W., L.E.W. designed, managed and
coordinated the project.
T.E.F., J.M.N., D.S., R.N.B., J.L.N., F.K. conducted phenotyping.
T.H. and K.D.T. carried out genotyping in GUARDIAN.
N.W., X.G., A.H.X., J.C., A.W.M., Y-D.I.C. carried out initial data analysis in GUARDIAN.
X.G., J.G., R.V. coordinated and carried out data analysis in LALES.
C.L.H., N.J.C., H.M.H., J.E.B. coordinated and carried out data analysis in Starr County Health
Studies.
A.L.W., N.P.B., C.A.A-S., A.H-C., C.G-V., L.O., C.A.H. coordinated and carried out data
analysis in the SIGMA T2D Consortium.
M.Y.T., W.C.J., J.Y., L.R-T., J.P. coordinated and carried out data analysis in the MESA and
MESA Family Studies.
B.S., R.D.J., S.L. coordinated and carried out data analysis in WHI.
J.T.Z., A.H.W., C.D.L., N.W., R.M.W. carried out meta-analysis of the data.
All authors have read and approved the manuscript.
Drs. Jerome I. Rotter, Richard M. Watanabe, and Lynne E. Wagenknecht are the guarantors of
this work and, as such, had full access to all the data in the study and take full responsibility for
the integrity of the data and the accuracy of the analysis.
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ACKNOWLEDGEMENTS
This research was supported by the GUARDIAN Study DK085175 from the The National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and from the following
grants: HL047887 (IRAS), HL047889 (IRAS), HL047890 (IRAS), HL47902 (IRAS), HL060944
(IRASFS), HL061019 (IRASFS), HL060919 (IRASFS), DK061628 (BetaGene), American
Diabetes Association Distinguished Clinical Scientist Award (BetaGene), HL088457 (MACAD),
HL0697974 (HTN-IR), HL055798 (NIDDM-Atherosclerosis), and DK079888 (work related to
insulin clearance in HTN-IR, MACAD and NIDDM-Atherosclerosis). Research support for the
Translation cohorts was provided by U10EY011753 (LALES), R01EY022651 (LALES),
P30EY001792 (LALES), an unrestricted Departmental Grant from the Research to
Prevent Blindness, New York, NY 10022 (LALES), DK073541 (Starr County Health Studies),
DK085501 (Starr County Health Studies), DK020595 (Starr County Health Studies), HL102830
(Starr County Health Studies), and Consejo Nacional de Ciencia y Tecnología grants 138826,
128877, CONACyT- SALUD 2009-01- 115250, Mexico City (SIGMA Type 2 Diabetes
Consortium; UNAM/INCMNSZ Diabetes Study). The Multi-Ethnic Study of Atherosclerosis
(MESA) was supported by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01HC-95168, N01-HC-95169 and by grants UL1-TR-000040 and UL1-RR-025005 from NCRR .
Funding for MESA Family was provided by grants R01-HL-071051, R01-HL-071205, R01-HL071250, R01-HL-071251, R01-HL-071252, R01-HL-071258, R01-HL-071259, and UL1-RR025005. Funding for MESA SHARe genotyping was provided by NHLBI Contract N02-HL-64278. The provision of genotyping data was supported in part by UL1TR000124 (CTSI), and
DK063491 (DRC).Computing resources were provided, in part, by the Wake Forest School of
Medicine Center for Public Health Genomics. The authors thank the other investigators, the staff,
and the participants of the studies for their valuable contributions.
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25
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Table 1. Clinical characteristics of the Discovery cohorts.
FSIGT Cohorts
Clamp Cohorts
BetaGene
TRIPOD
IRAS
IRAS Family
HTN-IR
MACAD
NIDDM-Athero
1202
125
187
1034
694
752
182
34.6±7.9
34.8±6.3
58.8±8.3
40.6±13.7
37.4±14.2
34.5±8.8
31.8±9.69
Women (%)
72.1
100.0
58.3
59.0
59.4
56.7
58.2
BMI (kg/m2)
29.5±6.1
30.6±5.4
28.9±5.1
28.3±5.7
28.8±5.5
28.9±5.1
28.6±6.3
AIRg (µU ml-1 min)
569±480
488±450
673±702
760±649
NA
NA
NA
NA
NA
NA
NA
NA
NA
Sample Size
Age (yr)
SG (min-1)
MCRI (L/min)
MCRI (ml m-2 min-1)
SI (x10-4 min-1 µU-1 ml)
M (µmol m-2 min-1)
DI
DI (µmol m-2 min-1)
0.0178±0.0067 0.0157±0.0041 0.0208±0.0088 0.0202±0.0091
10.1±5.7
NA*
4.2±2.0
5.5±2.4
NA
NA
NA
NA
3.03±1.63
2.57±1.79
1.33±1.24
2.14±1.86
NA
NA
NA
NA
NA
NA
NA
1273±547
1364±646
1255±533
1409±946
1004±724
1245±1184
NA
NA
NA
NA
NA
NA
NA†
136.8±100.2
93.23±54.4
1202±1236
NA
458.2±111.8 471.8±116.3
416.2±140.3
Values are expressed as the mean and standard deviation unless otherwise indicated. *MCRI is not available for TRIPOD due to the
use of tolbutamide in the FSIGT. †DI is not available for HTN-IR due to the lack of 30-minute insulin values from oral glucose
tolerance testing. Abbreviations: NA, not available.
26
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Table 2. Top Discovery hits from the GUARDIAN Consortium ordered by trait.
SNP
rs2302063
rs1602084
rs896232
rs6719442
rs1978648
rs896598
rs4887140
rs196701
rs10492494
rs11683087
rs10830963
rs1387153
rs2206734
rs3847554
rs9368222
rs6803803
rs10830963
rs1387153
rs2149423
rs3812570
rs523079
rs780093
rs788338
Chr
19
4
2
2
2
15
15
6
13
2
11
11
6
11
6
3
11
11
13
9
3
2
19
Position*
3150418
128843480
2732877
2722295
43371542
74036629
74046663
80147187
74920186
227586606
92708710
92673828
20694884
92668826
20686996
180116563
92708710
92673828
36772381
139275204
187615862
27742603
50778543
Gene Name
GNA15
MFSD8
MYT1L / TSSC1
MYT1L / TSSC1
HAAO / ZFP36L2 / THADA§
C15orf59
C15orf59 / TBC1D21
HMGN3 / LCA5
KLF12 / LINC00347
LOC646736 / IRS1||
MTNR1B¶
FAT3 / MTNR1B#
CDKAL1**
FAT3 / MTNR1B††
CDKAL1‡‡
PEX5L / TTC14
MTNR1B¶
FAT3 / MTNR1B#
CCDC169-SOHLH2; SOHLH2
SNAPC4
BCL6 / LPP
GCKR§§
MYH14
Alleles†
A/C
G/A
T/C
A/G
T/C
A/G
G/T
C/T
A/C
G/A
G/C
T/C
T/C
A/G
A/C
C/T
G/C
T/C
G/A
A/C
T/C
T/C
C/T
RAF‡
0.336
0.041
0.291
0.184
0.324
0.116
0.139
0.132
0.240
0.412
0.220
0.220
0.198
0.341
0.264
0.003
0.230
0.220
0.315
0.461
0.069
0.341
0.287
Trait
MCRI
SI+M
SI+M
SI+M
SI
SI
SI
SI
M
M
AIRg
AIRg
AIRg
AIRg
AIRg
AIRg
DI
DI
DI
DI
SG
SG
SG
Beta
-0.29
8.97
-5.28
-5.03
0.20
0.37
0.31
-0.35
-22.02
20.54
-2.76
-2.55
-2.05
-1.64
-1.46
17.53
-3.40
-3.20
2.18
-1.87
0.25
0.14
-0.17
P-value
7.31E-08
5.20E-07
1.26E-06
1.53E-06
5.31E-07
5.83E-07
6.91E-08
1.37E-06
5.04E-07
7.42E-07
5.23E-12
2.21E-09
1.02E-06
1.08E-06
1.28E-06
1.64E-06
1.03E-11
1.32E-09
3.67E-07
1.72E-06
1.53E-07
1.12E-06
1.66E-06
Independent signals (r2<0.80) with evidence of association (P<2.00E-06) with the nearest annotated RefSeq gene(s) listed. *Build
hg19, †Reference Allele/Other Allele, ‡Reference Allele Frequency, §Previously identified T2D locus (THADA rs7578597; r2=0.0079,
||
Previously identified T2D locus (IRS1 rs2943641; r2=0.04), ¶Previously identified T2D locus (MTNR1B rs1387153; r2=0.69),
#
Previously identified T2D locus (MTNR1B rs1387153), **Previously identified T2D locus (CDKAL1 rs7754840; r2=0.42),
††
Previously identified T2D locus (MTNR1B rs1387153; r2=0.54), ‡‡Previously identified T2D locus (CDKAL1 rs7754840; r2=0.72),
§§
Previously identified T2D locus (GCKR rs780094; r2=0.98)
27
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Page 30 of 127
Table 3. Top regions from GWAS of T2D-related quantitative traits with translation to T2D in Mexican-origin cohorts ordered by
trait from the Discovery stage.
Discovery Cohorts
Marker
Chr
rs7219451
rs6815953
rs7581057
rs322394
rs17060946
rs13252932
rs10830963
rs2206734
rs7018475
rs1387153
rs2129969
rs2053797
rs9553849
rs10870202
rs10898909
rs2237897
rs4266763
rs2064197
rs2291004
rs1260326
17
4
2
5
9
8
11
6
9
11
11
2
13
9
11
11
9
6
19
2
*
Position
38957002
183109012
115958079
172157768
77808519
25198091
92708710
20694884
22137685
92673828
45586169
46370892
27082326
139257411
72952496
2858546
139289825
8998811
37997952
27730940
Gene
KRT28 / KRT10
TENM3
DPP10
NEURL1B / DUSP1
OSTF1 / PCSK5
DOCK5
MTNR1B||
CDKAL1¶
CDKN2B-AS1# / DMRTA1
MTNR1B**
PRDN11 / CHST1
PRKCE
CDK8 / WASF3
DNLZ
P2RY2
KCNQ1††
SNAPC4
SLC35B3 / TFAP2A
ZNF793
GCKR‡‡
Translation Cohorts
Trait
RA†
RAF‡
Beta
P-value
OR (95% CI)§
P-value
SI +M
SI +M
SI +M
M
M
M
AIRg
AIRg
AIRg
AIRg
AIRg
AIRg
AIRg
AIRg
AIRg
DI
DI
SG
SG
SG
C
T
G
C
G
T
G
T
G
T
G
A
A
T
A
A
A
G
A
T
0.380
0.431
0.056
0.360
0.068
0.049
0.220
0.194
0.323
0.220
0.477
0.162
0.199
0.430
0.404
0.251
0.489
0.164
0.153
0.335
-6.80
4.10
-5.47
-15.83
37.86
47.71
-2.76
-2.05
-1.64
-2.55
1.14
1.89
1.57
-1.04
1.41
1.75
-2.00
-0.19
0.16
0.13
3.92E-06
3.14E-05
1.74E-04
3.38E-05
2.56E-06
5.17E-06
5.23E-12
1.02E-06
4.90E-06
2.21E-09
2.10E-05
5.02E-05
6.70E-05
5.37E-05
4.03E-06
7.04E-06
3.46E-06
7.23E-06
3.82E-05
4.04E-06
1.08 (1.00-1.16)
0.92 (0.86-0.99)
1.29 (1.10-1.50)
1.17 (1.09-1.26)
0.87 (0.75-1.01)
0.89 (0.75-1.04)
1.08 (1.00-1.18)
1.19 (1.09-1.30)
1.09 (1.02-1.17)
1.07 (0.98-1.16)
0.91 (0.85-0.98)
0.91 (0.83-1.00)
0.86 (0.79-0.94)
1.12 (1.05-1.20)
0.94 (0.86-1.02)
0.73 (0.68-0.79)
1.10 (1.03-1.18)
1.18 (1.08-1.30)
0.89 (0.82-0.97)
0.96 (0.89-1.03)
1.06E-02
1.25E-02
6.67E-03
7.87E-04
6.89E-02
6.61E-02
1.83E-01
1.41E-03
2.34E-03
1.97E-01
2.38E-02
1.42E-02
1.29E-02
2.08E-02
9.27E-02
1.89E-19
1.23E-02
7.01E-04
9.88E-03
5.58E-02
Discovery and
Translation
Meta-Analysis
P-value
3.97E-07
2.47E-06
4.82E-06
1.12E-07
3.99E-06
6.11E-06
5.86E-09
1.11E-08
7.31E-08
2.72E-07
4.10E-06
4.21E-06
4.70E-06
7.10E-06
8.64E-06
1.24E-21
4.34E-07
2.56E-08
2.18E-06
3.99E-06
SNPs with evidence of association with the nearest annotated RefSeq gene(s) listed. *Build hg19, †Reference Allele, ‡Reference Allele
Frequency, §Odds Ratio (OR) and 95% Confidence Interval (95% CI), ||Previously identified T2D locus (MTNR1B rs1387153,
r2=0.69), ¶Previously identified T2D locus (CDKAL1 rs7754840, r2=0.42), #Previously identified T2D locus (CDKN2B rs7018475),
**
Previously identified T2D locus (MTNR1B rs1387153), ††Previously identified T2D locus (KCNQ1 rs2237892, r2=0.90; and KCNQ1
rs231362, r2=0.038), ‡‡Previously identified T2D locus (GCKR rs780094, r2=0.91)
28
Page 31 of 127
Diabetes
FIGURE LEGENDS
Figure 1. Genome-wide Manhattan plots for the GUARDIAN Discovery meta-analysis. a)
Metabolic Clearance Rate of Insulin (MCRI), b) Insulin Sensitivity (SI+M), c) SI, d) M, e) Acute
Insulin Response (AIRg), f) Disposition Index (DI), g) Glucose Effectiveness (SG).
Figure 2. Regional plot of the MTNR1B locus in the GUARDIAN Discovery cohorts metaanalysis. a) Disposition Index (DI) b) Acute Insulin Response (AIRg), and c) Insulin Sensitivity
(SI). Genotyped SNPs passing quality control measures across all Discovery cohorts are plotted
with their Discovery meta-analysis p-values (as -log10 values) as a function of genomic position
(hg19). In each panel, the index variant is represented by a purple diamond. Color of additional
variants indicates correlation with the index SNP (red, r2≥0.80; orange, 0.60≤r2<0.80; green,
0.40≤r2<0.60; blue, 0.20≤r2<0.40; white, r2<0.20; gray no r2 value available) based on pairwise r2
values from HapMap. Estimated recombination rates (taken from HapMap) are plotted to reflect
the local LD structure. Gene annotations were taken from the University of California Santa
Cruz genome browser.
Figure 3. Regional plots of loci attaining genome-wide significance (P<5.00x10-8) in the
combined Discovery and Translation meta-analysis. a) KCNQ1 rs2237897 with DI/T2D, b)
MTNR1B rs10830963 with AIRg/T2D, c) CDKAL1 rs2206734 and AIRg/T2D d) 6p24.3
rs2064197 and SG/T2D. Genotyped SNPs passing quality control measures across all Discovery
cohorts are plotted with their Discovery meta-analysis p-values (as -log10 values) as a function of
genomic position (hg19). In each panel, the index variant from the Discovery cohort is
represented by a purple circle and the Discovery and Translation meta-analysis is represented by
a purple square. Color of additional variants indicates correlation with the index SNP (red,
r2≥0.80; orange, 0.60≤r2<0.80; green, 0.40≤r2<0.60; blue, 0.20≤r2<0.40; white, r2<0.20; gray no
r2 value available) based on pairwise r2 values from HapMap. Estimated recombination rates
(taken from HapMap) are plotted to reflect the local LD structure. Gene annotations were taken
from the University of California Santa Cruz genome browser.
29
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Page 32 of 127
Figure 1.
a.
MCRI
GNA15
b.
SI+M
MYT1L/TSSC1
MFSD8
c.
SI
HAAO/ZFP36L2/THADA
HMGN3/LCA5
C15orf59
30
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Diabetes
d.
M
LOC646736/IRS1
KLF12/LINC00347
e.
AIRg
MTNR1B
PEX5L/TTC14
CDKAL1
f.
DI
MTNR1B
SNAPC4
SOHLH2/CCDC169
31
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Page 34 of 127
g.
SG
GCKR
BCL6/LPP
MYH14
32
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Diabetes
Figure 2.
a. DI
b. AIRg
c. SI
33
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Page 36 of 127
Figure 3.
a.
b.
DI/T2D
c.
AIRg/T2D
d.
AIRg/T2D
SG/T2D
34
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Diabetes
SUPPLEMENTARY MATERIALS
Supplementary Text ………………………………………………………………………………….
Discovery Cohort Descriptions …………………………………………………………………….
Translational Cohort Descriptions ………………………………………………………………….
Clinical characteristics of the Translation cohorts …………………………………………………
References ………………………………………………………………………………………….
Page
2
2
6
7
8
Supplementary Table 1. Pearson’s correlation matrix for T2D-related quantitative traits in the
Discovery cohorts. A) Euglycemic clamp cohorts including MACAD, HTN-IR, NIDDM-Athero and
B) FSIGT cohorts including IRAS, IRAS Family, BetaGene, TRIPOD. …………………………...... 10
Supplementary Table 2. Top Discovery hits (P<1.00x10‐4) from the GUARDIAN Consortium.
SNPs with evidence of association are tabulated by trait (a. MCRI, b. SI+M, c. SI, d. M, e. AIRg, f.
DI, g. SG) in order of genomic position. ...…………………………………………………………...... 11
Supplementary Table 3. Top Discovery hits from the GUARDIAN Consortium ordered by trait. …
41
Supplementary Table 4. Top Discovery hits from the GUARDIAN Consortium ordered by trait
with conditional analyses performed at loci with multiple signals of association or in close proximity
to previously identified T2D loci. ……………………………………………………………………... 42
Supplementary Table 5. Association with reported type 2 diabetes (T2D) susceptibility loci (a.
MCRI, b. SI+M, c. SI, d. M, e. AIRg, f. DI, and g. SG) in GUARDIAN Hispanic Americans
(nmax=3,787). Index SNPs reaching genome‐wide significance (P<5.0E‐08) for association with T2D
were selected from the NHGRI GWAS catalog. ……………………………………………………… 43
Supplementary Table 6. All SNPs from GWAS of T2D-related quantitative traits with Translation
to T2D in Mexican-origin cohorts ordered by trait from the Discovery stage. ………………………..
65
Supplementary Table 7. Top regions from GWAS of T2D-related quantitative traits with
translation to T2D in Mexican-origin. ………………………………………………………………… 86
Supplementary Table 8. Top regions from GWAS of T2D-related quantitative traits with
translation to T2D in Mexican-origin cohorts ordered by trait from the Discovery stage with
conditional analyses performed at loci with multiple signals of association or in close proximity to
previously identified T2D loci. ………………………………………………………………………... 87
Supplementary Figure 1. Power to detect association with T2D (n=6,463 T2D cases and 9,232
controls) with an α of 5.00x10-8 at minor allele frequencies (MAF) ranging from 0.05-0.45. ………..
89
Supplementary Figure 2. Regional plots of loci with evidence of association (P<2.00x10-6) in the
Discovery meta-analysis. A) GNA15 rs2302063 with MCRI/T2D, B) MFSD8 rs1602084 with
SI+M/T2D, C) MYT1L/TSSC1 rs896232 with SI+M/T2D, D) HAAO/SFP36L2/THADA rs1978648
with SI/T2D, E) C15orf59 rs4887140 with SI/T2D, F) HMGN3/LCA5 rs196701 with SI/T2D, G)
KLF12/LINC00347 rs10492494 with M/T2D, H) LOC646736/IRS1 rs11683087 with M/T2D, I)
MTNR1B rs10830963 with AIRg/T2D, J) CDKAL1 rs2206734 with AIRg/T2D, K) PEX5L/TTC14
rs6803803 with AIRg/T2D, L) SOHLH2 rs2149423 with DI/T2D, M) SNAPC4 rs3812570 with
DI/T2D, N) BCL6/LPP rs523079 with SG/T2D, O) GCKR rs780093 with SG/T2D, and P) MYH14
rs788338 with SG/T2D. ……………………………………………………........................................... 91
1
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SUPPLEMENTARY TEXT
Discovery Cohort Descriptions
BetaGene. BetaGene was a family study designed to identify genetic determinants of beta-cell
function (1). BetaGene recruited non-diabetic women with a history of gestational diabetes
mellitus (GDM), their adult family members, and women without history of GDM. GUARDIAN
includes 1217 of these individuals in 390 pedigrees, 238 families of probands with previous
GDM and 152 families of probands with normal pregnancies. Recruitment occurred in the Los
Angeles area. Insulin sensitivity was obtained by FSIGT. Other phenotypes include OGTT and
total body fat by DXA scan.
TRIPOD. The Troglitazone in the Prevention of Diabetes (TRIPOD) study was designed to
address the impact of troglitazone treatment on -cell function and glucose levels in women with
prior GDM (2). TRIPOD recruited non-diabetic women with history of GDM in the Los Angeles
area; family members were not recruited. GUARDIAN includes baseline (pre-intervention) data
from 217 of these individuals. Insulin sensitivity was obtained by tolbutamide-modified FSIGT.
Other phenotypes include OGTT and carotid intima-media thickness by B-mode
ultrasonography.
IRAS. The Insulin Resistance Atherosclerosis Study (IRAS) was an epidemiologic cohort study
designed to examine the relationship between insulin resistance and carotid atherosclerosis
across a range of glucose tolerance (3). Individuals of self-reported Mexican-American ethnicity
were recruited in San Antonio, TX and San Luis Valley, CO. Recruitment was balanced across
age and glucose tolerance status. GUARDIAN includes 194 individuals from the IRAS. Insulin
sensitivity was obtained by FSIGT. Other phenotypes include OGTT and carotid intima-media
thickness by B-mode ultrasonography.
IRAS Family Study. The Insulin Resistance Atherosclerosis Study (IRAS) Family Study was a
family study designed to examine the genetic and epidemiologic basis of glucose homeostasis
traits and abdominal adiposity; details of the IRAS Family Study are described elsewhere (4).
2
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Diabetes
Briefly, self-reported Mexican pedigrees were recruited in San Antonio, TX and San Luis
Valley, CO. Probands with large families were recruited from the initial non-family-based IRAS
Study (3), which was modestly enriched for impaired glucose tolerance and T2D. GUARDIAN
includes 1040 individuals in 88 pedigrees from the IRAS Family Study. Insulin sensitivity was
obtained by FSIGT. Other phenotypes include abdominal fat areas measured by computed
tomography scan and total body fat by dual X-ray absorptiometry (DXA) scan.
HTN-IR. The Hypertension-Insulin Resistance Family Study (HTN-IR) was designed as a
family study to examine the genetic basis of hypertension and insulin resistance (5). Family
members of probands with documented hypertension were recruited in the Los Angeles area.
GUARDIAN includes 708 of these individuals from 156 families. Insulin sensitivity was
obtained by euglycemic clamp. Other phenotypes include OGTT, carotid intima-media thickness
by B-mode ultrasonography, and salt sensitivity.
MACAD. The Mexican-American Coronary Artery Disease (MACAD) Study was designed as a
family study to examine the genetic basis of coronary artery disease and insulin resistance (6).
Family members of probands with documented coronary artery disease were recruited from the
Los Angeles area. GUARDIAN includes 772 of these individuals from 208 families. Insulin
sensitivity was obtained by euglycemic clamp. Other phenotypes include OGTT, carotid intimamedia thickness by B-mode ultrasonography, total body fat by DXA scan, and post-heparin
lipase activity assessment.
NIDDM-Athero. The NIDDM-Atherosclerosis Study was designed as a family study to examine
the genetic basis of subclinical atherosclerosis and diabetes (7). Family members of probands
with T2D were recruited in the Los Angeles area. GUARDIAN includes 188 of these individuals
from 93 families. Insulin sensitivity was obtained by euglycemic clamp. Other phenotypes
include OGTT and carotid intima-media thickness by B-mode ultrasonography.
3
Diabetes
Translation Cohort Descriptions
MESA. The Multi-Ethnic Study of Atherosclerosis (MESA) was initiated in 2000 to investigate
the prevalence, correlates, and progression of subclinical cardiovascular disease (CVD) in a
population-based sample of 6,814 men and women aged 45-84 years (8). Participant who were
free of clinically apparent CVD were recruited from portions of 6 US communities: Baltimore
City and Baltimore County, Maryland; Chicago, Illinois; Forsyth County, North Carolina; Los
Angeles County, California; Northern Manhattan and the Bronx, New York; and St. Paul,
Minnesota. Each field site recruited from locally available sources, which included lists of
residents, lists of dwellings, and telephone exchanges. Twenty-two percent (1494) of the cohort
is Hispanic; this analysis was limited to Hispanic participants who were classified as ‘Mexican’
via principal component analysis (all Caribbean Hispanics were excluded in this study). The
PCA classified ‘Mexicans’ were mainly self-identified as Mexican, South America, or CentralAmerican. Diabetes was defined as fasting glucose >126 mg/dL or use of hypoglycemic
medication at baseline.
MESA Family. The MESA Family Study is an ancillary study to MESA. This study recruited
family members specifically for genetic analysis. Participants in the MESA Family Study
include 2,128 individuals from 528 families. Similarly, this analysis considers only those
families classified as ‘Mexican’ via principal component analysis. Diabetes was defined as
fasting glucose ≥126 mg/dL or use of insulin or hypoglycemic medication.
LALES. The Los Angeles Latino Eye Study (LALES) is a population-based study of 6357
Latinos, living in six census tracts in the city of La Puente, Los Angeles County, California (9).
All subjects were 40 years of age and older. Written, informed consent was obtained from all
participants. The data obtained from LALES have been used to document the prevalence,
incidence, and impact of visual impairment in Latinos. GWAS data from 1,768 samples was
used for in silico translation.
Starr County. The Starr County study participants were selected from genetic and
epidemiological resources developed in the Mexican-American population in Starr County, TX
(10). Diabetes was defined using the 1997 ADA criteria. Of 931 successfully genotyped case
samples, 837 unrelated individuals were used for in silico translation. A representative type 2
4
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diabetes control sample was selected from a systematic survey of the primary population centers
of Starr County conducted from 2002 to 2006.
WHI. The Women’s Health Initiative (WHI) consisted of multiple components including an
observational study and clinical trial cohorts of postmenopausal women in the US (11). All
participating institutions obtained Institutional Review Board approval. WHI SHARe included a
total sample of 3,642 self-identified Mexican or Hispanic origin subjects from WHI, who had
consented to genetic research. Type 2 diabetes was defined by self-report as ever being treated
for diabetes (insulin shots or oral hypoglycemic medication) when participants were not
pregnant. Medical histories were obtained at baseline and updates on disease status were
obtained through self-administered questionnaires or contact with clinical staff every 6 months
for the randomized clinical trial or annually for the observational study participants. Prevalent
type 2 diabetes was identified from self-report in the baseline medical history. Incident type 2
diabetes was identified as first-time use of hypoglycemic medication after baseline. Both
prevalent and incident cases were used for in silico translation.
SIGMA. The Slim Initiative in Genomic Medicine for the Americas (SIGMA) Type 2 Diabetes
Consortium was conducted to characterize the genetic basis of type 2 diabetes in Mexican and
other Latin American populations (12). Four cohorts contributed to the SIGMA GWAS. Diabetes
in Mexico Study: A prospective cohort residing in Mexico City, Mexico, including 690 cases
(defined as either a previous T2D diagnosis or fasting glucose levels above 125 mg/dL;
individuals with fasting glycemia between 100-125 mg/dL were excluded) and 472 controls who
were unrelated healthy subjects older than 45 years and with fasting glucose levels below 100
mg/dL. Mexico City Diabetes Study: A prospective cohort residing in Mexico City, Mexico,
including 287 cases (defined using the ADA criteria, fasting glucose 126 mg/dL or more or 2 hr
post 75 gr of glucose load 200 or more; in addition, a participant diagnosed as diabetic by a
physician and under pharmacologic therapy for diabetes was considered as diabetic regardless
the blood glucose levels) and 613 participants without diabetes ever as diagnosed by ADA
criteria. UNAM/INCMNSZ Diabetes Study: A prospective cohort residing in Mexico City,
Mexico, including 815 cases (defined in accordance with ADA criteria, fasting plasma glucose
values ≥126 mg/dL, current treatment with a hypoglycemic agent, or casual glucose values ≥200
mg/dL) and 1,138 control subjects who were recruited from a cohort of adults aged 45 years or
5
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older among government employees, blue collar workers and subjects seeking for attention in
medical units for any condition besides those considered as exclusion criteria. Normoglycemic
status was defined as having a fasting plasma glucose concentration < 100 mg/dl and no previous
history of hyperglycemia, gestational diabetes or use of metformin. Multiethnic Cohort: A casecontrol study conducted in Los Angeles, California, USA, including 2056 cases defined as (a) a
self-report of diabetes on the baseline questionnaire, 2nd questionnaire or 3rd questionnaire; and
(b) self-report of taking medication for T2D at the time of blood draw; and (c) no diagnosis of
T1D in the absence of a T2D diagnosis from the OSHPD (California Residents). Controls
(n=2,143) were defined as: (a) no self-report of diabetes; (b) no use of medications for T2D at
the time of blood draw; and (c) no diabetes diagnosis (type 1 or 2) from the OSHPD, Hawaii
Medical Service Association (HMSA) or Kaiser Permanente Hawaii (KPH) registries.
6
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Clinical characteristics of the Translation cohorts.
Sample Size
Gender
(% female)
Case Control
Case
Control
Starr County, TX
805
340
60
70
MESA Family
81
304
62
56
MESA
221
886
47
52
WHI
614
2869
100
100
LALES
894
467
57
50
SIGMA
3848*
4366*
57
57
Age
(range)
Case
Control
57
37
(25-87)
(26-77)
62
60
(41-90)
(45-85)
64
61
(44-84)
(45-84)
60
60
(50-79)
(50-78)
58
60
(40-92)
(40-88)
58
58
(19-89)
(34-94)
*47% of cases and 51% of controls from Mexico City, Mexico.
7
BMI
(range)
Case
Control
31.7
29.6
(15.4-60.8)
(18.4-55.3)
34
29.4
(22.3-56.3)
(17.3-50.1)
31.6
29.2
(19.6-49.8)
(17.6-52.5)
31.5
28.3
(18.4-55.3)
(17.2-60.9)
32.4
29.2
(17.7–58.5)
(14.6-52.1)
29.5
27.5
(15.0-67.8)
(11.0-57.4)
Genotyping Platform
Affy 6.0
Imputed to 1000G
Affy 6.0
Imputed to 1000G
Affy 6.0
Imputed to 1000G
Affy 6.0
Illumina OmniExpress
Illumina 2.5M
Imputed to 1000G
Diabetes
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REFERENCES
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10. Below JE, Gamazon ER, Morrison JV, Konkashbaev A, Pluzhnikov A, McKeigue PM, Parra
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Manning AK, Neale B, Reich D, Stram DO, Fernandez-Lopez JC, Romero-Hidalgo S,
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Abboud HE, Defronzo RA, Jenkinson CP, Lehman DM, Curran JE, Cortes ML: Sequence
variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico. Nature, 2013
9
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Supplementary Table 1. Pearson’s correlation matrix for T2D-related quantitative traits in the Discovery
cohorts. A) Euglycemic clamp cohorts including MACAD, HTN-IR, NIDDM-Athero and B) FSIGT
cohorts including IRAS, IRAS Family, BetaGene, TRIPOD.
A)
MCRI
M
0.172
MCRI
M
DI
DI
0.14
0.423
B)
SI
SI
Sg
AIRg
DI
MCRI
Sg
AIRg
0.29436
DI
-0.3181
0.2193
10
MCRI
0.421
0.5312
0.4597
0.6555
0.02974
-0.32868
0.17068
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Diabetes
Supplementary Table 2. Top Discovery hits (P<1.00x10‐4) from the GUARDIAN Consortium. SNPs with evidence of association are tabulated by trait (a. MCRI, b. SI+M, c. SI, d. M, e. AIRg, f. DI, g. SG) in order of genomic position. For each SNP, position from Build hg19 is listed with the nearest annotated RefSeq gene. 11
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a. MCRI (nmax=3,787) Marker rs4350219 rs11247954 rs2278979 rs3790645 rs1064196 rs282177 rs6697598 rs6718111 rs1044280 rs7572039 rs6745880 rs13024014 rs11688831 rs6741187 rs9847647 rs13321674 rs6444236 rs16835397 rs2124794 rs6821028 rs6822279 rs7728957 rs7726659 rs4957640 rs523848 rs220933 Chr 1 1 1 1 1 1 1 2 2 2 2 2 2 2 3 3 3 4 4 4 4 5 5 5 6 6 Position Gene ref/nonref
19858807 T/C 26741285 LIN28A A/G 26877708 RPS6KA1 A/G 26884864 RPS6KA1 A/G 26887592 RPS6KA1 C/T 26899125 RPS6KA1 T/C 241105515 RGS7 C/T 8201262 LINC00299 C/T 8871342 KIDINS220 A/C 31061392 T/G 171105318 MYO3B G/A 173530946 T/C 199299078 A/G 222065721 T/C 19813225 G/A 51704721 C/T 187225416 G/A 4268642 T/C 62290634 LPHN3 A/G 62293449 LPHN3 A/C 99745705 C/A 64505977 ADAMTS6 G/T 74478078 ANKRD31 G/A 111601600 EPB41L4A C/T 15830025 A/G 15845797 C/T Ref Allele Freq 0.244 0.179 0.405 0.421 0.424 0.451 0.042 0.487 0.287 0.078 0.138 0.023 0.384 0.010 0.024 0.009 0.195 0.018 0.437 0.376 0.406 0.075 0.015 0.048 0.467 0.421 12
β±SE 0.24 ± 0.07 0.26 ± 0.08 0.31 ± 0.07 0.34 ± 0.07 0.34 ± 0.07 0.34 ± 0.08 ‐0.60 ± 0.15 ‐0.19 ± 0.05 0.19 ± 0.07 0.36 ± 0.10 ‐0.30 ± 0.09 ‐0.62 ± 0.19 ‐0.14 ± 0.05 2.15 ± 0.72 0.58 ± 0.18 ‐1.57 ± 0.38 0.22 ± 0.07 ‐0.71 ± 0.21 ‐0.15 ± 0.05 ‐0.13 ± 0.05 ‐0.21 ± 0.06 0.30 ± 0.10 ‐0.90 ± 0.25 ‐0.41 ± 0.14 0.20 ± 0.05 ‐0.19 ± 0.05 Best model dom dom dom dom dom dom dom add dom dom dom dom add dom dom dom dom dom add add add dom dom dom add add Direction of Association (BetaGene, HTN, IRAS, IRASFS, MACAD, NIDDM) ++++++ +++++‐ ++++++ ++++++ ++++++ ++‐++? ‐‐‐‐‐? ‐‐‐‐‐‐ ++++++ ++++++ ‐‐+‐‐‐ ‐+‐‐‐? ‐‐‐‐‐‐ +?++?? +++++? ‐?‐‐‐? ++++++ ‐‐‐‐‐? ‐‐+‐‐‐ ‐‐‐‐‐‐ ‐?‐‐‐‐ +++++‐ ‐‐‐‐‐? ‐‐‐‐‐? ++++++ ‐‐‐‐‐+ Best p‐value 7.45E‐05 9.76E‐05 3.16E‐05 6.07E‐06 9.75E‐06 3.30E‐05 1.88E‐05 9.33E‐05 6.97E‐05 2.74E‐05 7.34E‐05 9.17E‐05 7.08E‐05 8.62E‐05 8.50E‐05 7.70E‐05 8.73E‐05 1.85E‐05 5.27E‐05 1.03E‐04 2.33E‐05 9.73E‐05 4.58E‐05 5.85E‐05 3.48E‐05 9.83E‐05 Page 49 of 127
rs3749855 rs6938736 rs13219760 rs723685 rs17166951 rs4629751 rs10251809 rs1597137 rs11136431 rs6651438 rs13258014 rs4434590 rs6468694 rs4409375 rs13253073 rs12544943 rs7851513 rs7025024 rs6602203 rs10825203 rs1911409 rs716594 rs11016332 rs7944706 rs2449501 rs16918932 rs10400279 rs7124 rs1784499 rs2510094 rs1334870 rs9565115 rs9530368 Diabetes
6 6 6 6 7 7 7 8 8 8 8 8 8 8 8 8 9 9 10 10 10 10 10 11 11 11 11 11 11 11 13 13 13 17283321 RBM24 22441270 110761189 SLC22A16 110763875 SLC22A16 13302054 16825580 32044030 PDE1C 464083 C8orf42 1791433 ARHGEF10 1794023 ARHGEF10 4165460 CSMD1 100860657 VPS13B 100865836 VPS13B 100889987 100897383 COX6C 100903890 COX6C 9842176 PTPRD 25816219 17596121 55798117 PCDH15 55806316 PCDH15 112006311 MXI1 130363802 10331311 20044696 NAV2 29309078 36270057 57174559 PRG2 73359236 PLEKHB1 102981300 DYNC2H1 54838415 75269569 75270057 G/T C/T G/A G/A A/C G/T T/C C/T T/C C/T T/C T/C A/G A/C A/C G/A A/C G/A T/C A/C G/A A/G G/A A/G G/A G/T G/A A/G T/C C/T A/C G/A C/A 0.057 0.469 0.111 0.114 0.06 0.284 0.180 0.365 0.383 0.377 0.392 0.161 0.125 0.143 0.129 0.129 0.129 0.342 0.403 0.268 0.243 0.019 0.008 0.285 0.198 0.003 0.058 0.003 0.018 0.044 0.309 0.364 0.358 13
‐0.52 ± 0.12 0.22 ± 0.05 0.35 ± 0.09 0.33 ± 0.09 0.42 ± 0.12 0.26 ± 0.07 ‐0.25 ± 0.08 0.18 ± 0.05 0.14 ± 0.05 0.20 ± 0.06 0.26 ± 0.07 ‐0.29 ± 0.08 ‐0.34 ± 0.08 ‐0.33 ± 0.08 ‐0.35 ± 0.08 ‐0.34 ± 0.08 0.38 ± 0.09 ‐0.18 ± 0.05 ‐0.32 ± 0.07 0.23 ± 0.07 0.23 ± 0.07 ‐0.65 ± 0.21 2.07 ± 0.49 0.31 ± 0.07 ‐0.22 ± 0.07 3.45 ± 0.84 ‐0.31 ± 0.12 8.24 ± 1.81 0.97 ± 0.22 0.45 ± 0.14 ‐0.26 ± 0.07 ‐0.22 ± 0.07 ‐0.22 ± 0.07 dom add dom dom dom dom dom add add add add dom dom dom dom dom dom add dom dom dom dom dom dom dom dom dom dom dom dom dom dom dom ‐‐‐‐‐? +++++? +++++‐ +++++‐ +‐+++? ++++++ ‐‐‐‐‐‐ ++++++ ++++++ ++++?+ +?+++? ‐‐‐‐‐‐ ‐‐‐‐‐‐ ‐‐‐‐‐‐ ‐‐‐‐‐‐ ‐‐‐‐‐‐ ++++++ ‐‐‐‐‐‐ ‐‐‐‐‐‐ ++++++ ++++++ ‐‐‐‐‐? +?++?? ++++++ ‐‐+‐‐‐ +??+?? ‐‐‐‐‐? ??+??? +++++? +++++? ‐‐‐‐‐+ ‐‐‐‐‐? ‐‐‐‐‐? 5.04E‐06 7.64E‐05 3.15E‐06 8.04E‐06 8.25E‐05 9.58E‐05 4.28E‐05 7.91E‐05 6.90E‐05 9.10E‐05 7.99E‐05 8.09E‐05 2.13E‐05 3.64E‐05 5.89E‐06 6.90E‐06 2.72E‐05 8.33E‐05 4.80E‐06 5.80E‐05 5.05E‐05 3.84E‐05 4.72E‐05 4.70E‐05 1.27E‐05 4.38E‐05 8.87E‐05 8.33E‐06 5.50E‐06 5.69E‐05 8.31E‐05 9.23E‐05 6.37E‐05 Diabetes
rs6576136 rs2210313 rs2031271 rs8003026 rs10147864 rs637568 rs11853158 rs2718934 rs8032549 rs11857306 rs12441883 rs7172809 rs2701405 rs781856 rs4790177 rs2325989 rs1986507 rs4791426 rs2274892 rs16530 rs9912528 rs2339345 rs11872993 rs2276210 rs3786947 rs2302063 rs7247790 14 14 14 14 14 15 15 15 15 15 15 15 15 17 17 17 17 17 17 17 17 18 18 18 19 19 19 28737460 40835874 42344822 72482760 97919601 29692391 56364902 56557418 56572176 56746003 58456850 77819676 87539918 3950224 4067900 4199320 10082301 10752513 16852027 37357034 77387550 49957255 71104519 74587458 3114229 3150418 5311412 LRFN5 RGS6 FAM189A1 MNS1 ALDH1A2 AGBL1 ZZEF1 ANKFY1 UBE2G1 GAS7 TNFRSF13B
RPL19 RBFOX3 DCC ZNF236 GNA11 GNA15 PTPRS C/T G/A C/A G/T C/T G/A A/G G/A G/A C/A A/G A/G A/C A/G T/C G/A A/G A/G G/T T/C C/T A/C T/C A/G A/G A/C G/T 0.381 0.085 0.158 0.003 0.005 0.027 0.320 0.466 0.328 0.341 0.370 0.484 0.486 0.014 0.012 0.015 0.152 0.098 0.372 0.099 0.150 0.343 0.006 0.015 0.222 0.336 0.185 14
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0.18 ± 0.06 0.32 ± 0.10 0.23 ± 0.08 3.07 ± 0.75 3.27 ± 0.86 ‐0.46 ± 0.17 ‐0.18 ± 0.06 ‐0.17 ± 0.05 ‐0.18 ± 0.05 ‐0.19 ± 0.05 0.23 ± 0.07 0.18 ± 0.05 ‐0.23 ± 0.06 0.94 ± 0.25 0.95 ± 0.28 1.10 ± 0.26 ‐0.26 ± 0.08 ‐0.16 ± 0.09 ‐0.16 ± 0.05 ‐0.34 ± 0.09 0.27 ± 0.08 ‐0.25 ± 0.06 ‐1.74 ± 0.49 ‐0.89 ± 0.24 ‐0.28 ± 0.07 ‐0.29 ± 0.07 ‐0.28 ± 0.08 add dom dom dom dom dom add add add add dom add add dom dom dom dom dom add dom dom add dom dom dom dom dom +++++? +++++? ++++++ +?++?? +??+?? ‐‐‐‐‐? ‐‐‐‐‐+ ‐‐+‐‐+ ‐‐‐‐‐+ ‐‐‐‐‐+ +++++‐ +++++? ‐‐‐‐?‐ +++++? +++++? ++++‐? ‐‐+‐‐‐ ‐‐‐‐‐‐ ‐‐‐‐‐+ ‐‐‐‐‐‐ ++++++ ‐‐‐‐‐? ‐?‐+‐? ‐‐‐‐‐? ‐‐‐‐‐+ ‐‐‐‐‐‐ ‐‐‐‐‐‐ 9.18E‐05 1.01E‐04 3.73E‐05 4.04E‐05 6.21E‐05 8.96E‐05 6.96E‐05 2.50E‐05 7.52E‐05 7.27E‐05 3.60E‐05 9.20E‐06 2.15E‐05 7.06E‐06 4.21E‐05 5.63E‐05 9.92E‐05 6.50E‐05 7.67E‐05 6.22E‐05 1.65E‐05 7.80E‐06 8.65E‐05 9.92E‐05 1.21E‐05 7.31E‐08 6.88E‐05 Page 51 of 127
Diabetes
b. SI+M (nmax=4,153) Marker rs10492966 rs3766466 rs6685355 rs7411591 rs1507290 rs4658244 rs1256941 rs9427477 rs6719442 rs896232 rs12620694 rs13411840 rs4233921 rs1044158 rs6733550 rs207910 rs7426289 rs6723449 rs6767721 rs843532 rs10007938 rs10023791 rs1602084 Chr 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 3 3 4 4 4 Position 8598005 54505437 79458347 86683345 86684713 92069188 201392764 202032235 2722295 2732877 2763051 29973281 37354149 85826132 85828014 217018422 218966315 218997580 87630433 196482211 32452973 99425353 128843480 Gene RERE TMEM59 ELTD1 TNNI1 ALK EIF2AK2 TMEM150A TMEM150A XRCC5 CXCR2 PAK2 TSPAN5 MFSD8 ref/nonref
T/C A/C C/A A/G G/A A/G A/C T/G A/G T/C A/G C/A A/G A/G G/T G/A T/C C/T G/T C/T G/A A/G G/A Ref Allele Freq 0.258 0.047 0.326 0.119 0.206 0.359 0.128 0.345 0.185 0.282 0.170 0.046 0.301 0.303 0.303 0.150 0.490 0.474 0.071 0.057 0.241 0.426 0.042 15
β±SE SI 0.10 ± 0.08 ‐0.21 ± 0.16 ‐0.13 ± 0.06 0.26 ± 0.10 0.23 ± 0.09 ‐0.06 ± 0.06 0.33 ± 0.09 ‐0.21 ± 0.06 ‐0.29 ± 0.08 ‐0.2 ± 0.06 ‐0.38 ± 0.08 ‐0.28 ± 0.16 ‐0.12 ± 0.07 ‐0.14 ± 0.08 ‐0.13 ± 0.08 0.09 ± 0.09 0.15 ± 0.06 0.15 ± 0.06 0.29 ± 0.12 0.29 ± 0.12 0.20 ± 0.08 0.15 ± 0.06 0.43 ± 0.16 β±SE M 18.42 ± 5.67 ‐25.2 ± 9.4 ‐18.36 ± 4.25 13.79 ± 6.51 11.58 ± 5.6 ‐13.2 ± 4.07 7.02 ± 6.36 ‐9.95 ± 4.09 ‐11.55 ± 5.87 ‐12.27 ± 4.23 ‐12.42 ± 5.82 ‐33.75 ± 8.94 ‐13.79 ± 4.09 ‐16.93 ± 5.39 ‐17.47 ± 5.4 17.1 ± 6.27 11.06 ± 3.81 10.56 ± 3.82 14.74 ± 8 29.38 ± 9.08 15.78 ± 5.5 9.35 ± 3.86 20.7 ± 9.19 Direction of Association (BetaGene, HTN, IRAS, IRASFS, MACAD, Best NIDDM, model TRIPOD) dom +++++‐+ dom ‐‐+‐‐0‐ add +‐‐‐‐‐‐ dom +++++‐+ dom +++++‐+ add ‐‐+‐‐‐‐ dom +++++‐+ add ‐‐‐‐‐‐‐ dom ‐‐‐‐‐+‐ add ‐‐‐‐‐‐‐ dom ‐‐‐‐‐+‐ dom ‐‐‐‐‐‐‐ add ‐‐+‐‐‐‐ dom ‐‐‐‐‐‐‐ dom ‐‐‐‐‐‐‐ dom +++++++ add ++++++‐ add ++‐+++‐ dom +++++++ dom +++++++ dom ++++++‐ add +‐+++++ dom +++++++ Best p‐
value 1.01E‐04 7.39E‐05 6.27E‐05 6.56E‐05 6.54E‐05 9.64E‐05 9.52E‐05 1.03E‐04 1.53E‐06 1.26E‐06 3.29E‐06 2.69E‐06 2.11E‐06 4.74E‐05 5.44E‐05 4.51E‐05 5.47E‐05 6.39E‐05 5.90E‐05 9.23E‐06 4.74E‐05 4.31E‐05 5.20E‐07 Diabetes
rs34766684 rs6815953 rs16894006 rs7732393 rs7724522 rs29848 rs3129963 rs9268530 rs3135382 rs2001098 rs2001097 rs2227138 rs3135376 rs3135375 rs3135374 rs3135372 rs2187820 rs2395161 rs2395162 rs3135366 rs3135356 rs1041885 rs7749057 rs7785730 rs24003 rs2726051 rs17141982 rs10268984 rs3177186 rs7799219 rs12682418 rs12675420 rs6475448 4 4 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 8 8 9 146023924 183109012 24833120 114018075 142081559 151449400 32380208 32383223 32383441 32383837 32383858 32384500 32385470 32385573 32385605 32385782 32385873 32387752 32387780 32388709 32391516 32412809 32448904 28096199 30748323 36155071 70133502 98963340 98984399 123895098 62891832 62924308 20497142 ABCE1 ODZ3 AK097686 AK001582 HLA‐DRA JAZF1 INMT AUTS2 ARPC1A ARPC1A EU233817 MLLT3 C/T T/G C/T C/T C/T T/G G/A C/T G/T A/G T/G T/C G/A A/G A/C A/C T/C C/A T/G C/T A/G A/T G/A G/A C/T C/A T/C T/C T/C T/C A/G T/C G/A 0.008 0.431 0.020 0.087 0.038 0.328 0.138 0.128 0.128 0.128 0.128 0.110 0.128 0.128 0.128 0.128 0.128 0.128 0.128 0.129 0.127 0.140 0.131 0.131 0.471 0.223 0.340 0.103 0.105 0.228 0.065 0.069 0.303 16
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0.79 ± 0.3 0.19 ± 0.06 ‐0.48 ± 0.18 0.30 ± 0.10 ‐0.57 ± 0.13 0.17 ± 0.06 0.28 ± 0.09 0.27 ± 0.09 0.27 ± 0.09 0.27 ± 0.09 0.27 ± 0.09 0.22 ± 0.10 0.27 ± 0.09 0.27 ± 0.09 0.27 ± 0.09 0.27 ± 0.09 0.27 ± 0.09 0.27 ± 0.09 0.27 ± 0.09 0.27 ± 0.09 0.28 ± 0.09 0.27 ± 0.09 0.21 ± 0.09 ‐0.17 ± 0.09 ‐0.14 ± 0.06 0.25 ± 0.08 0.20 ± 0.08 ‐0.20 ± 0.10 ‐0.19 ± 0.10 0.24 ± 0.08 0.24 ± 0.12 0.27 ± 0.12 ‐0.06 ± 0.06 43.66 ± 28.57 9.47 ± 3.97 ‐31.85 ± 15.38 16.44 ± 7.86 ‐18.32 ± 11.87 15.44 ± 4.21 22.25 ± 6.51 23.44 ± 6.66 23.09 ± 6.67 23.51 ± 6.66 23.45 ± 6.65 24.9 ± 7 23.45 ± 6.65 23.41 ± 6.66 23.45 ± 6.65 23.45 ± 6.65 23.46 ± 6.66 23.45 ± 6.65 23.45 ± 6.65 23.27 ± 6.65 20.36 ± 6.67 20.45 ± 6.51 21.37 ± 6.6 ‐17.84 ± 6.61 ‐12.91 ± 4.15 14.29 ± 5.53 9.1 ± 5.58 ‐16.38 ± 7.12 ‐16.45 ± 7.12 14.82 ± 5.58 25.42 ± 8.47 23.61 ± 8.33 ‐18.68 ± 4.43 dom add dom dom dom add dom dom dom dom dom dom dom dom dom dom dom dom dom dom dom dom dom dom add dom dom dom dom dom dom dom add ++++00+ +++++++ ‐‐‐‐‐0‐ +++++0‐ ‐‐‐‐+0+ ++++++‐ +++++++ +++++++ +++++++ +++++++ +++++++ +++++++ +++++++ +++++++ +++++++ +++++++ +++++++ +++++++ +++++++ +++++++ +++++++ +++++++ +++++++ ‐‐‐‐‐+‐ ‐‐‐‐‐0+ +++++++ ++++++‐ ‐‐‐‐‐‐‐ ‐‐‐‐‐‐‐ +++++++ +++++++ +++++++ ‐‐‐+‐0‐ 5.11E‐05 3.14E‐05 4.38E‐05 4.40E‐05 5.11E‐05 5.08E‐05 4.47E‐05 3.71E‐05 4.41E‐05 3.82E‐05 3.69E‐05 7.04E‐05 3.69E‐05 3.78E‐05 3.69E‐05 4.21E‐05 3.71E‐05 3.79E‐05 3.70E‐05 3.61E‐05 1.01E‐04 1.01E‐04 4.18E‐05 8.23E‐05 6.24E‐05 5.27E‐05 9.89E‐05 5.59E‐05 6.58E‐05 6.95E‐05 1.01E‐04 8.87E‐05 3.31E‐05 Page 53 of 127
rs10966384 rs4817 rs10739874 rs4837024 rs10904919 rs2688789 rs12413935 rs1223629 rs10870303 rs10160242 rs948178 rs3781827 rs1479451 rs11180162 rs11108203 rs10860482 rs7974375 rs17512574 rs673078 rs884844 rs7305647 rs4772128 rs12717423 rs10129385 rs2617235 rs10454039 rs10851411 rs2241998 rs7497796 rs12438945 rs11631474 rs884202 rs7178383 Diabetes
9 9 9 9 10 10 10 10 10 11 11 11 12 12 12 12 12 12 12 12 12 13 14 14 15 15 15 15 15 15 15 15 15 24672959 33917498 105991203 128739400 17334745 17733014 85453920 95906315 134191811 108498885 113195595 121411041 23836547 75081042 96100594 100038835 118585698 118788003 118791441 118814838 118855566 99385553 52940827 52959478 42758738 42832534 42859235 42869028 55136506 55226570 67934167 68054388 99159956 UBE2R2 BC035187 STAM PLCE1 LRRC27 TTC12 SORL1 SOX5 NTN4 ANKS1B TAOK3 TAOK3 SUDS3 SUDS3 SLC15A1 TXNDC16 TXNDC16 ZFP106 HAUS2 STARD9 MAP2K5 MAP2K5 C/T C/T C/T T/C T/C G/A G/T A/G G/A C/T A/G G/A A/C C/T T/C C/T T/G T/C C/A T/C A/G A/G G/A C/T C/T C/T T/G A/G A/C C/A G/A A/G C/T 0.057 0.314 0.092 0.465 0.374 0.419 0.020 0.039 0.429 0.058 0.337 0.434 0.199 0.189 0.069 0.372 0.104 0.110 0.125 0.113 0.105 0.029 0.253 0.253 0.366 0.429 0.428 0.417 0.376 0.230 0.262 0.381 0.332 17
‐0.24 ± 0.12 ‐0.14 ± 0.06 0.22 ± 0.10 0.16 ± 0.09 ‐0.27 ± 0.06 ‐0.08 ± 0.06 ‐0.73 ± 0.23 ‐0.74 ± 0.17 ‐0.13 ± 0.06 0.41 ± 0.11 0.21 ± 0.08 0.10 ± 0.06 0.21 ± 0.08 0.20 ± 0.08 ‐0.47 ± 0.12 0.09 ± 0.06 ‐0.13 ± 0.10 ‐0.08 ± 0.09 ‐0.08 ± 0.09 ‐0.07 ± 0.09 ‐0.08 ± 0.09 ‐0.51 ± 0.18 ‐0.21 ± 0.08 ‐0.21 ± 0.08 0.14 ± 0.06 0.14 ± 0.06 0.14 ± 0.06 0.12 ± 0.06 0.17 ± 0.08 0.19 ± 0.08 ‐0.24 ± 0.08 ‐0.10 ± 0.06 ‐0.16 ± 0.08 ‐23.3 ± 9.47 ‐8.04 ± 4.3 27.16 ± 8.11 22.18 ± 5.96 ‐10.32 ± 10.74 ‐14.73 ± 3.84 ‐44.19 ± 19.71 ‐17.55 ± 11.1 ‐4.07 ± 3.89 5.25 ± 9.53 13.09 ± 5.42 10.77 ± 5.33 10.02 ± 5.65 7.9 ± 5.74 ‐17.93 ± 8.36 13.33 ± 4.09 ‐23.88 ± 6.93 ‐29.28 ± 6.72 ‐30.26 ± 6.55 ‐28.67 ± 6.67 ‐29.15 ± 6.88 ‐20.52 ± 12.21 ‐10.05 ± 5.5 ‐9.92 ± 5.48 14.3 ± 4.02 13.79 ± 3.94 12.78 ± 3.93 11.94 ± 3.93 21.92 ± 5.65 23.49 ± 5.54 ‐6.71 ± 5.56 ‐8.87 ± 4.16 ‐19.57 ± 5.48 dom add dom dom add add dom dom add dom dom add dom dom dom add dom dom dom dom dom dom dom dom add add add add dom dom dom add dom ‐‐‐‐‐‐‐ ‐‐‐‐‐‐+ +++++0+ +++++++ ‐0‐‐0‐‐ ‐‐‐+‐‐‐ ‐‐‐‐00+ ‐‐‐‐‐0‐ ‐‐+‐+‐‐ +‐+++0+ +++++++ +0++++‐ +++++++ +++++‐+ ‐‐‐‐‐0‐ +++++++ ‐‐+‐‐‐+ ‐‐+‐‐‐+ ‐‐+‐‐‐+ ‐‐+‐‐‐+ ‐‐+‐‐‐+ ‐‐‐‐‐0‐ ‐‐‐‐‐‐‐ ‐‐‐‐‐‐‐ +++++++ +++++++ +++++++ +++++++ +++++++ +++++++ ‐‐‐‐‐+‐ ‐‐‐‐‐‐‐ ‐‐‐‐‐‐+ 9.06E‐05 7.96E‐05 1.00E‐04 8.73E‐05 1.03E‐04 9.47E‐05 4.11E‐05 3.05E‐06 1.02E‐04 6.26E‐05 9.43E‐05 6.12E‐05 3.79E‐05 8.30E‐05 4.07E‐05 9.80E‐05 8.96E‐05 3.19E‐05 4.71E‐06 6.71E‐05 5.90E‐05 5.57E‐05 3.87E‐05 5.48E‐05 9.05E‐05 7.78E‐06 5.64E‐06 7.70E‐05 2.63E‐05 5.38E‐05 3.72E‐05 9.64E‐05 8.42E‐05 Diabetes
rs4624233 rs7219451 rs10558 rs9303297 rs3760333 rs2291447 rs2192990 rs691336 rs759635 rs3108582 rs6133145 rs6139486 rs6075733 rs8130631 rs1061325 17 17 17 17 17 17 17 17 19 19 20 20 20 21 22 38955961 38957002 38991003 39005990 39023875 43212963 68801676 76518426 3351890 37221835 4576230 4578080 20856254 35535498 19184095 KRT28 TMEM99 ACBD4 DNAH17 CLTCL1 A/G C/T C/T T/C C/T T/G A/C T/C C/T G/A A/C A/G C/T T/C C/T 0.137 0.380 0.138 0.138 0.173 0.346 0.122 0.263 0.460 0.293 0.400 0.366 0.346 0.101 0.451 18
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‐0.28 ± 0.09 ‐0.17 ± 0.06 ‐0.31 ± 0.09 ‐0.31 ± 0.09 ‐0.31 ± 0.09 ‐0.24 ± 0.06 0.12 ± 0.10 ‐0.27 ± 0.08 0.20 ± 0.06 0.21 ± 0.08 0.15 ± 0.08 0.14 ± 0.08 ‐0.06 ± 0.06 0.26 ± 0.10 0.12 ± 0.10 ‐17.68 ± 6.28 ‐15.91 ± 4.04 ‐16.19 ± 6.25 ‐17.14 ± 6.28 ‐13.41 ± 5.81 ‐10.49 ± 4.16 15.54 ± 6.44 ‐7.68 ± 5.54 12.32 ± 3.92 17.6 ± 5.5 13.34 ± 6.02 12.06 ± 5.52 ‐18.29 ± 4.13 16.36 ± 7.38 ‐13.72 ± 9.23 dom add dom dom dom add dom dom add dom dom dom add dom rec ‐‐‐‐+‐+ ‐‐‐‐‐‐+ ‐‐‐‐+‐+ ‐‐‐‐+‐+ ‐‐‐‐+‐‐ ‐‐‐‐‐‐‐ +++++++ ‐‐‐‐+‐‐ +++++++ +++++++ +++++0‐ ++++++‐ ‐‐+‐‐‐‐ +++++0+ ‐‐‐‐00‐ 2.46E‐05 3.92E‐06 1.48E‐05 9.98E‐06 2.09E‐05 7.95E‐05 1.04E‐04 2.77E‐05 1.20E‐05 1.01E‐04 4.52E‐05 7.29E‐05 3.40E‐05 5.21E‐05 9.96E‐05 Page 55 of 127
Diabetes
c. SI (nmax=2,549) Marker rs880554 rs17385225 rs1256941 rs6719442 rs12620694 rs1978648 rs4952971 rs10167465 rs12464602 rs1044710 rs6782551 rs1872552 rs716975 rs7690543 rs1848056 rs9997902 rs1602084 rs11943562 rs17069175 rs6868526 rs16875556 rs7717247 rs462647 rs6880017 rs17155849 Chr 1 1 1 2 2 2 2 2 2 2 3 3 4 4 4 4 4 4 4 5 5 5 5 5 5 Position 19954014 164475201 201392764 2722295 2763051 43371542 43373119 43397176 43397614 211297355 74922055 85049088 38349236 68056613 125755019 125763629 128843480 167652786 181226698 5399472 5402163 27839258 81080808 81185254 103142399 Gene MINOS1 TNNI1 LANCL1 CADM2 MFSD8 Ref Allele Freq 0.278 0.134 0.126 0.18 0.162 0.328 0.438 0.419 0.424 0.395 0.014 0.444 0.226 0.177 0.484 0.49 0.038 0.130 0.241 0.188 0.167 0.136 0.334 0.314 0.290 ref/nonref T/G A/G A/C A/G A/G T/C A/G G/A G/A A/G A/G A/G T/C T/C T/C A/G G/A C/T A/G C/T A/G C/A C/T G/A T/C 19
β±SE 0.21 ± 0.08 0.28 ± 0.10 0.33 ± 0.09 ‐0.29 ± 0.08 ‐0.38 ± 0.08 0.2 ± 0.06 0.18 ± 0.06 0.19 ± 0.06 0.38 ± 0.10 ‐0.2 ± 0.06 0.57 ± 0.22 ‐0.20 ± 0.06 ‐0.27 ± 0.08 0.28 ± 0.09 0.09 ± 0.06 0.10 ± 0.06 0.43 ± 0.16 ‐0.25 ± 0.09 ‐0.27 ± 0.08 0.27 ± 0.09 0.26 ± 0.09 ‐0.33 ± 0.09 0.32 ± 0.08 ‐0.17 ± 0.06 ‐0.29 ± 0.08 Direction of Association (BetaGene, IRAS, IRASFS, Best model TRIPOD) dom +‐++ dom ++++ dom ++++ dom ‐‐‐‐ dom ‐‐‐‐ add ++++ add ++++ add ++++ rec ++++ add ‐‐‐‐ dom ++++ add ‐‐‐‐ dom ‐‐‐‐ dom ++++ add +‐++ add +‐++ dom ++++ dom ‐‐‐+ dom ‐‐‐‐ dom +++‐ dom +++‐ dom ‐‐‐+ dom ++++ add ‐‐‐+ dom ‐‐‐‐ Best p‐
value 3.87E‐05 4.87E‐05 1.03E‐04 1.53E‐05 3.42E‐05 5.31E‐07 2.31E‐05 9.30E‐05 7.28E‐06 8.93E‐05 9.04E‐05 8.59E‐05 9.86E‐06 2.34E‐06 3.21E‐05 2.29E‐05 3.10E‐06 6.27E‐05 7.04E‐05 2.22E‐05 3.47E‐05 4.16E‐05 8.79E‐05 7.51E‐05 7.13E‐05 Diabetes
rs1898910 rs1042711 rs12194985 rs10080664 rs4716224 rs724941 rs2148261 rs943086 rs196705 rs196701 rs17062582 rs7803642 rs9406428 rs10964496 rs10811340 rs1581979 rs10780305 rs10867395 rs1885984 rs2819042 rs2819039 rs359297 rs11817459 rs12256421 rs945296 rs1223629 rs10870301 rs4443996 rs10870302 rs10870303 rs4568920 rs7117567 rs121704 5 5 6 6 6 6 6 6 6 6 6 7 9 9 9 9 9 9 9 10 10 10 10 10 10 10 10 10 10 10 10 11 11 124555847 148206348 6892411 15864284 18161563 76723011 76736996 76755221 80138778 80147187 133789961 21641629 11463799 20248264 20283406 23407435 81978708 82118185 119078249 10230151 10232363 17333680 17594247 17614097 26704514 95906315 134186772 134191005 134191738 134191811 134324451 7715079 17904634 SH3TC2 KDM1B IMPG1 IMPG1 IMPG1 EYA4 DNAH11 PAPPA PLCE1 LRRC27 LRRC27 LRRC27 LRRC27 OVCH2 SERGEF A/C C/T T/G A/G A/G C/T T/C G/A T/C C/T A/G T/C C/T A/G G/A C/A A/G C/T T/C A/C C/T A/G G/T A/G C/T A/G C/T C/A T/G G/A T/C G/A G/A 0.161 0.212 0.032 0.384 0.306 0.446 0.449 0.449 0.123 0.128 0.144 0.321 0.132 0.091 0.098 0.310 0.431 0.304 0.009 0.455 0.456 0.213 0.396 0.387 0.305 0.038 0.435 0.441 0.436 0.436 0.077 0.356 0.474 20
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‐0.38 ± 0.09 0.31 ± 0.08 ‐0.40 ± 0.17 0.15 ± 0.06 ‐0.19 ± 0.08 0.17 ± 0.06 0.15 ± 0.06 0.15 ± 0.06 ‐0.36 ± 0.10 ‐0.35 ± 0.10 ‐0.18 ± 0.09 ‐0.18 ± 0.06 0.33 ± 0.09 0.34 ± 0.10 0.27 ± 0.10 ‐0.18 ± 0.06 0.15 ± 0.06 0.13 ± 0.08 ‐0.79 ± 0.25 ‐0.18 ± 0.06 ‐0.19 ± 0.06 ‐0.28 ± 0.08 ‐0.14 ± 0.06 ‐0.2 ± 0.06 0.2 ± 0.06 ‐0.74 ± 0.17 ‐0.12 ± 0.06 ‐0.11 ± 0.06 ‐0.13 ± 0.06 ‐0.13 ± 0.06 ‐0.29 ± 0.12 ‐0.21 ± 0.06 0.15 ± 0.06 dom dom dom add dom add add add dom dom dom add dom dom dom add add dom dom add add dom add add add dom add add add add dom add add ‐‐‐+ ++++ ‐‐‐‐ ++++ ‐‐‐‐ +++‐ ++++ ++++ ‐‐‐+ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ++++ +++‐ +++‐ ‐‐‐‐ ++++ ++++ ‐?‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ++++ ‐‐‐‐ ‐+‐‐ ‐+‐‐ ‐+‐‐ ‐+‐‐ ‐+‐‐ ‐‐‐‐ +++‐ 6.60E‐06 9.07E‐05 8.50E‐05 9.95E‐05 9.37E‐05 9.34E‐05 3.41E‐05 6.49E‐05 9.35E‐06 1.37E‐06 1.02E‐04 9.92E‐05 7.63E‐05 5.14E‐05 7.35E‐05 8.14E‐05 8.69E‐06 6.04E‐05 9.14E‐05 1.38E‐05 1.61E‐05 5.10E‐05 7.01E‐05 9.07E‐05 1.02E‐04 4.72E‐06 7.93E‐05 9.70E‐05 9.64E‐05 6.94E‐05 7.13E‐05 8.87E‐05 5.97E‐05 Page 57 of 127
rs10160242 rs2368785 rs1947234 rs7136587 rs10785139 rs9554019 rs17376318 rs9559508 rs2383580 rs10129961 rs17123946 rs10498430 rs17123969 rs4901281 rs11631474 rs896598 rs4887140 rs2415230 rs27230 rs16530 rs691336 rs6139479 rs6100794 Diabetes
11 12 12 12 12 13 13 13 14 14 14 14 14 14 15 15 15 15 16 17 17 20 20 108498885 260682 39450491 39487541 75089475 27951711 108013050 109805793 34749512 34767305 51929722 51942961 51946458 52980190 67934167 74036629 74046663 74059081 3434699 37357034 76518426 4566415 58799036 IQSEC3 FAM155A MYO16 TXNDC16 MAP2K5 C15orf59 ZNF434 RPL19 DNAH17 AX747739 C/T C/T A/C A/G C/T A/G C/T T/C A/C A/G G/A T/C G/A A/C G/A A/G G/T A/G G/A T/C T/C A/G T/C 0.060 0.150 0.197 0.136 0.307 0.061 0.119 0.240 0.161 0.146 0.251 0.243 0.245 0.148 0.272 0.119 0.143 0.171 0.107 0.102 0.261 0.308 0.012 21
0.41 ± 0.11 0.19 ± 0.09 0.13 ± 0.08 0.17 ± 0.09 0.19 ± 0.06 ‐0.36 ± 0.13 ‐0.41 ± 0.10 ‐0.17 ± 0.08 0.29 ± 0.08 0.33 ± 0.09 ‐0.29 ± 0.08 ‐0.30 ± 0.08 ‐0.30 ± 0.08 ‐0.29 ± 0.09 ‐0.24 ± 0.08 0.37 ± 0.10 0.31 ± 0.10 0.26 ± 0.09 ‐0.23 ± 0.09 ‐0.33 ± 0.10 ‐0.27 ± 0.08 0.23 ± 0.08 ‐0.63 ± 0.24 dom dom dom dom add dom dom dom dom dom dom dom dom dom dom dom add dom dom dom dom dom dom ++++ +‐++ ++++ +‐++ ++++ ‐‐‐‐ ‐‐‐‐ ‐+‐‐ ++++ ++++ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ++++ ++++ ++++ ‐‐‐+ ‐‐‐‐ ‐‐‐‐ ++++ ‐‐‐+ 4.33E‐06 4.51E‐05 7.83E‐05 1.01E‐04 5.31E‐05 2.76E‐05 4.00E‐05 9.54E‐05 7.06E‐05 2.25E‐05 9.17E‐05 4.05E‐05 5.36E‐05 5.98E‐05 3.36E‐05 5.83E‐07 6.91E‐08 7.20E‐06 5.85E‐05 2.97E‐05 2.91E‐05 9.73E‐05 4.80E‐06 Diabetes
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d. M (nmax=1,604) Marker rs2235438 rs2744761 rs11209072 rs12135476 rs10493454 rs4650135 rs6685355 rs1886644 rs13375429 rs11582424 rs6665426 rs17047682 rs6681101 rs10926618 rs7558483 rs17031893 rs7595513 rs2138397 rs10179986 rs1996589 rs4953902 rs1111961 rs13030335 rs10178963 rs1546676 rs2178704 Chr 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 Position 4849384 26040514 67908644 69649328 69659840 69684997 79458347 85350658 112103322 154363985 200148319 218523025 242243325 242251696 11537452 44283172 46687867 86974049 134864344 134865196 134876049 134880830 142231898 142349495 154509239 227579207 Gene BC037321 MAN1C1 ELTD1 LPAR3 ADORA3 TGFB2 PLD5 RMND5A LRP1B LRP1B Ref Allele Freq 0.357 0.229 0.393 0.118 0.136 0.157 0.311 0.295 0.015 0.292 0.309 0.078 0.401 0.386 0.244 0.101 0.198 0.442 0.467 0.230 0.140 0.158 0.382 0.446 0.325 0.244 ref/nonref T/C G/T G/A A/G G/A C/T C/A C/A A/G C/A A/G G/A A/G T/C T/C G/A G/A A/G G/A C/T C/A G/A A/G C/A A/G G/A 22
β±SE 15.45 ± 4.12 ‐21.75 ± 5.8 ‐22.54 ± 5.52 ‐31.54 ± 6.61 ‐29.41 ± 6.22 ‐29.56 ± 6.00 ‐18.36 ± 4.25 ‐22.90 ± 5.42 107.86 ± 27.77 20.19 ± 5.41 ‐19.74 ± 5.46 ‐31.01 ± 7.63 ‐23.30 ± 6.08 ‐23.32 ± 6.02 ‐19.51 ± 5.58 27.41 ± 6.78 ‐22.09 ± 5.80 ‐24.39 ± 5.86 ‐17.78 ± 3.89 ‐21.95 ± 5.57 ‐25.81 ± 6.31 ‐25.37 ± 6.10 ‐33.45 ± 8.00 24.53 ± 6.30 23.62 ± 5.49 25.31 ± 5.41 Best model add dom dom dom dom dom add dom dom dom dom dom dom dom dom dom dom dom add dom dom dom rec dom dom dom Direction of Association (HTN, MACAD, NIDDM) +++ ‐‐‐ ‐‐‐ ‐‐‐ ‐‐‐ ‐‐‐ ‐‐‐ ‐‐‐ ?+? +++ ‐‐‐ ‐‐‐ ‐‐? ‐‐? ‐‐‐ +++ ‐‐‐ ‐‐‐ ‐‐‐ ‐‐‐ ‐‐‐ ‐‐‐ ‐‐? ++? +++ +++ Best p‐
value 3.95E‐05 5.54E‐05 7.60E‐05 3.75E‐06 6.08E‐06 2.31E‐06 1.33E‐05 6.28E‐06 1.03E‐04 1.02E‐04 8.31E‐05 1.19E‐05 9.80E‐05 8.79E‐05 7.39E‐05 9.83E‐05 6.66E‐05 3.71E‐05 7.95E‐06 3.97E‐05 1.41E‐05 1.40E‐05 4.13E‐05 9.64E‐05 8.00E‐06 8.83E‐05 Page 59 of 127
rs11683087 rs2251692 rs10205233 rs16822640 rs11130721 rs2596937 rs2279440 rs17050395 rs3806667 rs13106 rs635787 rs9682976 rs17062321 rs12493716 rs3773155 rs12487584 rs13094259 rs9824464 rs11920292 rs11709891 rs1426260 rs10937355 rs12511127 rs6448852 rs1025877 rs4834882 rs1382751 rs9997603 rs4320186 rs11930824 rs4627838 rs4695784 rs2448425 Diabetes
2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 4 4 5 227586606 227589780 227614005 227647907 6008503 9480906 9518511 9533974 9860880 12624580 32466487 60118879 60122156 106777359 127438528 132300293 142444625 167635899 188246257 188248624 188260703 188289697 5142212 12017993 12074137 12108239 12138827 66438114 66483593 161451545 175602762 175608905 55917956 IRS1 IRS1 SETD5 SETD5 ARPC4‐TTLL3 MKRN2 CMTM7 FHIT FHIT LOC100302640 MGLL ACAD11 TRPC1 LOC646168 LPP LPP LPP LPP STK32B EPHA5 EPHA5 GLRA3 GLRA3 G/A A/G T/C T/G C/A C/T T/C G/A G/T A/G A/G T/C T/C G/A G/A T/C T/G T/C T/C C/T T/C T/C G/A C/T G/A T/C C/T T/G A/G A/G A/C T/C C/T 0.412 0.483 0.185 0.210 0.070 0.238 0.203 0.235 0.272 0.028 0.453 0.152 0.163 0.253 0.110 0.284 0.091 0.468 0.509 0.510 0.501 0.306 0.325 0.468 0.455 0.314 0.316 0.080 0.079 0.445 0.427 0.426 0.494 23
20.54 ± 3.87 17.31 ± 3.84 23.19 ± 4.75 20.51 ± 4.61 ‐33.07 ± 8.52 ‐17.41 ± 4.43 ‐21.57 ± 4.63 ‐17.84 ± 4.48 ‐20.45 ± 5.51 126.46 ± 30.51 ‐22.82 ± 5.22 ‐24.49 ± 6.11 ‐24.84 ± 5.99 ‐16.3 ± 4.47 25.12 ± 6.87 19.13 ± 4.34 ‐29.40 ± 7.77 27.97 ± 7.05 28.44 ± 6.08 27.77 ± 6.06 27.98 ± 6.08 ‐23.26 ± 5.41 ‐16.49 ± 4.07 15.04 ± 3.88 ‐14.32 ± 3.91 18.23 ± 4.13 17.13 ± 4.16 ‐31.75 ± 7.58 ‐30.58 ± 7.68 29.13 ± 5.90 19.97 ± 5.71 19.97 ± 5.71 ‐15.23 ± 3.95 add add add add dom add add add dom dom add dom dom add dom add dom rec add add add dom add add add add add dom dom dom dom dom add +++ +++ ‐++ ‐++ ‐‐‐ ‐‐‐ ‐‐‐ ‐‐‐ ‐‐+ ??+ ?‐‐ ‐‐‐ ‐‐‐ ‐‐‐ +++ +++ ‐‐? ++‐ ?+? ?+? ?+? ‐‐‐ ‐‐‐ +++ ‐‐‐ +++ +++ ‐‐‐ ‐‐‐ ++? ++‐ ++‐ ‐‐‐ 7.42E‐07 1.98E‐05 2.35E‐05 1.04E‐04 7.00E‐05 9.76E‐05 3.31E‐06 8.31E‐05 2.79E‐05 3.41E‐05 1.24E‐05 5.93E‐05 2.39E‐05 9.21E‐05 4.27E‐05 2.87E‐05 9.10E‐05 8.41E‐05 2.90E‐06 4.54E‐06 4.25E‐06 4.12E‐05 6.59E‐05 5.55E‐05 9.65E‐05 2.08E‐05 7.86E‐05 1.54E‐05 2.41E‐05 7.46E‐05 7.25E‐05 7.25E‐05 3.69E‐05 Diabetes
rs6877846 rs4835696 rs13361457 rs1019507 rs1465417 rs322394 rs241439 rs16884633 rs987672 rs665791 rs484621 rs490010 rs510432 rs9637984 rs4134409 rs2282909 rs11768415 rs11764734 rs296307 rs296316 rs2188256 rs1588422 rs2968865 rs441606 rs17197236 rs13267838 rs13252932 rs11780263 rs9650426 rs4732617 rs1715350 rs4737430 rs660416 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 8 8 8 8 8 8 8 8 8 8 81160103 137972584 152797679 152798614 153790531 172157768 32797537 53902171 77410315 106674850 106734408 106740458 106774030 170275554 170279658 28844815 52347667 52356515 52432938 52439967 88213062 97329406 124810399 17903046 25193338 25196710 25198091 27823832 27827391 27829251 50396852 57303823 102465300 GALNT10 TAP2 MLIP ATG5 ATG5 ATG5 CREB5 AX746567 DOCK5 DOCK5 DOCK5 SCARA5 SCARA5 SCARA5 A/G A/G T/C C/A T/C C/T G/T A/G G/A G/A T/C A/G T/C G/A A/G T/G A/G T/C T/C T/C C/T T/C G/A A/G G/A T/G T/C A/G C/T G/A T/G A/G A/G 0.328 0.383 0.477 0.409 0.198 0.360 0.426 0.234 0.358 0.328 0.323 0.316 0.341 0.245 0.245 0.409 0.519 0.520 0.470 0.369 0.179 0.278 0.459 0.462 0.034 0.035 0.049 0.210 0.334 0.330 0.258 0.404 0.337 24
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20.99 ± 5.55 35.18 ± 8.27 23.81 ± 5.60 ‐18.01 ± 4.10 ‐20.39 ± 5.87 ‐15.83 ± 4.02 18.67 ± 5.34 ‐23.78 ± 5.58 ‐17.03 ± 3.98 18.17 ± 4.21 18.89 ± 4.22 18.72 ± 4.23 16.93 ± 4.17 19.29 ± 4.45 19.26 ± 4.45 22.37 ± 5.70 ‐17.74 ± 4.17 ‐18.43 ± 4.20 ‐15.67 ± 4.05 ‐16.72 ± 4.15 ‐21.95 ± 5.85 44.15 ± 10.17 29.85 ± 7.01 26.11 ± 6.49 54.29 ± 11.11 54.96 ± 10.96 47.71 ± 9.20 ‐16.34 ± 4.67 15.63 ± 4.06 20.45 ± 5.52 ‐19.15 ± 4.39 17.9 ± 5.57 ‐16.42 ± 4.07 dom rec add add dom add add dom add add add add add add add dom add add add add dom rec rec dom dom dom dom add add dom add dom add +++ ++? ?++ ‐‐‐ ‐‐+ ‐‐‐ ?++ ‐‐‐ ‐‐‐ +++ +++ +++ +++ +++ +++ +++ ‐‐? ‐‐? ‐‐‐ ‐‐‐ ‐‐‐ ++? ++? ++? +++ +++ +++ ‐‐+ +++ +++ ‐‐‐ ++‐ ‐‐‐ 5.27E‐05 1.74E‐05 9.63E‐06 2.10E‐05 7.72E‐05 3.38E‐05 9.23E‐05 3.67E‐05 9.05E‐05 8.39E‐06 4.12E‐06 5.91E‐06 2.61E‐05 3.63E‐05 3.79E‐05 1.05E‐04 2.80E‐05 1.41E‐05 8.25E‐05 9.52E‐05 6.79E‐05 3.19E‐05 1.40E‐05 9.48E‐05 7.13E‐06 4.03E‐06 5.17E‐06 6.64E‐05 6.38E‐05 1.02E‐04 7.31E‐05 6.71E‐05 5.79E‐05 Page 61 of 127
rs633142 rs618854 rs4333664 rs224025 rs6475448 rs17781302 rs17060946 rs7030420 rs12001098 rs1888221 rs10828046 rs17100713 rs11202465 rs17099236 rs1488933 rs10841497 rs7964191 rs10770655 rs7311799 rs17512574 rs673078 rs884844 rs7305647 rs11059101 rs4760067 rs2874868 rs7329452 rs4520736 rs4885169 rs1041515 rs7992923 rs1331765 rs10492494 Diabetes
8 8 9 9 9 9 9 9 9 9 10 10 10 10 11 12 12 12 12 12 12 12 12 12 12 13 13 13 13 13 13 13 13 102466767 102467706 6556948 20309831 20497142 24142314 77808519 77809075 110407586 117778355 20676173 84510336 89366214 92484110 17267029 20524202 20551038 20574060 84718394 118788003 118791441 118814838 118855566 127874250 130611682 36356679 39000963 59174647 74900793 74905950 74907043 74907933 74920186 GLDC MLLT3 NRG3 PDE3A PDE3A PDE3A TAOK3 TAOK3 SUDS3 SUDS3 MAB21L1 T/G T/C T/C T/C G/A C/A G/A G/A A/G A/G A/G T/C G/A A/G T/C G/T C/T C/A A/C T/C C/A T/C A/G C/T T/C G/T G/T C/T A/G C/T A/G G/A A/C 0.337 0.343 0.432 0.449 0.316 0.178 0.068 0.080 0.106 0.310 0.157 0.017 0.007 0.114 0.448 0.356 0.150 0.180 0.469 0.11 0.124 0.111 0.103 0.100 0.432 0.233 0.498 0.415 0.239 0.243 0.427 0.372 0.240 25
‐16.14 ± 4.08 ‐16.61 ± 4.06 16.94 ± 3.95 ‐23.94 ± 5.98 ‐18.68 ± 4.43 21.35 ± 5.03 37.86 ± 8.30 29.63 ± 7.63 27.75 ± 7.15 19.08 ± 4.30 ‐23.63 ± 6.04 104.22 ± 24.6 146.07 ± 36.66 28.87 ± 6.89 30.81 ± 7.44 17.05 ± 4.02 24.85 ± 6.10 23.56 ± 5.90 ‐27.14 ± 6.83 ‐29.28 ± 6.72 ‐30.26 ± 6.55 ‐28.67 ± 6.67 ‐29.15 ± 6.88 ‐25.34 ± 7.18 ‐23.40 ± 5.73 16.78 ± 5.49 ‐23.70 ± 6.11 ‐21.75 ± 5.23 ‐23.04 ± 5.58 ‐21.78 ± 4.53 ‐13.94 ± 3.94 ‐15.35 ± 4.04 ‐22.02 ± 4.55 add add add dom add add dom dom dom add dom dom dom dom rec add dom dom rec dom dom dom dom dom dom dom dom add dom add add add add ‐‐‐ ‐‐‐ +++ ‐‐? ‐‐? +++ +++ +++ ++? +++ ‐‐‐ ?+? ?+? +++ ++‐ +++ +++ +++ ‐‐? ‐‐‐ ‐‐‐ ‐‐‐ ‐‐‐ ‐‐‐ ‐‐‐ ++‐ ‐‐‐ ‐?‐ ‐‐‐ ‐‐‐ ‐‐‐ ‐‐‐ ‐‐‐ 8.10E‐05 5.04E‐05 1.15E‐05 4.00E‐05 1.89E‐05 6.10E‐05 2.56E‐06 5.75E‐05 1.00E‐04 2.52E‐06 4.18E‐05 2.28E‐05 6.76E‐05 5.13E‐05 2.76E‐05 3.17E‐05 5.20E‐05 9.20E‐05 9.33E‐05 7.24E‐06 2.41E‐06 6.48E‐06 6.15E‐06 9.30E‐05 2.54E‐05 6.40E‐05 3.64E‐05 2.56E‐05 5.31E‐06 5.14E‐07 7.86E‐05 2.15E‐05 5.04E‐07 Diabetes
rs2325620 rs2325622 rs9543599 rs555647 rs9559222 rs6572117 rs17120327 rs7154149 rs12050106 rs7165441 rs2222314 rs7497796 rs12438478 rs17818867 rs11637842 rs12438945 rs17238052 rs1076471 rs17175749 rs3826347 rs740559 rs907900 rs6501303 rs11872936 rs626410 rs12961613 rs10408924 rs892024 rs864140 rs913555 rs911112 rs6075733 rs11907984 13 13 13 13 13 14 14 14 14 15 15 15 15 15 15 15 15 16 16 17 17 17 17 18 18 18 19 19 20 20 20 20 20 74927727 74932425 74937657 98632349 108699887 42360633 49073392 49075564 49084116 27828539 46405908 55136506 55159177 55175350 55200927 55226570 55259099 54100518 86343912 64970002 64971249 77345200 77430593 7352783 65855591 66309996 9253139 33399344 3088010 3090124 3144664 20856254 20862068 IPO5 LRFN5 FTO CACNG4 CACNG4 RBFOX3 RBFOX3 ZNF317 CEP89 LOC100134015 LOC100134015 ProSAPiP1 T/C A/C C/T G/A A/G T/C A/G A/G A/G G/A T/G A/C G/T C/T A/G C/A G/A A/G T/G G/A A/G C/T A/G T/C A/C T/C G/T A/G A/G A/G T/C C/T T/C 0.069 0.247 0.433 0.403 0.424 0.374 0.199 0.204 0.204 0.408 0.455 0.384 0.248 0.255 0.225 0.230 0.235 0.244 0.036 0.424 0.446 0.011 0.046 0.009 0.398 0.229 0.370 0.168 0.294 0.295 0.254 0.346 0.370 26
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‐34.55 ± 8.40 ‐21.66 ± 4.51 ‐13.69 ± 3.94 20.89 ± 5.72 ‐43.53 ± 11.20 ‐29.20 ± 7.08 ‐22.43 ± 5.65 ‐21.10 ± 5.62 ‐21.07 ± 5.63 22.79 ± 5.63 ‐25.24 ± 5.89 21.92 ± 5.65 22.72 ± 5.49 19.09 ± 4.48 20.78 ± 4.62 21.63 ± 4.59 22.68 ± 5.53 ‐21.36 ± 5.52 47.74 ± 11.31 25.26 ± 6.14 24.31 ± 6.28 126.16 ± 30.94 33.3 ± 10.26 152.75 ± 35.1 16.55 ± 3.99 ‐22.84 ± 5.59 22.59 ± 5.62 ‐23.28 ± 5.87 21.29 ± 5.54 21.8 ± 5.54 22.86 ± 5.65 ‐18.29 ± 4.13 ‐16.12 ± 4.10 dom add add dom rec dom dom dom dom dom dom dom dom add add add dom dom dom dom dom dom dom dom add dom dom dom dom dom dom add add ‐‐? ‐‐‐ ‐‐‐ +++ ?‐? ‐?‐ ‐‐‐ ‐‐‐ ‐‐‐ +++ ‐‐‐ +++ +++ +++ +++ +++ +++ ‐‐‐ ++? ++? ++? ?+? ++‐ ?+? +++ ‐‐‐ +++ ‐‐‐ +++ +++ +++ ‐‐‐ ‐‐‐ 3.28E‐05 5.61E‐07 8.26E‐05 8.65E‐05 1.01E‐04 9.45E‐05 3.06E‐05 1.01E‐04 1.04E‐04 6.52E‐05 1.64E‐05 4.56E‐05 2.98E‐05 1.24E‐05 1.43E‐05 4.34E‐06 9.39E‐05 1.01E‐04 2.46E‐05 4.44E‐05 1.04E‐04 4.54E‐05 4.32E‐05 1.35E‐05 2.88E‐05 6.23E‐05 9.94E‐05 8.92E‐05 1.04E‐04 6.92E‐05 6.70E‐05 8.61E‐06 9.28E‐05 Page 63 of 127
rs4813402 rs6137217 rs1028444 rs4813452 rs17192831 rs819136 rs6018406 rs155004 rs2277827 rs763040 Diabetes
20 20 20 20 20 20 20 20 21 22 20889803 20997702 22267058 22276813 22281954 32848719 45941326 57870356 47986001 44763606 ASIP ZMYND8 DIP2A BC037321 C/T T/C C/T G/T T/C A/G C/A G/A G/T A/G 0.366 0.349 0.404 0.382 0.386 0.103 0.247 0.283 0.435 0.205 27
‐16.68 ± 4.03 24.96 ± 5.54 26.33 ± 6.24 24.54 ± 6.20 24.83 ± 6.21 29.44 ± 7.35 18.51 ± 4.50 ‐24.33 ± 5.43 29.78 ± 7.30 22.54 ± 5.70 add dom dom dom dom dom add dom rec dom ‐‐‐ +++ ++? ++? ++? ++? +++ ‐‐‐ ++? +++ 5.21E‐05 9.01E‐06 5.22E‐06 2.16E‐05 1.64E‐05 8.26E‐05 5.91E‐05 2.48E‐05 1.02E‐04 6.91E‐05 Diabetes
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e. AIRg (nmax=2,548) Marker rs2784739 rs11121182 rs10492966 rs10492965 rs11121203 rs12061717 rs7537721 rs11185362 rs961490 rs17018659 rs2053797 rs4953320 rs10200604 rs1345516 rs6756027 rs6546079 rs13002043 rs7594935 rs9809000 rs6803803 rs17013808 rs11943562 rs3893856 rs10041174 rs11750248 Chr 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 3 3 4 4 5 5 5 Position 8497558 8522553 8598005 8598127 8648240 55024928 88514479 104561488 227219076 4211781 46370892 46374529 56575020 64703286 64720254 64725466 64726449 235255122 154268934 180116563 89004957 167652786 111163 11710193 52153066 Gene RERE RERE RERE RERE RERE ACOT11 CDC42BPA PRKCE PRKCE CCDC85A CTNND2 ITGA1 Ref Allele Freq 0.243 0.270 0.273 0.271 0.286 0.080 0.010 0.309 0.003 0.004 0.162 0.099 0.314 0.420 0.432 0.438 0.437 0.116 0.080 0.002 0.056 0.130 0.096 0.080 0.068 ref/nonref G/T A/C T/C A/G C/T T/C A/G G/A T/C G/A A/G C/T A/G A/C A/G G/T A/G T/C G/A C/T A/G C/T A/G G/A T/C 28
β±SE ‐1.98 ± 0.45 ‐1.92 ± 0.44 ‐1.96 ± 0.44 ‐1.93 ± 0.44 ‐1.86 ± 0.44 ‐2.10 ± 0.61 8.45 ± 1.80 ‐1.65 ± 0.44 43.04 ± 10.6 10.57 ± 2.50 1.89 ± 0.49 2.13 ± 0.57 ‐1.33 ± 0.34 1.04 ± 0.32 1.09 ± 0.31 1.08 ± 0.31 1.07 ± 0.31 1.91 ± 0.54 2.17 ± 0.65 17.53 ± 3.72 ‐3.15 ± 0.80 1.71 ± 0.51 2.09 ± 0.58 ‐2.59 ± 0.65 2.43 ± 0.62 Best model dom dom dom dom dom dom dom dom dom dom dom dom add add add add add dom dom dom dom dom dom dom dom Direction of Association (BetaGene, IRAS, IRASFS, TRIPOD) ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ‐+‐‐ +?++ ‐‐‐‐ ?+?? +++? +‐++ +‐++ ‐‐‐‐ ++++ ++++ +‐++ +‐++ ++++ +++‐ +++? ‐‐‐‐ +‐++ +++‐ ‐‐‐‐ ++++ Best p‐
value 1.91E‐05 5.01E‐05 4.70E‐05 5.08E‐05 4.42E‐05 2.66E‐05 2.92E‐05 3.21E‐05 6.62E‐05 5.39E‐05 5.02E‐05 8.13E‐05 8.09E‐05 4.11E‐05 6.05E‐05 6.66E‐05 7.92E‐05 2.88E‐05 2.76E‐05 1.64E‐06 4.05E‐05 2.39E‐05 7.21E‐05 2.36E‐05 2.88E‐05 Page 65 of 127
rs1545696 rs6887101 rs10071705 rs193541 rs17149748 rs6891052 rs10476419 rs10078423 rs10051450 rs12198482 rs4712523 rs6456369 rs7754840 rs7756992 rs9368222 rs2206734 rs1040558 rs6935599 rs10946403 rs9358357 rs9356746 rs3873380 rs236358 rs35473403 rs7750450 rs17082388 rs11963462 rs2358010 rs9321207 rs4897370 rs11970367 rs2038586 rs9295206 Diabetes
5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 122102442 122109207 122132725 122253304 122267367 122358015 162296335 162312823 162378040 15218671 20657564 20660365 20661250 20679709 20686996 20694884 20713706 20717095 20717404 20719145 20720279 31262438 36800611 43480822 55714563 120892140 121021878 121028021 130397238 130466676 138544807 158091108 163326692 SNX2 SNX24 SNX24 CDKAL1 CDKAL1 CDKAL1 CDKAL1 CDKAL1 CDKAL1 CDKAL1 CDKAL1 CDKAL1 CDKAL1 CDKAL1 HLA‐B CPNE5 YIPF3 BMP5 L3MBTL3 SAMD3 KIAA1244 ZDHHC14 PACRG A/G A/G T/C C/T G/A T/G G/A G/A T/C C/A G/A C/T C/G G/A A/C T/C G/A G/A G/A G/A C/T T/C A/C T/C C/T G/A C/T A/C A/G G/A A/G T/C G/A 0.282 0.270 0.273 0.253 0.093 0.092 0.010 0.005 0.005 0.213 0.315 0.350 0.310 0.309 0.262 0.194 0.218 0.245 0.242 0.247 0.193 0.408 0.427 0.002 0.322 0.236 0.232 0.232 0.365 0.346 0.006 0.184 0.400 29
‐1.60 ± 0.44 ‐1.70 ± 0.44 ‐1.65 ± 0.44 ‐1.71 ± 0.44 ‐2.14 ± 0.57 ‐2.31 ± 0.56 4.71 ± 2.26 7.29 ± 2.36 7.39 ± 2.36 1.65 ± 0.46 ‐1.17 ± 0.33 ‐0.98 ± 0.32 ‐1.26 ± 0.33 ‐1.13 ± 0.34 ‐1.46 ± 0.35 ‐2.05 ± 0.45 ‐1.92 ± 0.44 ‐1.73 ± 0.44 ‐1.74 ± 0.44 ‐1.77 ± 0.44 ‐1.73 ± 0.45 1.55 ± 0.46 1.05 ± 0.32 16.32 ± 4.38 1.40 ± 0.34 1.67 ± 0.45 1.60 ± 0.45 1.59 ± 0.45 ‐0.97 ± 0.32 1.43 ± 0.44 11.97 ± 3.94 1.97 ± 0.48 ‐1.18 ± 0.32 dom dom dom dom dom dom dom dom dom dom add add add add add dom dom dom dom dom dom dom add dom add dom dom dom add dom dom dom add ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ +‐++ +?+? +?+? ++++ ‐‐‐‐ ‐+‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐+ ‐‐‐+ +‐++ +++‐ ++?? ++++ ++‐+ ++‐+ ++‐+ ‐‐‐+ ++++ ++++ ++++ ‐‐‐‐ 4.93E‐05 1.24E‐05 1.52E‐05 7.64E‐06 5.70E‐05 2.32E‐05 8.86E‐05 4.94E‐05 3.14E‐05 8.95E‐05 1.60E‐05 5.17E‐05 3.83E‐06 1.01E‐04 1.28E‐06 1.02E‐06 5.52E‐06 5.83E‐05 5.56E‐05 3.60E‐05 3.29E‐05 4.50E‐05 3.39E‐05 7.58E‐05 6.21E‐05 1.49E‐05 6.06E‐05 6.50E‐05 7.43E‐05 3.80E‐05 9.07E‐05 1.49E‐05 4.78E‐05 Diabetes
rs7779074 rs10230193 rs10232215 rs2111200 rs10237822 rs10242768 rs17881463 rs11779094 rs11203714 rs4645564 rs7000560 rs4922265 rs6988635 rs7018475 rs13301551 rs2295926 rs7341705 rs9696881 rs1602111 rs2287005 rs7036846 rs12348950 rs1128905 rs10870202 rs10781496 rs2855022 rs7919192 rs10509794 rs6584696 rs2129969 rs10838488 rs510398 rs11227856 7 7 7 7 7 7 7 8 8 8 8 8 8 9 9 9 9 9 9 9 9 9 9 9 9 10 10 10 10 11 11 11 11 22986107 50364626 92097166 92140397 93760001 93784157 100495687 10666813 15477945 15494159 16993943 16996435 95744466 22137685 25683697 101593825 107651348 109274146 109277184 113791313 119798885 123327435 139253839 139257411 139261086 70849959 93660727 107460228 107578214 45586169 45596965 66054823 67377758 FAM126A IKZF1 PEX1 SOX7 TUSC3 TUSC3 DPY19L4 GALNT12 ABCA1 BC017988 BC017988 LPAR1 ASTN2 CDK5RAP2 GPSM1 DNLZ CARD9 SRGN YIF1A NDUFV1 A/G A/G G/A T/C G/T C/T T/C A/G G/T T/C C/A A/C G/A G/T T/C C/T C/T G/A C/A C/T C/T C/T T/C T/C A/G G/A C/T C/T C/T G/A C/T C/T T/C 0.101 0.479 0.248 0.251 0.025 0.022 0.003 0.075 0.217 0.210 0.476 0.469 0.444 0.323 0.075 0.348 0.003 0.233 0.233 0.068 0.005 0.469 0.435 0.430 0.493 0.465 0.216 0.004 0.026 0.477 0.479 0.003 0.005 30
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2.13 ± 0.60 ‐1.79 ± 0.53 1.96 ± 0.44 1.96 ± 0.44 3.94 ± 1.18 3.94 ± 1.13 43.04 ± 10.60 ‐2.18 ± 0.64 1.11 ± 0.46 1.04 ± 0.46 2.00 ± 0.49 2.11 ± 0.49 1.18 ± 0.31 ‐1.64 ± 0.34 2.39 ± 0.62 ‐1.61 ± 0.44 13.32 ± 4.28 ‐1.47 ± 0.45 ‐1.53 ± 0.45 2.61 ± 0.66 10.86 ± 2.43 1.95 ± 0.53 ‐1.05 ± 0.32 ‐1.04 ± 0.32 ‐1.07 ± 0.32 ‐1.72 ± 0.53 ‐1.45 ± 0.46 7.64 ± 2.29 4.14 ± 0.99 1.14 ± 0.32 1.14 ± 0.32 12.63 ± 2.96 6.51 ± 2.48 dom rec dom dom dom dom dom dom dom dom dom dom add add dom dom dom dom dom dom dom rec add add add rec dom dom dom add add dom dom ++++ ‐+‐‐ ++++ ++++ +++‐ +++‐ ?+?? ‐‐‐+ +‐+‐ +‐+‐ ++++ ++++ ++++ ‐‐‐‐ ++++ ‐‐‐‐ +‐++ ‐‐‐‐ ‐‐‐‐ +++‐ ++++ ++++ ‐‐‐‐ ‐‐‐+ ‐‐‐‐ ‐‐‐+ ‐‐‐+ +‐+‐ ++++ ++++ ++++ +?++ +‐++ 9.56E‐05 7.09E‐06 4.41E‐05 3.21E‐05 3.53E‐05 6.87E‐05 6.62E‐05 8.16E‐05 1.00E‐04 1.04E‐04 3.35E‐05 6.61E‐06 7.73E‐05 4.90E‐06 8.39E‐05 2.21E‐05 1.77E‐05 6.80E‐05 2.16E‐05 6.49E‐05 9.25E‐06 5.73E‐05 8.83E‐05 5.37E‐05 6.97E‐05 2.73E‐05 5.00E‐05 1.02E‐04 2.66E‐05 2.10E‐05 2.70E‐05 4.37E‐06 5.34E‐05 Page 67 of 127
rs12295232 rs10082595 rs11227870 rs10898909 rs3847554 rs1387153 rs2166706 rs10830961 rs10830963 rs686413 rs12292105 rs11216770 rs7927108 rs7962050 rs247352 rs12816878 rs3847896 rs1489076 rs11049971 rs1489078 rs11113214 rs3026485 rs16940879 rs10774579 rs10744163 rs9553849 rs9670049 rs9585660 rs7158254 rs1690356 rs2701405 rs2570133 rs428233 Diabetes
11 11 11 11 11 11 11 11 11 11 11 11 11 12 12 12 12 12 12 12 12 12 12 12 12 13 13 13 14 15 15 15 16 67379575 67383433 67400566 72952496 92668826 92673828 92691532 92694757 92708710 117537710 117983479 117983801 134038949 1031454 14900457 23155705 23159966 29129874 29130200 29141413 107588082 110782027 110928719 121405210 124383950 27082326 31692454 101962642 37264674 55301874 87539918 87604296 1085393 NDUFV1 TBX10 MTNR1B DSCAML1 TMPRSS4 TMPRSS4 NCAPD3 RAD52 AK094733 AK094733 ATP2A2 DNAH10 NALCN SLC25A21 AGBL1 A/G T/C A/G A/G T/C T/C C/T G/A G/C A/G G/T T/C T/G G/A C/T T/C C/T T/C T/C G/A G/A C/T G/A C/T T/C A/G C/T A/G C/T A/C A/C C/T C/A 0.005 0.005 0.005 0.404 0.343 0.220 0.308 0.331 0.220 0.327 0.024 0.024 0.004 0.323 0.013 0.283 0.453 0.377 0.376 0.376 0.219 0.002 0.003 0.252 0.200 0.199 0.176 0.006 0.007 0.003 0.485 0.416 0.295 31
6.51 ± 2.48 6.51 ± 2.48 6.63 ± 2.50 1.41 ± 0.33 ‐1.64 ± 0.32 ‐2.55 ± 0.45 ‐1.70 ± 0.33 ‐1.59 ± 0.33 ‐2.76 ± 0.45 ‐1.19 ± 0.33 3.77 ± 1.18 3.78 ± 1.18 10.54 ± 2.49 1.20 ± 0.33 4.42 ± 1.49 1.31 ± 0.35 1.12 ± 0.31 ‐1.37 ± 0.33 ‐1.37 ± 0.33 ‐1.34 ± 0.33 ‐1.93 ± 0.47 15.24 ± 5.06 11.03 ± 4.51 1.59 ± 0.44 1.75 ± 0.46 1.57 ± 0.47 1.81 ± 0.47 8.29 ± 2.16 7.18 ± 1.90 13.41 ± 3.63 0.91 ± 0.30 ‐1.00 ± 0.31 1.54 ± 0.44 dom dom dom add add dom add add dom add dom dom dom add dom add add add add add dom dom dom dom dom dom dom dom dom dom add add dom +‐++ +‐++ +‐++ +++‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ++++ ++++ +++‐ +++‐ +‐++ ++++ +++‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ +?+? +?+‐ ++++ ++++ +‐++ ++++ +?++ +++‐ +??+ +++‐ ‐‐‐+ ++++ 5.38E‐05 5.40E‐05 6.28E‐05 4.03E‐06 1.08E‐06 2.21E‐09 1.24E‐06 1.91E‐06 5.23E‐12 5.67E‐05 3.77E‐05 3.67E‐05 4.35E‐05 7.67E‐05 9.24E‐05 9.69E‐05 6.47E‐05 1.97E‐05 1.78E‐05 2.48E‐05 6.21E‐05 6.78E‐06 6.21E‐05 7.01E‐05 2.66E‐05 6.70E‐05 9.20E‐05 2.60E‐05 3.91E‐05 1.47E‐05 8.78E‐05 6.64E‐05 9.59E‐05 Diabetes
rs12921387 rs7192071 rs16953087 rs1006703 rs2619996 rs899596 rs9947929 rs9955097 rs9950590 rs2068732 rs12608167 rs4567819 rs153508 rs33845 rs6030572 rs17646111 rs1892700 rs5752933 16 16 17 17 17 17 18 18 18 18 18 18 19 19 20 21 21 22 25978823 78953857 420033 3865399 71703758 71735485 6662650 7965469 8043661 26236729 71893294 74894653 34009392 34014316 41598995 34954782 35016137 29902192 HS3ST4 WWOX VPS53 ATP2A3 PTPRM PTPRM PEPD PTPRT DONSON DONSON C/T G/A C/T T/C T/C G/A T/C C/A T/C C/A G/A T/C T/C A/G C/A A/G A/G C/A 0.223 0.024 0.13 0.087 0.042 0.230 0.193 0.004 0.005 0.120 0.264 0.469 0.362 0.361 0.175 0.237 0.236 0.230 32
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‐1.76 ± 0.45 4.34 ± 1.03 ‐1.81 ± 0.52 2.13 ± 0.57 3.15 ± 0.81 2.20 ± 0.45 1.87 ± 0.45 11.62 ± 2.75 11.99 ± 2.72 2.42 ± 0.53 1.36 ± 0.35 1.09 ± 0.31 1.01 ± 0.33 1.00 ± 0.33 ‐1.96 ± 0.47 ‐1.57 ± 0.45 ‐1.52 ± 0.45 2.11 ± 0.45 dom dom dom dom dom dom dom dom dom dom add add add add dom dom dom dom ‐‐‐‐ ++++ ‐‐‐‐ +++‐ ++++ ++++ +++‐ +?++ +?++ ++++ ++++ ++++ ++++ ++++ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ++++ 9.72E‐05 7.30E‐05 3.26E‐05 2.65E‐06 7.69E‐05 2.64E‐06 2.15E‐05 3.10E‐05 5.19E‐06 6.85E‐05 2.48E‐05 1.01E‐04 7.18E‐05 7.03E‐05 8.83E‐05 3.16E‐05 5.02E‐05 1.36E‐05 Page 69 of 127
Diabetes
f. DI (nmax=3,083) Marker rs2985125 rs16866049 rs513553 rs185580 rs266549 rs474939 rs10919851 rs6427807 rs7603311 rs4482537 rs17492567 rs12986646 rs881952 rs1366828 rs6753918 rs7560169 rs684428 rs7559293 rs28415051 rs7629006 rs9832209 rs602149 rs612304 Chr 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 Position 17004186 35836440 182494063 182519861 182528269 182538615 200187504 200189305 49041322 49052255 50212116 52372389 60888202 83753456 137214258 142148511 220505265 236422975 66008918 96801930 96825782 185244569 185251001 Gene ZMYM4 RGSL1 RGSL1 RGSL1 NRXN1 LRP1B SLC4A3 AGAP1 MAGI1 EPHA6 EPHA6 LIPH LIPH Ref Allele Freq 0.052 0.002 0.262 0.227 0.229 0.239 0.442 0.462 0.441 0.404 0.089 0.044 0.477 0.452 0.012 0.388 0.170 0.408 0.003 0.371 0.356 0.059 0.059 ref/nonref G/A G/A G/A A/G T/C A/G C/T A/C C/T T/C C/T A/G C/T T/C C/T T/C T/C A/G G/A A/G A/G T/G C/T 33
β±SE 3.11 ± 0.85 21.17 ± 5.11 ‐1.83 ± 0.49 ‐1.47 ± 0.50 ‐1.59 ± 0.50 ‐1.69 ± 0.49 ‐1.16 ± 0.36 1.15 ± 0.36 1.44 ± 0.36 1.38 ± 0.36 2.54 ± 0.65 2.64 ± 0.89 ‐2.30 ± 0.52 ‐1.99 ± 0.53 6.77 ± 1.65 1.57 ± 0.49 1.61 ± 0.52 1.95 ± 0.51 15.79 ± 6.09 2.25 ± 0.49 2.00 ± 0.49 ‐2.95 ± 0.81 ‐3.25 ± 0.81 Direction of Association (BetaGene, IRAS, IRASFS, MACAD, NIDDM, Best model TRIPOD) dom ++++?+ dom +?+??? dom ‐‐‐+‐‐ dom ‐+‐‐‐‐ dom ‐‐‐‐‐‐ dom ‐‐‐‐‐‐ add ‐‐‐‐?+ add ++++?‐ add ++++?+ add ++++?+ dom ++++?+ dom +‐++?‐ dom ‐‐‐‐++ dom ‐‐‐‐?‐ dom ++++?+ dom +++++‐ dom ++++‐‐ dom +++++‐ dom +++??‐ dom ++++‐+ dom ++++++ dom ‐‐‐‐?+ dom ‐‐‐‐?‐ Best p‐
value 3.02E‐05 3.08E‐05 8.14E‐05 9.30E‐05 6.29E‐05 3.59E‐05 5.29E‐05 6.79E‐05 2.30E‐05 5.52E‐05 4.51E‐05 8.76E‐05 4.59E‐06 9.92E‐05 2.54E‐05 8.79E‐05 8.27E‐05 6.75E‐05 5.80E‐05 1.33E‐05 5.13E‐05 4.20E‐05 3.31E‐05 Diabetes
rs233991 rs1520323 rs467650 rs4712428 rs9470003 rs13193467 rs1510292 rs17086954 rs10225719 rs10267836 rs1346111 rs10278107 rs12539028 rs1077489 rs12546336 rs13253406 rs2382470 rs2020927 rs10121901 rs2066720 rs11145750 rs3812560 rs3812570 rs4266763 rs8413 rs10870194 rs10781542 rs1148233 rs1414894 rs2488069 rs7081634 rs17108007 rs7909248 4 4 5 6 6 6 6 6 7 7 7 7 7 8 8 8 9 9 9 9 9 9 9 9 9 9 9 10 10 10 10 10 10 104665738 125146503 97969453 10203618 35337931 85211681 124371914 156337304 12691988 30755583 49742459 125278195 154812950 6635669 39620015 143200557 14387817 107553185 107553524 107554069 139259249 139269905 139275204 139289825 139323311 139327034 139327439 31461599 89785190 94505421 94685886 94711701 94721776 MRDS1 PPARD NKAIN2 SCIN INMT ADAM2 NFIB ABCA1 ABCA1 ABCA1 CARD9 SNAPC4 SNAPC4 INPP5E INPP5E INPP5E EXOC6 EXOC6 EXOC6 A/C T/C C/T T/C C/G T/C A/G G/A T/C T/C C/T C/T A/G T/C A/G G/T A/G G/A G/A T/C A/G T/C A/C A/G T/C A/G A/G T/C C/T G/T G/A C/T T/G 0.457 0.021 0.271 0.326 0.011 0.132 0.060 0.220 0.418 0.041 0.226 0.477 0.435 0.072 0.333 0.390 0.255 0.161 0.161 0.161 0.474 0.465 0.461 0.489 0.470 0.446 0.446 0.008 0.286 0.002 0.002 0.002 0.002 34
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‐2.07 ± 0.65 ‐3.68 ± 1.19 1.94 ± 0.49 2.08 ± 0.48 8.07 ± 2.39 ‐2.10 ± 0.57 ‐3.05 ± 0.81 2.02 ± 0.49 ‐2.17 ± 0.62 3.20 ± 0.90 ‐2.04 ± 0.49 ‐1.90 ± 0.53 ‐1.74 ± 0.52 ‐2.37 ± 0.75 1.65 ± 0.48 ‐1.77 ± 0.46 ‐1.59 ± 0.49 ‐1.74 ± 0.53 ‐1.74 ± 0.53 ‐1.74 ± 0.53 ‐1.69 ± 0.53 ‐1.83 ± 0.52 ‐1.87 ± 0.52 ‐2.00 ± 0.54 ‐1.77 ± 0.52 ‐1.58 ± 0.51 ‐1.59 ± 0.51 8.86 ± 2.17 1.67 ± 0.48 ‐18.48 ± 5.14 ‐22.06 ± 5.64 ‐21.94 ± 5.65 ‐22.02 ± 5.65 rec dom dom dom dom dom dom dom dom dom dom dom dom dom dom add dom dom dom dom dom dom dom dom dom dom dom dom dom dom dom dom dom ‐‐‐‐?‐ ‐‐‐‐?‐ +++‐++ +++‐‐+ ++++?+ ‐‐‐‐?‐ ‐+‐‐?‐ +++‐++ ‐‐‐?‐+ +‐++?‐ ‐‐‐‐‐‐ ‐‐‐‐‐‐ ‐‐‐‐‐‐ ‐+‐‐?‐ ++++++ ‐‐‐??‐ ‐‐‐‐‐+ ‐+‐‐‐‐ ‐+‐‐‐‐ ‐+‐‐‐‐ ‐+‐‐‐+ ‐+‐‐?+ ‐+‐‐?+ ‐+‐‐?+ ‐‐‐‐?+ ‐+‐‐?+ ‐+‐‐?+ ++++?+ ++++‐+ ‐‐‐??‐ ‐?‐??‐ ‐?‐??‐ ‐?‐??‐ 8.69E‐05 6.82E‐05 3.33E‐05 3.43E‐05 3.92E‐05 4.66E‐05 5.10E‐05 2.71E‐05 3.17E‐05 6.27E‐06 2.28E‐05 5.14E‐05 8.46E‐05 9.47E‐05 9.24E‐05 6.65E‐05 2.02E‐05 5.74E‐05 5.63E‐05 5.74E‐05 2.71E‐05 6.16E‐06 1.72E‐06 3.46E‐06 2.83E‐05 5.86E‐05 5.77E‐05 9.09E‐06 4.62E‐05 5.73E‐05 2.62E‐05 2.84E‐05 2.70E‐05 Page 71 of 127
rs17093817 rs835252 rs835237 rs835242 rs835243 rs835246 rs835254 rs835255 rs9420601 rs7068036 rs2237896 rs2237897 rs5241 rs4756016 rs744434 rs3847554 rs1387153 rs2166706 rs10830961 rs10830963 rs1351571 rs17108749 rs7971324 rs17107718 rs7304911 rs1537435 rs17085484 rs17085485 rs870767 rs2764026 rs9575380 rs9575437 rs9575445 Diabetes
10 10 10 10 10 10 10 10 10 10 11 11 11 11 11 11 11 11 11 11 11 11 12 12 12 13 13 13 13 13 13 13 13 94740586 94749417 94754464 94756734 94757548 94761707 94763426 94765333 94771867 95315193 2858440 2858546 14990543 45699134 65847982 92668826 92673828 92691532 92694757 92708710 98408860 108796817 3098924 70488764 129705400 27909319 27930039 27936526 27938560 36291051 36708286 36731208 36731586 EXOC6 EXOC6 EXOC6 EXOC6 EXOC6 EXOC6 EXOC6 EXOC6 EXOC6 KCNQ1 KCNQ1 CALCA PACS1 MTNR1B DDX10 TEAD4 TMEM132D MAB21L1 G/A G/A A/G C/T G/A A/G G/A A/G A/G T/C A/G T/C T/G G/A G/T T/C T/C C/T G/A G/C T/C G/T C/A T/C T/C T/C C/T G/T G/A G/A G/A G/A A/G 0.002 0.002 0.002 0.002 0.002 0.002 0.002 0.002 0.002 0.156 0.247 0.251 0.016 0.416 0.003 0.339 0.220 0.308 0.328 0.218 0.472 0.009 0.056 0.054 0.223 0.316 0.318 0.228 0.233 0.282 0.281 0.296 0.285 35
‐22.00 ± 5.63 ‐22.01 ± 5.65 ‐21.96 ± 5.65 ‐22.02 ± 5.64 ‐21.99 ± 5.66 ‐22.01 ± 5.65 ‐22.01 ± 5.65 ‐22.01 ± 5.65 ‐22.76 ± 6.29 1.94 ± 0.55 1.64 ± 0.51 1.75 ± 0.51 5.81 ± 1.55 1.50 ± 0.51 15.07 ± 3.98 ‐2.19 ± 0.48 ‐3.20 ± 0.51 ‐2.29 ± 0.48 ‐2.37 ± 0.48 ‐3.40 ± 0.51 ‐1.31 ± 0.44 ‐9.79 ± 2.41 3.44 ± 0.81 2.52 ± 0.85 ‐1.40 ± 0.49 1.61 ± 0.48 1.52 ± 0.49 1.51 ± 0.49 1.53 ± 0.49 ‐1.77 ± 0.48 1.66 ± 0.48 2.02 ± 0.48 1.88 ± 0.48 dom dom dom dom dom dom dom dom dom dom dom dom dom dom dom dom dom dom dom dom add dom dom dom dom dom dom dom dom dom dom dom dom ‐?‐??‐ ‐?‐??‐ ‐?‐??‐ ‐?‐??‐ ‐?‐??‐ ‐?‐??‐ ‐?‐??‐ ‐?‐??‐ ‐?‐??? +‐++?+ ++++?‐ ++++?‐ +++‐?+ +‐++++ +++??+ ‐‐‐++‐ ‐‐‐+?‐ ‐‐‐++‐ ‐‐‐++‐ ‐‐‐+?‐ ‐+‐??+ ‐‐‐??‐ ++++?+ ++++?‐ ‐+‐‐‐‐ ++++++ ++++++ ++++++ +‐++++ ‐‐‐‐‐+ ++++++ ++++++ ++++++ 2.66E‐05 2.72E‐05 2.84E‐05 2.69E‐05 2.80E‐05 2.71E‐05 2.71E‐05 2.71E‐05 7.36E‐05 6.79E‐05 1.57E‐05 7.04E‐06 9.58E‐05 4.61E‐05 5.45E‐05 1.03E‐04 1.32E‐09 4.46E‐05 7.43E‐06 1.03E‐11 4.20E‐05 7.57E‐05 5.00E‐05 6.92E‐05 2.69E‐05 5.12E‐05 8.64E‐05 7.43E‐05 5.87E‐05 6.43E‐05 7.91E‐05 2.08E‐05 1.48E‐05 Diabetes
rs1328641 rs2149423 rs2054715 rs11073891 rs4238710 rs2326274 rs9891963 rs654136 rs4073064 rs2541872 rs2587374 rs4802566 rs1217356 rs6076157 rs8128305 rs219628 rs2833555 rs133937 13 13 15 15 16 16 17 18 18 18 18 19 20 20 21 21 21 22 36745029 36772381 59607007 90363995 84546021 84546108 2875114 48464204 59532727 63632952 63638807 49632309 4170187 23862844 27861993 27865420 33285149 33395851 SOHLH2 SOHLH2 MYO1E RAP1GAP2 ME2 RNF152 PPFIA3 CYYR1 CYYR1 HUNK SYN3 T/C G/A C/T C/A A/G T/G T/C T/C C/T A/G A/G T/C G/A G/A A/G C/T T/C C/A 0.227 0.315 0.172 0.274 0.310 0.308 0.038 0.359 0.010 0.385 0.250 0.392 0.450 0.479 0.250 0.255 0.079 0.335 36
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1.96 ± 0.49 2.18 ± 0.48 ‐1.35 ± 0.55 1.37 ± 0.48 ‐2.08 ± 0.48 ‐2.1 ± 0.48 ‐3.23 ± 1.01 ‐1.43 ± 0.49 ‐10.09 ± 2.54 ‐1.93 ± 0.5 ‐2.07 ± 0.48 1.77 ± 0.50 ‐2.35 ± 0.63 2.09 ± 0.55 1.61 ± 0.49 1.4 ± 0.49 ‐2.93 ± 0.73 1.65 ± 0.50 dom dom dom dom dom dom dom dom dom dom dom dom dom dom dom dom dom dom ++++++ ++++++ ‐+‐‐?+ +‐++‐+ ‐‐‐‐‐‐ ‐‐‐‐‐‐ ‐‐‐+?+ ‐+‐‐‐‐ ‐‐‐??‐ ‐‐‐‐?‐ ‐‐‐‐‐‐ ++++++ ‐‐‐??‐ ++++?+ +++++‐ +++++‐ ‐‐‐‐?‐ ++++++ 1.96E‐05 3.67E‐07 6.02E‐05 9.68E‐05 3.68E‐05 3.97E‐05 8.32E‐05 9.26E‐05 7.42E‐05 9.90E‐05 5.93E‐05 2.84E‐05 5.21E‐05 9.63E‐05 1.63E‐05 5.01E‐05 6.09E‐05 6.74E‐05 Page 73 of 127
Diabetes
g. SG (nmax=2,542) Marker rs1674879 rs780593 rs1572823 rs11805807 rs563988 rs471910 rs7570259 rs1049817 rs11684134 rs10205219 rs4665969 rs6716894 rs7586601 rs11695549 rs2280737 rs7602534 rs12475426 rs13472 rs1260342 rs4803 rs11126999 rs704795 rs1260320 Chr 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 Position 4497217 4507743 19889959 155064844 182474160 182474704 23202248 27550967 27558252 27568565 27574953 27583273 27584666 27586155 27589810 27592423 27599132 27600239 27663416 27667297 27670307 27716494 27722416 Gene RGSL1 RGSL1 GTF3C2 GTF3C2 GTF3C2 GTF3C2 EIF2B4 EIF2B4 SNX17 ZNF513 NRBP1 KRTCAP3 IFT172 FNDC4 GCKR Ref Allele Freq 0.079 0.081 0.125 0.004 0.268 0.269 0.002 0.464 0.436 0.463 0.468 0.468 0.425 0.479 0.469 0.465 0.459 0.469 0.46 0.459 0.474 0.460 0.467 ref/nonref T/C C/T T/C T/C C/T C/T A/C A/G A/G T/C T/C A/G A/G C/A T/C C/T G/A G/A G/T A/G G/A G/A G/A 37
β±SE 0.19 ± 0.05 0.19 ± 0.05 ‐0.14 ± 0.04 1.14 ± 0.27 ‐0.11 ± 0.04 ‐0.11 ± 0.04 1.59 ± 0.35 0.11 ± 0.03 0.1 ± 0.03 0.11 ± 0.03 0.11 ± 0.03 0.11 ± 0.03 0.11 ± 0.03 ‐0.11 ± 0.03 0.11 ± 0.03 0.11 ± 0.03 0.11 ± 0.03 0.11 ± 0.03 0.11 ± 0.03 0.11 ± 0.03 0.11 ± 0.03 0.11 ± 0.03 0.11 ± 0.03 Direction of Association (BetaGene, IRAS, IRASFS, MACAD, NIDDM, Best model TRIPOD) dom ++++ dom ++++ dom ‐‐‐‐ dom +??? dom ‐+‐‐ dom ‐+‐‐ dom +??? add ++++ add ++++ add ++++ add ++++ add ++++ add ++++ add ‐‐‐‐ add ++++ add ++++ add ++++ add ++++ add ++++ add ++++ add ++++ add ++++ add ++++ Best p‐
value 5.99E‐05 1.03E‐04 6.36E‐05 2.89E‐05 9.29E‐05 5.55E‐05 5.51E‐06 1.89E‐05 5.99E‐05 3.42E‐05 1.44E‐05 3.40E‐05 3.20E‐05 3.21E‐05 3.38E‐05 5.06E‐05 8.93E‐05 4.28E‐05 1.02E‐04 8.09E‐05 3.09E‐05 7.12E‐05 9.73E‐05 Diabetes
rs2293571 rs1260326 rs780094 rs780093 rs11681351 rs4852424 rs3755388 rs6743318 rs14234 rs9816690 rs11927192 rs523079 rs13059988 rs10000105 rs3775781 rs1011631 rs6871313 rs6885718 rs17165293 rs7708035 rs28011 rs4700708 rs2064197 rs699986 rs696718 rs367274 rs7744034 rs11752655 rs12536973 rs4720914 rs16876733 rs539518 rs1421221 2 2 2 2 2 2 2 2 2 3 3 3 3 4 4 4 5 5 5 5 5 5 6 6 6 6 6 6 7 7 7 7 8 27729480 27730940 27741237 27742603 27743423 70283210 70310878 70373677 70524142 82046207 183730657 187615862 187624906 53623677 70595637 82440730 2397617 31657655 126183502 161834699 179407229 179529895 8998811 49731027 49752742 90622187 135143748 135160309 10062341 10915448 10945193 73753250 97004203 GCKR GCKR GCKR GCKR GCKR PCBP1‐AS1 PCBP1‐AS1 FAM136A BC031255 ABCC5 SULT1B1 PDZD2 RNF130 RASGEF1C CLIP2 G/A T/C T/C T/C G/A G/A G/A G/T A/G A/G A/G T/C T/G A/G T/C T/C G/A G/A A/G A/G C/T A/G G/A G/A T/G T/C A/G G/A G/A C/T C/A T/C C/T 0.476 0.335 0.341 0.341 0.479 0.382 0.388 0.392 0.412 0.055 0.004 0.069 0.063 0.002 0.027 0.328 0.372 0.081 0.041 0.003 0.325 0.419 0.164 0.472 0.473 0.418 0.253 0.081 0.312 0.132 0.129 0.366 0.385 38
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0.12 ± 0.03 0.13 ± 0.03 0.14 ± 0.03 0.14 ± 0.03 0.11 ± 0.03 ‐0.15 ± 0.04 ‐0.15 ± 0.04 ‐0.15 ± 0.04 0.10 ± 0.03 0.23 ± 0.06 0.77 ± 0.2 0.25 ± 0.06 0.22 ± 0.06 1.32 ± 0.34 ‐0.38 ± 0.10 0.09 ± 0.03 0.1 ± 0.03 0.22 ± 0.05 0.28 ± 0.07 1.71 ± 0.45 ‐0.08 ± 0.03 ‐0.08 ± 0.03 ‐0.19 ± 0.04 ‐0.18 ± 0.05 ‐0.18 ± 0.05 0.12 ± 0.03 0.13 ± 0.04 0.19 ± 0.05 ‐0.11 ± 0.03 ‐0.17 ± 0.04 ‐0.17 ± 0.04 0.09 ± 0.03 ‐0.11 ± 0.03 add add add add add dom dom dom add dom dom dom dom dom dom add add dom dom dom add add dom rec rec add dom dom add dom dom add add ++++ ++++ ++++ ++++ ++++ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ++++ ++++ +?++ +‐++ +‐++ +?++ ‐‐‐‐ +‐++ ++++ ++++ ++++ +++? ‐+‐‐ ‐+‐‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ ++++ +++‐ +++‐ ‐‐‐‐ ‐‐‐‐ ‐‐‐‐ +‐+‐ ‐‐‐‐ 1.98E‐05 4.04E‐06 1.97E‐06 1.12E‐06 3.35E‐05 5.50E‐05 6.51E‐05 4.91E‐05 2.34E‐05 7.44E‐05 5.32E‐05 1.53E‐07 3.40E‐07 7.67E‐05 3.26E‐05 9.08E‐05 4.12E‐05 4.62E‐05 8.94E‐05 1.99E‐05 8.59E‐05 6.82E‐05 7.23E‐06 6.24E‐05 9.37E‐05 2.51E‐05 5.45E‐05 1.12E‐05 5.09E‐05 8.42E‐05 5.24E‐05 9.40E‐05 9.91E‐05 Page 75 of 127
rs883952 rs12313180 rs4931283 rs909013 rs17518256 rs10843647 rs11837387 rs17042107 rs11104268 rs7296900 rs11113179 rs7319628 rs17081477 rs1748124 rs9550193 rs2145516 rs12432901 rs7140895 rs2353498 rs1429751 rs17650440 rs9964 rs516667 rs12901450 rs2456491 rs1115936 rs7203944 rs4783122 rs7202949 rs4299147 rs1559310 rs11150514 rs12933472 Diabetes
9 12 12 12 12 12 12 12 12 12 12 13 13 13 13 14 14 14 15 15 15 15 15 15 15 16 16 16 16 16 16 16 16 71514651 30308868 30334071 30334754 30339648 30341934 73467487 76600231 76627445 104177668 107452785 34502705 35134265 52455098 113324324 26129412 26494469 49724328 24150918 34116858 52504036 102194288 102204031 102224341 102305129 7171923 54438254 82535037 82593560 82883338 82918371 82923464 82924685 PIP5K1B NT5DC3 CRY1 RFC3 C13orf35 RYR3 MYO5C TARSL2 TARSL2 TARSL2 RBFOX1 CDH13 CDH13 CDH13 CDH13 G/A T/C G/A G/A C/A T/G C/T C/T G/A T/C T/C A/G C/T C/T T/G A/G A/G C/T T/C C/T A/G C/T G/A A/G T/C G/A G/A G/A G/A T/C G/T G/T A/G 0.478 0.336 0.322 0.317 0.295 0.331 0.001 0.038 0.042 0.453 0.286 0.006 0.013 0.480 0.351 0.457 0.105 0.123 0.329 0.253 0.004 0.450 0.448 0.449 0.461 0.363 0.314 0.243 0.474 0.410 0.437 0.414 0.435 39
0.10 ± 0.03 0.14 ± 0.03 0.16 ± 0.04 0.16 ± 0.04 0.17 ± 0.04 0.17 ± 0.04 2.02 ± 0.42 0.3 ± 0.08 0.33 ± 0.08 0.12 ± 0.03 ‐0.12 ± 0.03 0.95 ± 0.23 0.44 ± 0.13 ‐0.11 ± 0.03 ‐0.12 ± 0.03 0.09 ± 0.03 ‐0.18 ± 0.05 0.17 ± 0.05 0.1 ± 0.03 0.14 ± 0.04 2.09 ± 0.44 0.16 ± 0.05 0.16 ± 0.05 0.17 ± 0.05 0.18 ± 0.05 ‐0.13 ± 0.04 0.12 ± 0.03 ‐0.16 ± 0.04 ‐0.09 ± 0.03 0.10 ± 0.03 ‐0.11 ± 0.03 0.10 ± 0.03 ‐0.12 ± 0.03 add add dom dom dom dom dom dom dom add add dom dom add add add dom dom add dom dom rec rec rec rec dom add dom add add add add add ++++ ++++ ++++ ++++ ++++ ++++ ++?? ++++ ++++ ++++ ‐‐‐‐ +++‐ +++‐ ‐‐‐+ ‐‐‐‐ +‐++ ‐‐‐‐ ++++ +‐++ ++++ ???+ ++++ ++++ ++++ ++++ ‐+‐‐ ++++ ‐‐‐‐ ‐‐‐‐ ++++ ‐‐‐‐ ++++ ‐‐‐‐ 5.56E‐05 5.88E‐06 1.34E‐05 1.75E‐05 1.32E‐05 4.13E‐06 2.22E‐05 1.03E‐04 6.74E‐06 4.05E‐05 1.28E‐05 2.21E‐05 3.83E‐05 8.53E‐05 3.19E‐05 8.88E‐05 4.44E‐05 9.31E‐05 4.06E‐05 9.22E‐05 6.17E‐06 8.62E‐05 5.02E‐05 4.27E‐05 2.47E‐05 5.22E‐05 1.03E‐04 3.56E‐05 9.47E‐05 8.86E‐05 4.08E‐05 4.41E‐05 8.16E‐06 Diabetes
rs11150519 rs6565127 rs1559438 rs7499978 rs16947417 rs9896748 rs94312 rs2048132 rs6566045 rs1106581 rs2291004 rs788338 rs788332 rs2278998 rs2004423 rs4802723 rs4802724 rs2825882 rs9974077 16 16 16 16 17 17 18 18 18 19 19 19 19 19 19 19 19 21 21 82934307 83152261 83308559 85065085 13143819 64939574 7806492 73694904 75650801 293934 37997952 50778543 50782462 50939737 50939867 51172786 51173218 21283010 43835771 CDH13 CDH13 CDH13 KIAA0513 PTPRM ZNF793 MYH14 MYH14 MYBPC2 MYBPC2 SHANK1 SHANK1 UBASH3A G/A G/A C/T A/G G/T T/G G/A T/G C/T A/G A/C C/T A/C C/A A/G G/A C/A C/T T/G 0.441 0.373 0.476 0.434 0.053 0.070 0.049 0.225 0.289 0.451 0.153 0.287 0.264 0.343 0.325 0.150 0.151 0.474 0.259 40
Page 76 of 127
‐0.11 ± 0.03 0.09 ± 0.03 0.09 ± 0.03 0.11 ± 0.03 0.26 ± 0.06 0.27 ± 0.06 ‐0.27 ± 0.07 0.16 ± 0.04 0.14 ± 0.04 0.10 ± 0.03 0.16 ± 0.04 ‐0.17 ± 0.04 ‐0.16 ± 0.04 0.11 ± 0.03 0.12 ± 0.03 ‐0.16 ± 0.04 ‐0.16 ± 0.04 ‐0.10 ± 0.03 0.13 ± 0.04 add add add add dom dom dom dom dom add dom dom dom add add dom dom add dom ‐‐‐‐ ++++ +‐++ ++++ ++++ +++‐ ‐‐‐‐ ++++ ++++ ++++ +++‐ ‐‐‐+ ‐‐‐‐ ++++ ++++ ‐‐‐‐ ‐‐‐‐ ‐‐‐+ ++++ 4.32E‐05 6.14E‐05 6.67E‐05 5.49E‐05 2.24E‐05 2.37E‐05 8.39E‐05 2.16E‐05 4.52E‐05 9.35E‐05 3.82E‐05 1.66E‐06 1.77E‐05 1.00E‐04 4.51E‐05 1.90E‐05 1.81E‐05 9.16E‐05 3.44E‐05 Page 77 of 127
Diabetes
Supplementary Table 3. Top Discovery hits from the GUARDIAN Consortium ordered by trait.
§
SNP
rs2302063
rs1602084
rs896232
rs6719442
rs1978648
rs896598
rs4887140
rs196701
rs10492494
rs11683087
rs10830963
rs1387153
rs2206734
rs3847554
rs9368222
rs6803803
rs10830963
rs1387153
rs2149423
rs3812570
rs523079
rs780093
rs788338
Chr
19
4
2
2
2
15
15
6
13
2
11
11
6
11
6
3
11
11
13
9
3
2
19
Position*
3150418
128843480
2732877
2722295
43371542
74036629
74046663
80147187
74920186
227586606
92708710
92673828
20694884
92668826
20686996
180116563
92708710
92673828
36772381
139275204
187615862
27742603
50778543
Gene Name
Alleles†
RAF‡
Trait
GNA15
MFSD8
MYT1L / TSSC1
MYT1L / TSSC1
HAAO / ZFP36L2 / THADA¶
C15orf59
C15orf59 / TBC1D21
HMGN3 / LCA5
KLF12 / LINC00347
LOC646736 / IRS1#
MTNR1B**
FAT3 / MTNR1B††
CDKAL1‡‡
FAT3 / MTNR1B§§
CDKAL1||||
PEX5L / TTC14
MTNR1B**
FAT3 / MTNR1B††
CCDC169-SOHLH2; SOHLH2
SNAPC4
BCL6 / LPP
GCKR¶¶
MYH14
A/C
G/A
T/C
A/G
T/C
A/G
G/T
C/T
A/C
G/A
G/C
T/C
T/C
A/G
A/C
C/T
G/C
T/C
G/A
A/C
T/C
T/C
C/T
0.34
0.041
0.29
0.18
0.32
0.12
0.14
0.13
0.24
0.41
0.22
0.22
0.20
0.34
0.26
0.0030
0.23
0.22
0.32
0.46
0.069
0.34
0.29
MCRI
SI+M
SI+M
SI+M
SI
SI
SI
SI
M
M
AIRg
AIRg
AIRg
AIRg
AIRg
AIRg
DI
DI
DI
DI
SG
SG
SG
Model 1
Beta
P-value
-0.29
7.31E-08
8.97
5.20E-07
-5.28
1.26E-06
-5.03
1.53E-06
0.20
5.31E-07
0.37
5.83E-07
0.31
6.91E-08
-0.35
1.37E-06
-22.00
5.04E-07
20.54
7.42E-07
-2.76
5.23E-12
-2.55
2.21E-09
-2.05
1.02E-06
-1.64
1.08E-06
-1.46
1.28E-06
17.53
1.64E-06
-3.40
1.03E-11
-3.20
1.32E-09
2.18
3.67E-07
-1.87
1.72E-06
0.25
1.53E-07
0.14
1.12E-06
-0.17
1.66E-06
||
Model 2
Beta
P-value
-0.19
1.47E-05
11.15
7.29E-05
-6.44
4.43E-04
-4.79
5.06E-04
0.10
2.11E-05
0.28
7.14E-07
0.18
1.35E-06
-0.10
9.02E-03
-15.71
8.82E-05
17.45
8.25E-06
-2.81
3.22E-13
-2.62
2.16E-10
-1.90
5.03E-06
-1.70
1.27E-07
-1.36
4.74E-06
17.25
9.29E-07
-3.36
3.25E-12
-3.11
7.51E-10
2.07
7.35E-07
-1.63
5.89E-06
0.25
3.82E-08
0.13
3.11E-06
-0.17
1.98E-06
Independent signals (r2<0.80) with evidence of association (P<2.00E-06) with the nearest annotated RefSeq gene(s) listed. *Build
hg19, †Reference Allele/Other Allele, ‡Reference Allele Frequency, §Model 1 covariates included age, gender, study site (in multicenter recruitment studies), and admixture proportions, ||Model 2 covariates included age, gender, study site (in multi-center
recruitment studies), admixture proportions, and BMI, ¶Previously identified T2D locus (THADA rs7578597; r2=0.0079, #Previously
identified T2D locus (IRS1 rs2943641; r2=0.04), **Previously identified T2D locus (MTNR1B rs1387153; r2=0.69), ††Previously
identified T2D locus (MTNR1B rs1387153), ‡‡Previously identified T2D locus (CDKAL1 rs7754840; r2=0.42), §§Previously identified
T2D locus (MTNR1B rs1387153; r2=0.54), ||||Previously identified T2D locus (CDKAL1 rs7754840; r2=0.72), ¶¶Previously identified
T2D locus (GCKR rs780094; r2=0.98)
41
Diabetes
Page 78 of 127
Supplementary Table 4. Top Discovery hits from the GUARDIAN Consortium ordered by trait with conditional analyses performed at loci with
multiple signals of association or in close proximity to previously identified T2D loci.
*
SNP
Chr:Position
rs2302063
19:3150418
rs1602084
4:128843480
rs896232
2:2732877
rs6719442
2:2722295
rs1978648
2:43371542
rs896598
15:74036629
rs4887140
15:74046663
rs196701
6:80147187
rs10492494 13:74920186
rs11683087 2:227586606
rs10830963 11:92708710
rs1387153
11:92673828
rs2206734
6:20694884
rs3847554
11:92668826
Gene Name
GNA15
MFSD8
MYT1L / TSSC1
MYT1L / TSSC1
HAAO / ZFP36L2 / THADA||
C15orf59
C15orf59 / TBC1D21
HMGN3 / LCA5
KLF12 / LINC00347
LOC646736 / IRS1||
MTNR1B||
FAT3 / MTNR1B||
CDKAL1||
FAT3 / MTNR1B||
†
‡
Alleles
A/C
G/A
T/C
A/G
T/C
A/G
G/T
C/T
A/C
G/A
G/C
T/C
T/C
A/G
Conditional Analysis
r2§
P-value
SNP
RAF Trait Beta P-value
0.336 MCRI -0.29 7.31E-08
0.041 SI+M
8.97 5.20E-07
0.291 SI+M
-5.28 1.26E-06
0.184 SI+M
-5.03 1.53E-06
rs896232
0.37 8.21E-03
||
0.324
SI
0.20 5.31E-07 rs7578597 0.0079 6.88E-07
0.116
SI
0.37 5.83E-07
0.139
SI
0.31 6.91E-08
rs896598
0.79 3.41E-02
0.132
SI
-0.35 1.37E-06
0.240
M
-22.02 5.04E-07
0.412
M
20.54 7.42E-07 rs2943641||
0.04 1.29E-06
||
0.220 AIRg
-2.76 5.23E-12 rs1387153
0.69 8.67E-05
||
0.220 AIRg
-2.55 2.21E-09 rs10830963
0.69 8.27E-01
0.198 AIRg
-2.05 1.02E-06 rs7754840||
0.42 9.37E-03
||
0.341 AIRg
-1.64 1.08E-06 rs1387153
0.54 3.66E-01
rs10830963
0.36 5.95E-01
rs9368222
6:20686996
CDKAL1||
A/C
0.264 AIRg
-1.46 1.28E-06 rs7754840||
0.72 8.19E-02
rs2206734
0.57 3.06E-01
rs6803803
3:180116563
C/T
0.003 AIRg 17.53 1.64E-06
PEX5L / TTC14
||
rs10830963 11:92708710
MTNR1B
G/C
0.230
DI
-3.40 1.03E-11 rs1387153||
0.69 4.31E-04
rs1387153
11:92673828
FAT3 / MTNR1B||
T/C
0.220
DI
-3.20 1.32E-09 rs10830963||
0.69 7.27E-01
rs2149423
13:36772381 CCDC169-SOHLH2; SOHLH2
G/A
0.315
DI
2.18 3.67E-07
rs3812570
9:139275204
A/C
0.461
DI
-1.87 1.72E-06
SNAPC4
rs523079
3:187615862
T/C
0.069
SG
0.25 1.53E-07
BCL6 / LPP
rs780093
2:27742603
GCKR||
T/C
0.341
SG
0.14 1.12E-06
rs780094||
0.98 1.05E-01
rs788338
19:50778543
C/T
0.287
SG
-0.17 1.66E-06
MYH14
2
Independent signals (r <0.80) with evidence of association (P<2.00E-06) with the nearest annotated RefSeq gene(s) listed. *Build hg19, †Reference
Allele/Other Allele, ‡Reference Allele Frequency, §Correlation from the largest set of unrelated individuals from BetaGene ||Previously identified
T2D locus 42
Page 79 of 127
Diabetes
Supplementary Table 5A. Association with reported type 2 diabetes (T2D) susceptibility loci with MCRI in GUARDIAN Hispanic Americans (nmax=3,787). Index SNPs reaching genome‐wide significance (P<5.0E‐08) for association with T2D were selected from the NHGRI GWAS catalog (http://www.genome.gov/gwastudies). When the index variable was unavailable in GUARDIAN, a suitable proxy was selected using the HapMap 3 MEX (Mexican ancestry in Los Angeles, California) population. Index
SNP
rs10923931
rs2075423
rs17106184
rs6723108
rs7560163
rs7593730
rs3923113
rs7578326
rs2943641
rs780094
rs7578597
rs243021
rs11708067
rs1801282
rs4402960
rs16861329
rs6808574
rs7612463
rs831571
rs4607103
rs7656416
rs6815464
rs6813195
rs1801214
rs702634
rs459193
rs4457053
rs10946398
rs3130501
Ref
1
Proxy
rs2793831
r2
(MEX)
1.00
29
28
rs1278516
1.00
30
2
3
4
5
rs13405357
0.90
rs16861317
1.00
rs35837
0.92
31
29
1
5
29
6
4
28
32
8
1
9
8
28
5
28
33
5
12
28
rs7754840
0.96
Position
(hg19)
Gene(s)
1:120523902
1:212221342
1:50900021
2:135479980
2:151637936
2:161171454
2:165501849
2:227022036
2:227093745
2:27741237
2:43732823
2:60584819
3:123065778
3:12393125
3:185511687
3:186664728
3:187740523
3:23336450
3:64013249
3:64711904
4:1254535
4:1309901
4:153739925
4:6303022
5:53271420
5:55842508
5:76424949
6:20661250
6:31136453
NOTCH2
PROX1
FAF1
TMEM163
RND3 / FABP5P10
RBMS1
EIF3EP3 / SNORA70F
LOC646736
IRS1
GCKR
THADA
BCL11A
ADCY5
PPARG
IGF2BP2
ST6GAL1
LPP
UBE2E2
PSMD6 / PRICKLE2-AS1
ADAMTS9-AS2
CTBP1-AS1 / MAEA
MAEA
TMEM154
WFS1
ARL15
ANKRD55
ZBED3-AS1
CDKAL1
POU5F1-TCF19
43
Alleles
Risk Ref/Alt
T
G
G
T
C
C
A
A
C
C
T
A
A
C
T
G
C
C
C
C
C
C
C
T
A
G
G
C
G
T/C
G/A
T/G
A/G
C/T
C/T
T/C
A/G
A/G
C/G
T/G
G/A
C/T
C/A
C/T
C/T
A/G
G/A
C/G
G/A
Beta
SE
0.05
0.22
0.08
-0.12
-0.16
-0.09
0.12
-0.07
0.03
-0.11
0.05
0.12
-0.01
-0.19
0.05
0.07
-0.02
-0.02
0.16
-0.11
0.09
0.12
0.07
0.06
0.06
0.05
0.11
0.05
0.06
0.08
0.06
0.05
0.06
0.11
0.09
0.05
0.07
0.05
0.05
0.06
Heterogeneity
P-value
Additive
P-value
0.10
0.80
0.71
0.68
0.048
0.24
0.050
0.52
0.18
0.37
0.38
0.92
0.71
0.43
0.081
0.72
0.090
0.77
0.48
0.0087
0.061
0.072
0.012
0.53
0.15
0.82
0.42
0.017
0.20
0.67
0.25
0.0050
0.086
0.52
0.67
0.24
0.31
0.36
0.0025
0.81
Diabetes
rs9470794
rs1535500
rs1048886
rs9505118
rs6467136
rs10229583
rs972283
rs17168486
rs864745
rs10278336
rs13266634
rs515071
rs896854
rs10811661
rs7018475
rs7041847
rs13292136
rs2796441
rs17584499
rs7903146
rs10886471
rs12779790
rs1802295
rs12571751
rs1111875
rs2334499
rs5219
rs231362
rs2237892
rs1552224
rs1387153
rs7305618
rs7957197
rs4275659
rs10842994
rs11063069
8
rs3800364
0.83
8
15
28
8
16
5
29
1
rs1635852
1.00
29
11
9
5
rs508419
rs4735337
1.00
0.81
6
18
8
5
33
20
22
19
1
4
33
11
35
6
5
24
5
5
17
5
28
33
34
rs10882101
1.00
6:38121211
6:39284050
6:71289189
6:7290437
7:127164958
7:127246903
7:130466854
7:14898282
7:28189411
7:44211888
8:118184783
8:41522991
8:95973465
9:22134094
9:22137685
9:4287466
9:81952128
9:84308948
9:8879118
10:114758349
10:121149403
10:12328010
10:70931474
10:80612637
10:94462427
11:1696849
11:17409572
11:2691471
11:2839751
11:72433098
11:92673828
12:121402932
12:121460686
12:123447928
12:27965150
12:4374373
ZFAND3
KCNK16
C6orf57
SSR1-RREB1
ZNF800 / GCC1
FSCN3 / PAX4
KLF14 / MIR29A
DGKB
JAZF1
GCK
SLC30A8
ANK1
TP53INP1
CDKN2B-AS1 / DMRTA1
CDKN2B-AS1 / DMRTA1
GLIS3
KRT18P24 / CHCHD2P9
TLE1
PTPRD
TCF7L2
GRK5
CDC123 / MIR4480
VPS26A
ZMIZ1
HHEX / EXOC6
DUSP8
KCNJ11
KCNQ1;KCNQ1OT1
KCNQ1
ARAP1
FAT3 / MTNR1B
RPL12P33 / HNF1A-AS1
OASL
MPHOSPH9
KLHDC5
CCND2
44
Page 80 of 127
C
T
G
A
G
G
G
T
T
A
C
C
T
T
T
A
C
G
T
T
C
G
A
A
C
T
T
G
C
A
T
C
T
C
C
G
G/A
G/A
A/G
G/A
G/A
T/C
T/C
C/T
G/A
T/C
T/G
G/A
T/C
T/C
C/T
A/G
C/T
T/C
T/C
G/A
C/T
A/C
T/C
C/T
C/T
C/T
G/A
0.04
-0.01
0.05
0.09
-0.02
0.08
-0.06
0.09
0.05
0.04
-0.11
0.07
0.12
0.04
-0.06
-0.10
-0.06
0.05
-0.06
0.09
-0.10
0.12
-0.02
0.10
-0.02
0.02
-0.09
0.12
0.07
0.05
0.07
0.05
0.05
0.07
0.06
0.06
0.05
0.06
0.06
0.06
0.06
0.07
0.06
0.05
0.05
0.05
0.05
0.06
0.11
0.06
0.07
0.05
0.07
0.08
0.82
0.92
0.14
0.88
0.14
0.34
0.68
0.41
0.65
0.83
0.26
0.87
0.82
0.64
0.25
0.43
0.33
0.22
0.93
0.92
0.47
0.14
0.88
0.54
0.32
0.51
0.66
0.94
0.62
0.82
0.27
0.50
0.084
0.16
0.11
0.60
0.33
0.030
0.39
0.11
0.92
0.17
0.064
0.23
0.46
0.27
0.13
0.096
0.12
0.35
0.24
0.25
0.67
0.48
Page 81 of 127
rs1531343
rs2261181
rs7961581
rs9552911
rs1359790
rs7403531
rs7172432
rs7178572
rs11634397
rs2028299
rs8042680
rs8050136
rs7202877
rs391300
rs13342232
rs4430796
rs12970134
rs8090011
rs10401969
rs3786897
rs6017317
rs4812829
rs12010175
rs5945326
Diabetes
5
rs2612067
1.00
5
1
26
23
19
27
4
rs11857294
0.86
5
4
5
12
33
20
36
19
33
14
33
8
8
4
rs2144908
19
5
1.00
12:66170163
12:66212318
12:71663102
13:23864657
13:80717156
15:38822905
15:62396389
15:77596725
15:80432222
15:90374257
15:91521337
16:53816275
16:75247245
17:2216258
17:6945940
17:36098040
18:57884750
18:7068462
19:19407718
19:33893008
20:42946966
20:42985717
X:152862638
X:152899922
RPSAP52
HMGA2
TSPAN8 / LGR5
SGCG
NDFIP2 / SPRY2
RASGRP1
C2CD4A / C2CD4B
HMG20A
ZFAND6 / FAH
AP3S2;C15orf38-AP3S2
PRC1
FTO
BCAR1
SRR
SLC16A11
HNF1B
MC4R
LAMA1
CILP2
PEPD
FITM2 / R3HDML
HNF4A
FAM58A
KRT18P48 / DUSP9
45
C
T
C
G
G
T
A
G
G
C
A
A
T
G
G
G
A
G
C
A
G
A
G
A
G/T
T/C
C/T
T/C
C/T
G/A
C/A
A/C
A/C
T/G
G/A
G/A
A/G
C/T
A/G
A/G
-
0.08
0.06
-0.11
0.02
-0.10
0.13
0.09
0.03
-0.14
0.17
-0.02
0.05
-0.08
0.04
0.03
0.04
-
0.10
0.11
0.07
0.05
0.05
0.05
0.06
0.05
0.06
0.10
0.05
0.05
0.07
0.13
0.06
0.05
-
0.73
0.94
0.20
0.20
0.035
0.054
0.26
0.082
0.019
0.46
0.10
0.89
0.26
0.016
0.68
0.66
-
0.15
0.40
0.11
0.24
0.0053
0.093
0.51
0.33
0.34
0.057
0.99
0.28
0.16
0.95
0.18
0.20
-
Diabetes
Page 82 of 127
Supplementary Table 5B. Association with reported type 2 diabetes (T2D) susceptibility loci with SI+M in GUARDIAN Hispanic Americans (nmax=4,153). Index SNPs reaching genome‐wide significance (P<5.0E‐08) for association with T2D were selected from the NHGRI GWAS catalog (http://www.genome.gov/gwastudies). When the index SNP was unavailable in GUARDIAN, a suitable proxy was selected using the HapMap 3 MEX (Mexican ancestry in Los Angeles, California) population. Index
SNP
rs10923931
rs2075423
rs17106184
rs6723108
rs7560163
rs7593730
rs3923113
rs7578326
rs2943641
rs780094
rs7578597
rs243021
rs11708067
rs1801282
rs4402960
rs16861329
rs6808574
rs7612463
rs831571
rs4607103
rs7656416
rs6815464
rs6813195
rs1801214
rs702634
rs459193
rs4457053
rs10946398
rs3130501
Ref
1
Proxy
rs2793831
r2
(MEX)
1.00
29
28
rs1278516
1.00
30
2
3
4
5
rs13405357
0.90
rs16861317
1.00
rs35837
0.92
31
29
1
5
29
6
4
28
32
8
1
9
8
28
5
28
33
5
12
28
rs7754840
0.96
Position
(hg19)
Gene(s)
1:120523902
1:212221342
1:50900021
2:135479980
2:151637936
2:161171454
2:165501849
2:227022036
2:227093745
2:27741237
2:43732823
2:60584819
3:123065778
3:12393125
3:185511687
3:186664728
3:187740523
3:23336450
3:64013249
3:64711904
4:1254535
4:1309901
4:153739925
4:6303022
5:53271420
5:55842508
5:76424949
6:20661250
6:31136453
NOTCH2
PROX1
FAF1
TMEM163
RND3 / FABP5P10
RBMS1
EIF3EP3 / SNORA70F
LOC646736
IRS1
GCKR
THADA
BCL11A
ADCY5
PPARG
IGF2BP2
ST6GAL1
LPP
UBE2E2
PSMD6 / PRICKLE2-AS1
ADAMTS9-AS2
CTBP1-AS1 / MAEA
MAEA
TMEM154
WFS1
ARL15
ANKRD55
ZBED3-AS1
CDKAL1
POU5F1-TCF19
46
Alleles
Risk Ref/Alt
T
G
G
T
C
C
A
A
C
C
T
A
A
C
T
G
C
C
C
C
C
C
C
T
A
G
G
C
G
T/C
G/A
T/G
A/G
C/T
C/T
T/C
A/G
A/G
C/G
T/G
G/A
C/T
C/A
C/T
C/T
A/G
G/A
C/G
G/A
Beta
SE
0.22
-0.70
-1.67
2.44
0.85
-1.09
3.69
1.24
0.51
2.70
-0.01
0.07
-1.95
-2.64
-0.74
-2.29
-4.60
0.88
0.52
1.43
2.46
3.64
2.45
1.94
2.11
1.72
3.65
1.69
1.89
2.75
1.98
1.80
2.14
3.13
2.90
1.76
2.22
1.71
1.77
1.95
Heterogeneity
P-value
Additive
P-value
0.82
0.55
0.26
0.73
0.60
0.16
0.098
0.15
0.53
0.76
0.64
0.95
0.072
0.66
0.26
0.71
0.41
0.041
0.79
0.0081
0.75
0.85
0.24
0.10
0.099
0.99
0.94
0.12
0.47
0.51
0.12
0.14
0.12
0.52
0.97
0.03
0.73
0.94
0.019
0.57
Page 83 of 127
rs9470794
rs1535500
rs1048886
rs9505118
rs6467136
rs10229583
rs972283
rs17168486
rs864745
rs10278336
rs13266634
rs515071
rs896854
rs10811661
rs7018475
rs7041847
rs13292136
rs2796441
rs17584499
rs7903146
rs10886471
rs12779790
rs1802295
rs12571751
rs1111875
rs2334499
rs5219
rs231362
rs2237892
rs1552224
rs1387153
rs7305618
rs7957197
rs4275659
rs10842994
rs11063069
Diabetes
8
rs3800364
0.83
8
15
28
8
16
5
29
1
rs1635852
1.00
29
11
9
5
rs508419
rs4735337
1.00
0.81
6
18
8
5
33
20
22
19
1
4
33
11
35
6
5
24
5
5
17
5
28
33
34
rs10882101
1.00
6:38121211
6:39284050
6:71289189
6:7290437
7:127164958
7:127246903
7:130466854
7:14898282
7:28189411
7:44211888
8:118184783
8:41522991
8:95973465
9:22134094
9:22137685
9:4287466
9:81952128
9:84308948
9:8879118
10:114758349
10:121149403
10:12328010
10:70931474
10:80612637
10:94462427
11:1696849
11:17409572
11:2691471
11:2839751
11:72433098
11:92673828
12:121402932
12:121460686
12:123447928
12:27965150
12:4374373
ZFAND3
KCNK16
C6orf57
SSR1-RREB1
ZNF800 / GCC1
FSCN3 / PAX4
KLF14 / MIR29A
DGKB
JAZF1
GCK
SLC30A8
ANK1
TP53INP1
CDKN2B-AS1 / DMRTA1
CDKN2B-AS1 / DMRTA1
GLIS3
KRT18P24 / CHCHD2P9
TLE1
PTPRD
TCF7L2
GRK5
CDC123 / MIR4480
VPS26A
ZMIZ1
HHEX / EXOC6
DUSP8
KCNJ11
KCNQ1;KCNQ1OT1
KCNQ1
ARAP1
FAT3 / MTNR1B
RPL12P33 / HNF1A-AS1
OASL
MPHOSPH9
KLHDC5
CCND2
47
C
T
G
A
G
G
G
T
T
A
C
C
T
T
T
A
C
G
T
T
C
G
A
A
C
T
T
G
C
A
T
C
T
C
C
G
G/A
G/A
A/G
G/A
G/A
T/C
T/C
C/T
G/A
T/C
T/G
G/A
T/C
T/C
C/T
A/G
C/T
T/C
T/C
G/A
C/T
A/C
T/C
C/T
C/T
C/T
G/A
4.43
-0.15
1.09
-1.64
-2.74
1.28
-4.20
1.25
1.83
2.08
-1.75
-2.14
-1.01
0.33
-0.16
-4.82
-0.79
-2.48
2.75
-0.81
1.75
3.34
-2.52
1.20
0.55
-1.58
-1.71
3.25
2.09
1.67
2.24
1.67
1.68
1.62
1.92
2.09
1.54
1.79
1.65
1.98
1.87
1.48
1.94
1.72
1.59
1.71
1.79
1.84
3.15
1.87
2.15
1.64
2.47
2.31
0.99
0.40
0.095
0.73
0.49
0.71
0.41
0.10
0.94
0.67
0.97
0.41
0.15
0.76
0.60
0.32
0.13
0.16
0.19
0.23
0.36
0.47
0.61
0.90
0.61
0.079
0.99
0.022
0.36
0.90
0.80
0.014
0.21
0.068
0.21
0.73
0.35
0.22
0.86
0.41
0.34
0.30
0.0094
0.66
0.31
0.85
0.18
0.48
0.31
0.013
0.084
0.37
0.95
0.15
Diabetes
rs1531343
rs2261181
rs7961581
rs9552911
rs1359790
rs7403531
rs7172432
rs7178572
rs11634397
rs2028299
rs8042680
rs8050136
rs7202877
rs391300
rs13342232
rs4430796
rs12970134
rs8090011
rs10401969
rs3786897
rs6017317
rs4812829
rs12010175
rs5945326
5
rs2612067
1.00
5
1
26
23
19
27
4
rs11857294
0.86
5
4
5
12
33
20
36
19
33
14
33
8
8
4
rs2144908
19
5
1.00
12:66170163
12:66212318
12:71663102
13:23864657
13:80717156
15:38822905
15:62396389
15:77596725
15:80432222
15:90374257
15:91521337
16:53816275
16:75247245
17:2216258
17:6945940
17:36098040
18:57884750
18:7068462
19:19407718
19:33893008
20:42946966
20:42985717
X:152862638
X:152899922
RPSAP52
HMGA2
TSPAN8 / LGR5
SGCG
NDFIP2 / SPRY2
RASGRP1
C2CD4A / C2CD4B
HMG20A
ZFAND6 / FAH
AP3S2;C15orf38-AP3S2
PRC1
FTO
BCAR1
SRR
SLC16A11
HNF1B
MC4R
LAMA1
CILP2
PEPD
FITM2 / R3HDML
HNF4A
FAM58A
KRT18P48 / DUSP9
48
Page 84 of 127
C
T
C
G
G
T
A
G
G
C
A
A
T
G
G
G
A
G
C
A
G
A
G
A
G/T
T/C
C/T
T/C
C/T
G/A
C/A
A/C
A/C
T/G
G/A
G/A
A/G
C/T
A/G
A/G
-
-0.11
0.01
-4.73
0.47
-2.51
1.41
1.75
2.33
-4.64
-0.79
1.39
1.87
1.96
4.84
-4.10
3.58
-
3.01
3.29
2.20
1.70
1.70
1.55
2.24
1.83
1.93
2.89
1.71
1.69
2.36
3.67
1.89
1.72
-
0.30
0.52
0.051
0.58
0.40
0.79
0.94
0.17
0.78
0.16
0.31
0.36
0.36
0.015
0.10
0.56
-
0.26
0.45
0.094
0.63
0.067
0.14
0.017
0.25
0.0019
0.62
0.24
0.16
0.65
0.48
0.85
0.0046
-
Page 85 of 127
Diabetes
Supplementary Table 5C. Association with reported type 2 diabetes (T2D) susceptibility loci with SI in GUARDIAN Hispanic Americans (nmax=2,549). Index SNPs reaching genome‐wide significance (P<5.0E‐08) for association with T2D were selected from the NHGRI GWAS catalog (http://www.genome.gov/gwastudies). When the index variable was unavailable in GUARDIAN, a suitable proxy was selected using the HapMap 3 MEX (Mexican ancestry in Los Angeles, California) population. Index
SNP
rs10923931
rs2075423
rs17106184
rs6723108
rs7560163
rs7593730
rs3923113
rs7578326
rs2943641
rs780094
rs7578597
rs243021
rs11708067
rs1801282
rs4402960
rs16861329
rs6808574
rs7612463
rs831571
rs4607103
rs7656416
rs6815464
rs6813195
rs1801214
rs702634
rs459193
rs4457053
rs10946398
rs3130501
Ref
1
Proxy
rs2793831
r2
(MEX)
1.00
29
28
rs1278516
1.00
30
2
3
4
5
rs13405357
0.90
rs16861317
1.00
rs35837
0.92
31
29
1
5
29
6
4
28
32
8
1
9
8
28
5
28
33
5
12
28
rs7754840
0.96
Position
(hg19)
Gene(s)
1:120523902
1:212221342
1:50900021
2:135479980
2:151637936
2:161171454
2:165501849
2:227022036
2:227093745
2:27741237
2:43732823
2:60584819
3:123065778
3:12393125
3:185511687
3:186664728
3:187740523
3:23336450
3:64013249
3:64711904
4:1254535
4:1309901
4:153739925
4:6303022
5:53271420
5:55842508
5:76424949
6:20661250
6:31136453
NOTCH2
PROX1
FAF1
TMEM163
RND3 / FABP5P10
RBMS1
EIF3EP3 / SNORA70F
LOC646736
IRS1
GCKR
THADA
BCL11A
ADCY5
PPARG
IGF2BP2
ST6GAL1
LPP
UBE2E2
PSMD6 / PRICKLE2-AS1
ADAMTS9-AS2
CTBP1-AS1 / MAEA
MAEA
TMEM154
WFS1
ARL15
ANKRD55
ZBED3-AS1
CDKAL1
POU5F1-TCF19
49
Alleles
Risk Ref/Alt
T
G
G
T
C
C
A
A
C
C
T
A
A
C
T
G
C
C
C
C
C
C
C
T
A
G
G
C
G
T/C
G/A
T/G
A/G
C/T
C/T
T/C
A/G
A/G
C/G
T/G
G/A
C/T
C/A
C/T
C/T
A/G
G/A
C/G
G/A
Beta
SE
-0.01
0.07
0.02
-0.06
-0.12
-0.05
0.15
0.02
-0.07
-0.12
-0.02
0.04
0.09
0.01
0.02
0.04
-0.07
-0.02
0.08
-0.07
0.09
0.14
0.07
0.06
0.07
0.06
0.11
0.06
0.07
0.09
0.06
0.06
0.07
0.11
0.09
0.06
0.07
0.06
0.06
0.07
Heterogeneity
P-value
Additive
P-value
0.77
0.45
0.13
0.23
0.092
0.031
0.12
0.23
0.16
0.73
0.18
0.94
0.054
0.56
0.43
0.59
0.70
0.31
0.77
0.00094
0.46
0.85
0.23
0.89
0.34
0.92
0.90
0.083
0.26
0.54
0.036
0.18
0.21
0.25
0.93
0.021
0.54
0.99
0.015
0.74
Diabetes
rs9470794
rs1535500
rs1048886
rs9505118
rs6467136
rs10229583
rs972283
rs17168486
rs864745
rs10278336
rs13266634
rs515071
rs896854
rs10811661
rs7018475
rs7041847
rs13292136
rs2796441
rs17584499
rs7903146
rs10886471
rs12779790
rs1802295
rs12571751
rs1111875
rs2334499
rs5219
rs231362
rs2237892
rs1552224
rs1387153
rs7305618
rs7957197
rs4275659
rs10842994
rs11063069
8
rs3800364
0.83
8
15
28
8
16
5
29
1
rs1635852
1.00
29
11
9
5
rs508419
rs4735337
1.00
0.81
6
18
8
5
33
20
22
19
1
4
33
11
35
6
5
24
5
5
17
5
28
33
34
rs10882101
1.00
6:38121211
6:39284050
6:71289189
6:7290437
7:127164958
7:127246903
7:130466854
7:14898282
7:28189411
7:44211888
8:118184783
8:41522991
8:95973465
9:22134094
9:22137685
9:4287466
9:81952128
9:84308948
9:8879118
10:114758349
10:121149403
10:12328010
10:70931474
10:80612637
10:94462427
11:1696849
11:17409572
11:2691471
11:2839751
11:72433098
11:92673828
12:121402932
12:121460686
12:123447928
12:27965150
12:4374373
ZFAND3
KCNK16
C6orf57
SSR1-RREB1
ZNF800 / GCC1
FSCN3 / PAX4
KLF14 / MIR29A
DGKB
JAZF1
GCK
SLC30A8
ANK1
TP53INP1
CDKN2B-AS1 / DMRTA1
CDKN2B-AS1 / DMRTA1
GLIS3
KRT18P24 / CHCHD2P9
TLE1
PTPRD
TCF7L2
GRK5
CDC123 / MIR4480
VPS26A
ZMIZ1
HHEX / EXOC6
DUSP8
KCNJ11
KCNQ1;KCNQ1OT1
KCNQ1
ARAP1
FAT3 / MTNR1B
RPL12P33 / HNF1A-AS1
OASL
MPHOSPH9
KLHDC5
CCND2
50
Page 86 of 127
C
T
G
A
G
G
G
T
T
A
C
C
T
T
T
A
C
G
T
T
C
G
A
A
C
T
T
G
C
A
T
C
T
C
C
G
G/A
G/A
A/G
G/A
G/A
T/C
T/C
C/T
G/A
T/C
T/G
G/A
T/C
T/C
C/T
A/G
C/T
T/C
T/C
G/A
C/T
A/C
T/C
C/T
C/T
C/T
G/A
0.21
0.08
-0.11
0.09
-0.06
0.09
-0.03
0.10
0.02
-0.03
-0.04
0.03
0.12
0.03
-0.09
-0.07
-0.05
-0.09
-0.03
0.15
0.03
-0.02
-0.16
0.06
-0.09
0.02
-0.05
0.12
0.08
0.06
0.08
0.06
0.06
0.06
0.07
0.07
0.06
0.06
0.06
0.07
0.06
0.06
0.07
0.06
0.06
0.06
0.06
0.07
0.10
0.07
0.08
0.06
0.08
0.08
0.91
0.42
0.063
0.75
0.24
0.65
0.82
0.021
0.86
0.54
0.79
0.56
0.83
0.39
0.47
0.86
0.17
0.088
0.57
0.21
0.19
0.38
0.33
0.82
0.66
0.38
0.90
0.061
0.37
0.65
0.37
0.047
0.22
0.44
0.24
0.74
0.87
0.40
0.30
0.10
0.27
0.26
0.085
0.54
0.96
0.11
0.036
0.85
0.65
0.032
0.12
0.23
0.96
0.21
Page 87 of 127
rs1531343
rs2261181
rs7961581
rs9552911
rs1359790
rs7403531
rs7172432
rs7178572
rs11634397
rs2028299
rs8042680
rs8050136
rs7202877
rs391300
rs13342232
rs4430796
rs12970134
rs8090011
rs10401969
rs3786897
rs6017317
rs4812829
rs12010175
rs5945326
Diabetes
5
rs2612067
1.00
5
1
26
23
19
27
4
rs11857294
0.86
5
4
5
12
33
20
36
19
33
14
33
8
8
4
rs2144908
19
5
1.00
12:66170163
12:66212318
12:71663102
13:23864657
13:80717156
15:38822905
15:62396389
15:77596725
15:80432222
15:90374257
15:91521337
16:53816275
16:75247245
17:2216258
17:6945940
17:36098040
18:57884750
18:7068462
19:19407718
19:33893008
20:42946966
20:42985717
X:152862638
X:152899922
RPSAP52
HMGA2
TSPAN8 / LGR5
SGCG
NDFIP2 / SPRY2
RASGRP1
C2CD4A / C2CD4B
HMG20A
ZFAND6 / FAH
AP3S2;C15orf38-AP3S2
PRC1
FTO
BCAR1
SRR
SLC16A11
HNF1B
MC4R
LAMA1
CILP2
PEPD
FITM2 / R3HDML
HNF4A
FAM58A
KRT18P48 / DUSP9
51
C
T
C
G
G
T
A
G
G
C
A
A
T
G
G
G
A
G
C
A
G
A
G
A
G/T
T/C
C/T
T/C
C/T
G/A
C/A
A/C
A/C
T/G
G/A
G/A
A/G
C/T
A/G
A/G
-
0.23
0.18
0.07
0.00
-0.04
0.06
0.11
-0.07
-0.12
-0.03
0.08
-0.04
0.03
0.14
0.04
0.12
-
0.11
0.11
0.07
0.06
0.06
0.06
0.07
0.06
0.07
0.11
0.06
0.06
0.08
0.15
0.06
0.06
-
0.14
0.32
0.05
0.80
0.95
0.89
0.87
0.065
0.58
0.066
0.17
0.18
0.22
0.12
0.36
0.35
-
0.19
0.37
0.44
0.51
0.19
0.22
0.024
0.53
0.026
0.42
0.53
0.48
0.87
0.82
0.20
0.076
-
Diabetes
Page 88 of 127
Supplementary Table 5D. Association with reported type 2 diabetes (T2D) susceptibility loci with M in GUARDIAN Hispanic Americans (nmax=1604). Index SNPs reaching genome‐wide significance (P<5.0E‐08) for association with T2D were selected from the NHGRI GWAS catalog (http://www.genome.gov/gwastudies). When the index variable was unavailable in GUARDIAN, a suitable proxy was selected using the HapMap 3 MEX (Mexican ancestry in Los Angeles, California) population. Index
SNP
rs10923931
rs2075423
rs17106184
rs6723108
rs7560163
rs7593730
rs3923113
rs7578326
rs2943641
rs780094
rs7578597
rs243021
rs11708067
rs1801282
rs4402960
rs16861329
rs6808574
rs7612463
rs831571
rs4607103
rs7656416
rs6815464
rs6813195
rs1801214
rs702634
rs459193
rs4457053
rs10946398
rs3130501
Ref
1
Proxy
rs2793831
r2
(MEX)
1.00
29
28
rs1278516
1.00
30
2
3
4
5
rs13405357
0.90
rs16861317
1.00
rs35837
0.92
31
29
1
5
29
6
4
28
32
8
1
9
8
28
5
28
33
5
12
28
rs7754840
0.96
Position
(hg19)
Gene(s)
1:120523902
1:212221342
1:50900021
2:135479980
2:151637936
2:161171454
2:165501849
2:227022036
2:227093745
2:27741237
2:43732823
2:60584819
3:123065778
3:12393125
3:185511687
3:186664728
3:187740523
3:23336450
3:64013249
3:64711904
4:1254535
4:1309901
4:153739925
4:6303022
5:53271420
5:55842508
5:76424949
6:20661250
6:31136453
NOTCH2
PROX1
FAF1
TMEM163
RND3 / FABP5P10
RBMS1
EIF3EP3 / SNORA70F
LOC646736
IRS1
GCKR
THADA
BCL11A
ADCY5
PPARG
IGF2BP2
ST6GAL1
LPP
UBE2E2
PSMD6 / PRICKLE2-AS1
ADAMTS9-AS2
CTBP1-AS1 / MAEA
MAEA
TMEM154
WFS1
ARL15
ANKRD55
ZBED3-AS1
CDKAL1
POU5F1-TCF19
52
Alleles
Risk Ref/Alt
T
G
G
T
C
C
A
A
C
C
T
A
A
C
T
G
C
C
C
C
C
C
C
T
A
G
G
C
G
T/C
G/A
T/G
A/G
C/T
C/T
T/C
A/G
A/G
C/G
T/G
G/A
C/T
C/A
C/T
C/T
A/G
G/A
C/G
G/A
Beta
SE
0.62
-2.03
-4.00
5.87
2.18
-2.51
8.55
2.90
1.30
6.58
0.00
0.10
-4.75
-7.18
-1.79
-5.49
-10.81
2.12
1.13
3.49
6.68
9.91
5.82
4.59
5.00
4.09
8.66
4.02
4.48
6.52
4.70
4.28
5.08
8.49
6.88
4.18
5.28
4.06
4.21
4.62
Heterogeneity
P-value
Additive
P-value
0.35
1.00
0.88
0.35
0.20
0.63
0.48
0.40
0.45
0.96
0.36
0.85
0.64
0.15
0.40
0.94
0.40
0.044
0.43
0.93
0.67
0.75
0.48
0.058
0.11
0.91
0.54
0.48
0.47
0.70
0.45
0.12
0.20
0.88
0.72
0.11
0.76
0.60
0.72
0.23
Page 89 of 127
rs9470794
rs1535500
rs1048886
rs9505118
rs6467136
rs10229583
rs972283
rs17168486
rs864745
rs10278336
rs13266634
rs515071
rs896854
rs10811661
rs7018475
rs7041847
rs13292136
rs2796441
rs17584499
rs7903146
rs10886471
rs12779790
rs1802295
rs12571751
rs1111875
rs2334499
rs5219
rs231362
rs2237892
rs1552224
rs1387153
rs7305618
rs7957197
rs4275659
rs10842994
rs11063069
Diabetes
8
rs3800364
0.83
8
15
28
8
16
5
29
1
rs1635852
1.00
29
11
9
5
rs508419
rs4735337
1.00
0.81
6
18
8
5
33
20
22
19
1
4
33
11
35
6
5
24
5
5
17
5
28
33
34
rs10882101
1.00
6:38121211
6:39284050
6:71289189
6:7290437
7:127164958
7:127246903
7:130466854
7:14898282
7:28189411
7:44211888
8:118184783
8:41522991
8:95973465
9:22134094
9:22137685
9:4287466
9:81952128
9:84308948
9:8879118
10:114758349
10:121149403
10:12328010
10:70931474
10:80612637
10:94462427
11:1696849
11:17409572
11:2691471
11:2839751
11:72433098
11:92673828
12:121402932
12:121460686
12:123447928
12:27965150
12:4374373
ZFAND3
KCNK16
C6orf57
SSR1-RREB1
ZNF800 / GCC1
FSCN3 / PAX4
KLF14 / MIR29A
DGKB
JAZF1
GCK
SLC30A8
ANK1
TP53INP1
CDKN2B-AS1 / DMRTA1
CDKN2B-AS1 / DMRTA1
GLIS3
KRT18P24 / CHCHD2P9
TLE1
PTPRD
TCF7L2
GRK5
CDC123 / MIR4480
VPS26A
ZMIZ1
HHEX / EXOC6
DUSP8
KCNJ11
KCNQ1;KCNQ1OT1
KCNQ1
ARAP1
FAT3 / MTNR1B
RPL12P33 / HNF1A-AS1
OASL
MPHOSPH9
KLHDC5
CCND2
53
C
T
G
A
G
G
G
T
T
A
C
C
T
T
T
A
C
G
T
T
C
G
A
A
C
T
T
G
C
A
T
C
T
C
C
G
G/A
G/A
A/G
G/A
G/A
T/C
T/C
C/T
G/A
T/C
T/G
G/A
T/C
T/C
C/T
A/G
C/T
T/C
T/C
G/A
C/T
A/C
T/C
C/T
C/T
C/T
G/A
11.70
-0.45
2.75
-4.01
-6.42
2.91
-13.90
2.83
4.32
5.71
-4.11
-7.03
-2.55
0.75
-0.41
-11.34
-1.81
-5.77
6.57
-2.12
4.11
7.96
-6.57
2.77
1.42
-3.78
-4.55
8.83
4.96
3.97
5.32
3.96
3.99
5.39
4.57
4.95
4.18
4.24
5.36
4.69
4.45
6.44
4.60
4.08
3.77
4.05
4.24
4.36
7.47
5.08
5.10
3.89
5.86
6.28
0.93
0.19
0.26
0.56
0.53
0.37
0.20
0.71
0.94
0.74
0.93
0.86
0.053
0.97
1.00
0.050
0.10
0.55
0.55
0.66
0.47
0.32
0.83
0.56
0.32
0.016
0.95
0.19
0.73
0.44
0.47
0.15
0.63
0.021
0.60
0.34
0.18
0.36
0.17
0.45
0.87
0.95
0.045
0.96
0.12
0.083
0.64
0.37
0.28
0.20
0.41
0.96
0.87
0.46
Diabetes
rs1531343
rs2261181
rs7961581
rs9552911
rs1359790
rs7403531
rs7172432
rs7178572
rs11634397
rs2028299
rs8042680
rs8050136
rs7202877
rs391300
rs13342232
rs4430796
rs12970134
rs8090011
rs10401969
rs3786897
rs6017317
rs4812829
rs12010175
rs5945326
5
rs2612067
1.00
5
1
26
23
19
27
4
rs11857294
0.86
5
4
5
12
33
20
36
19
33
14
33
8
8
4
rs2144908
19
5
1.00
12:66170163
12:66212318
12:71663102
13:23864657
13:80717156
15:38822905
15:62396389
15:77596725
15:80432222
15:90374257
15:91521337
16:53816275
16:75247245
17:2216258
17:6945940
17:36098040
18:57884750
18:7068462
19:19407718
19:33893008
20:42946966
20:42985717
X:152862638
X:152899922
RPSAP52
HMGA2
TSPAN8 / LGR5
SGCG
NDFIP2 / SPRY2
RASGRP1
C2CD4A / C2CD4B
HMG20A
ZFAND6 / FAH
AP3S2;C15orf38-AP3S2
PRC1
FTO
BCAR1
SRR
SLC16A11
HNF1B
MC4R
LAMA1
CILP2
PEPD
FITM2 / R3HDML
HNF4A
FAM58A
KRT18P48 / DUSP9
54
Page 90 of 127
C
T
C
G
G
T
A
G
G
C
A
A
T
G
G
G
A
G
C
A
G
A
G
A
G/T
T/C
C/T
T/C
C/T
G/A
C/A
A/C
A/C
T/G
G/A
G/A
A/G
C/T
A/G
A/G
-
-0.58
-0.23
-11.34
1.10
-5.90
3.75
4.00
5.63
-10.84
-2.10
3.19
4.48
4.60
12.91
-9.78
8.33
-
7.15
7.80
5.21
4.03
4.04
4.20
5.32
4.35
4.58
7.86
4.05
4.00
5.60
9.96
4.48
4.09
-
0.51
0.49
0.14
0.17
0.054
0.18
0.73
0.44
0.57
0.60
0.40
0.52
0.46
0.0049
0.35
0.58
-
0.88
0.94
0.09
0.96
0.20
0.42
0.32
0.28
0.028
0.81
0.28
0.17
0.35
0.38
0.054
0.020
-
Page 91 of 127
Diabetes
Supplementary Table 5E. Association with reported type 2 diabetes (T2D) susceptibility loci with AIRg in GUARDIAN Hispanic Americans (nmax=2,548). Index SNPs reaching genome‐wide significance (P<5.0E‐08) for association with T2D were selected from the NHGRI GWAS catalog (http://www.genome.gov/gwastudies). When the index variable was unavailable in GUARDIAN, a suitable proxy was selected using the HapMap 3 MEX (Mexican ancestry in Los Angeles, California) population. Index
SNP
rs10923931
rs2075423
rs17106184
rs6723108
rs7560163
rs7593730
rs3923113
rs7578326
rs2943641
rs780094
rs7578597
rs243021
rs11708067
rs1801282
rs4402960
rs16861329
rs6808574
rs7612463
rs831571
rs4607103
rs7656416
rs6815464
rs6813195
rs1801214
rs702634
rs459193
rs4457053
rs10946398
rs3130501
Ref
1
Proxy
rs2793831
r2
(MEX)
1.00
29
28
rs1278516
1.00
30
2
3
4
5
rs13405357
0.90
31
29
1
5
29
6
4
rs16861317
1.00
rs35837
0.92
28
32
8
1
9
8
28
5
28
33
5
12
28
rs7754840
0.96
Position
(hg19)
Gene(s)
1:120523902
1:212221342
1:50900021
2:135479980
2:151637936
2:161171454
2:165501849
2:227022036
2:227093745
2:27741237
2:43732823
2:60584819
NOTCH2
PROX1
FAF1
TMEM163
RND3 / FABP5P10
RBMS1
EIF3EP3 / SNORA70F
LOC646736
IRS1
GCKR
THADA
BCL11A
T
G
G
T
C
C
A
A
C
C
T
A
3:123065778
3:12393125
3:185511687
3:186664728
3:187740523
3:23336450
3:64013249
3:64711904
4:1254535
4:1309901
4:153739925
4:6303022
5:53271420
5:55842508
5:76424949
6:20661250
6:31136453
ADCY5
PPARG
IGF2BP2
ST6GAL1
LPP
UBE2E2
PSMD6 / PRICKLE2-AS1
ADAMTS9-AS2
CTBP1-AS1 / MAEA
MAEA
TMEM154
WFS1
ARL15
ANKRD55
ZBED3-AS1
CDKAL1
POU5F1-TCF19
A
C
T
G
C
C
C
C
C
C
C
T
A
G
G
C
G
55
Alleles
Risk Ref/Alt
Beta
SE
T/C
G/A
T/G
A/G
C/T
C/T
T/C
A/G
-0.81
-1.32
-0.21
0.03
0.23
-0.61
-0.77
0.31
0.49
0.77
0.45
0.35
0.39
0.32
0.63
0.32
A/G
C/G
T/G
G/A
C/T
C/A
C/T
C/T
A/G
G/A
C/G
G/A
-1.01
1.05
-0.76
-0.25
-0.26
1.26
0.46
0.36
-0.26
-0.69
-1.26
0.10
0.37
0.49
0.35
0.34
0.39
0.61
0.52
0.34
0.41
0.33
0.33
0.38
Heterogeneity
P-value
Additive
P-value
0.25
0.14
0.021
0.30
0.63
0.42
0.16
0.29
0.52
8.85E05
0.013
0.016
0.12
0.26
0.20
0.99
0.093
0.45
0.027
3.8E-06
0.64
0.64
0.65
0.30
0.94
0.45
0.52
0.66
0.097
0.66
0.81
0.32
0.20
0.11
0.011
0.64
0.28
0.71
0.72
0.81
Diabetes
rs9470794
rs1535500
rs1048886
rs9505118
rs6467136
rs10229583
rs972283
rs17168486
rs864745
rs10278336
rs13266634
rs515071
rs896854
rs10811661
rs7018475
rs7041847
rs13292136
rs2796441
rs17584499
rs7903146
rs10886471
rs12779790
rs1802295
rs12571751
rs1111875
rs2334499
rs5219
rs231362
rs2237892
rs1552224
rs1387153
rs7305618
rs7957197
rs4275659
rs10842994
rs11063069
8
rs3800364
0.83
8
15
28
8
16
5
29
1
rs1635852
1.00
29
11
9
5
rs508419
rs4735337
1.00
0.81
6
18
8
5
33
20
22
19
1
4
33
11
35
6
5
24
5
5
17
5
28
33
34
rs10882101
1.00
6:38121211
6:39284050
6:71289189
6:7290437
7:127164958
7:127246903
7:130466854
7:14898282
7:28189411
7:44211888
8:118184783
8:41522991
8:95973465
9:22134094
9:22137685
9:4287466
9:81952128
9:84308948
9:8879118
10:114758349
10:121149403
10:12328010
10:70931474
10:80612637
10:94462427
11:1696849
11:17409572
11:2691471
11:2839751
11:72433098
11:92673828
12:121402932
12:121460686
12:123447928
12:27965150
12:4374373
ZFAND3
KCNK16
C6orf57
SSR1-RREB1
ZNF800 / GCC1
FSCN3 / PAX4
KLF14 / MIR29A
DGKB
JAZF1
GCK
SLC30A8
ANK1
TP53INP1
CDKN2B-AS1 / DMRTA1
CDKN2B-AS1 / DMRTA1
GLIS3
KRT18P24 / CHCHD2P9
TLE1
PTPRD
TCF7L2
GRK5
CDC123 / MIR4480
VPS26A
ZMIZ1
HHEX / EXOC6
DUSP8
KCNJ11
KCNQ1;KCNQ1OT1
KCNQ1
ARAP1
FAT3 / MTNR1B
RPL12P33 / HNF1A-AS1
OASL
MPHOSPH9
KLHDC5
CCND2
56
Page 92 of 127
C
T
G
A
G
G
G
T
T
A
C
C
T
T
T
A
C
G
T
T
C
G
A
A
C
T
T
G
C
A
T
C
T
C
C
G
G/A
G/A
A/G
G/A
G/A
T/C
T/C
C/T
G/A
T/C
T/G
G/A
T/C
T/C
C/T
A/G
C/T
T/C
T/C
G/A
C/T
A/C
T/C
C/T
C/T
C/T
G/A
0.66
0.07
0.14
-1.12
-0.11
-0.78
0.06
-0.50
-0.30
-0.25
1.64
-0.31
-1.27
-1.03
0.43
0.51
0.29
0.19
-0.10
-0.29
-0.73
-1.71
-1.99
-1.60
0.53
-0.94
-0.17
0.69
0.41
0.33
0.43
0.33
0.33
0.33
0.37
0.40
0.31
0.34
0.31
0.38
0.36
0.32
0.37
0.33
0.32
0.32
0.34
0.36
0.62
0.36
0.45
0.32
0.44
0.49
0.80
0.044
0.14
0.58
0.31
0.70
0.79
0.30
0.93
0.54
0.18
0.68
0.20
0.090
0.45
0.91
0.58
0.025
0.91
0.30
0.053
0.89
0.43
0.30
0.67
0.41
0.24
0.50
0.61
0.64
0.0028
0.94
0.033
0.83
0.021
0.61
0.35
4.9E-06
0.46
0.0037
2.5E-04
0.15
0.17
0.51
0.55
0.86
0.49
0.0077
0.0015
2.3E-08
5.8E-04
0.18
0.11
0.60
Page 93 of 127
rs1531343
rs2261181
rs7961581
rs9552911
rs1359790
rs7403531
rs7172432
rs7178572
rs11634397
rs2028299
rs8042680
rs8050136
rs7202877
rs391300
rs13342232
rs4430796
rs12970134
rs8090011
rs10401969
rs3786897
rs6017317
rs4812829
rs12010175
rs5945326
Diabetes
5
rs2612067
1.00
5
1
26
23
19
27
4
rs11857294
0.86
5
4
5
12
33
20
36
19
33
14
33
8
8
4
rs2144908
19
5
1.00
12:66170163
12:66212318
12:71663102
13:23864657
13:80717156
15:38822905
15:62396389
15:77596725
15:80432222
15:90374257
15:91521337
16:53816275
16:75247245
17:2216258
17:6945940
17:36098040
18:57884750
18:7068462
19:19407718
19:33893008
20:42946966
20:42985717
X:152862638
X:152899922
RPSAP52
HMGA2
TSPAN8 / LGR5
SGCG
NDFIP2 / SPRY2
RASGRP1
C2CD4A / C2CD4B
HMG20A
ZFAND6 / FAH
AP3S2;C15orf38-AP3S2
PRC1
FTO
BCAR1
SRR
SLC16A11
HNF1B
MC4R
LAMA1
CILP2
PEPD
FITM2 / R3HDML
HNF4A
FAM58A
KRT18P48 / DUSP9
57
C
T
C
G
G
T
A
G
G
C
A
A
T
G
G
G
A
G
C
A
G
A
G
A
G/T
T/C
C/T
T/C
C/T
G/A
C/A
A/C
A/C
T/G
G/A
G/A
A/G
C/T
A/G
A/G
-
-0.82
-0.54
-0.15
-0.14
-0.05
0.14
-0.72
-0.28
0.33
-0.94
0.08
-0.83
-0.18
0.37
-0.28
-0.12
-
0.60
0.64
0.39
0.32
0.33
0.31
0.38
0.33
0.36
0.63
0.34
0.32
0.43
0.81
0.35
0.31
-
0.84
0.75
0.027
0.47
0.59
0.26
0.19
0.096
0.82
0.0035
0.80
0.75
0.24
0.62
0.33
0.92
-
0.21
0.47
0.54
0.39
0.88
0.35
0.011
0.42
0.30
0.049
0.82
0.008
0.95
0.25
0.27
0.70
-
Diabetes
Page 94 of 127
Supplementary Table 5F. Association with reported type 2 diabetes (T2D) susceptibility loci with DI in GUARDIAN Hispanic Americans (nmax=3,083). Index SNPs reaching genome‐wide significance (P<5.0E‐08) for association with T2D were selected from the NHGRI GWAS catalog (http://www.genome.gov/gwastudies). When the index variable was unavailable in GUARDIAN, a suitable proxy was selected using the HapMap 3 MEX (Mexican ancestry in Los Angeles, California) population. Index
SNP
rs10923931
rs2075423
rs17106184
rs6723108
rs7560163
rs7593730
rs3923113
rs7578326
rs2943641
rs780094
rs7578597
rs243021
rs11708067
rs1801282
rs4402960
rs16861329
rs6808574
rs7612463
rs831571
rs4607103
rs7656416
rs6815464
rs6813195
rs1801214
rs702634
rs459193
rs4457053
rs10946398
rs3130501
Ref
1
Proxy
rs2793831
r2
(MEX)
1.00
29
28
rs1278516
1.00
30
2
3
4
5
rs13405357
0.90
rs16861317
1.00
rs35837
0.92
rs7754840
0.96
31
29
1
5
29
6
4
28
32
8
1
9
8
28
5
28
33
5
12
28
Position
(hg19)
Gene(s)
1:120523902
1:212221342
1:50900021
2:135479980
2:151637936
2:161171454
2:165501849
2:227022036
2:227093745
2:27741237
2:43732823
2:60584819
3:123065778
3:12393125
3:185511687
3:186664728
3:187740523
3:23336450
3:64013249
3:64711904
4:1254535
4:1309901
4:153739925
4:6303022
5:53271420
5:55842508
5:76424949
6:20661250
6:31136453
NOTCH2
PROX1
FAF1
TMEM163
RND3 / FABP5P10
RBMS1
EIF3EP3 / SNORA70F
LOC646736
IRS1
GCKR
THADA
BCL11A
ADCY5
PPARG
IGF2BP2
ST6GAL1
LPP
UBE2E2
PSMD6 / PRICKLE2-AS1
ADAMTS9-AS2
CTBP1-AS1 / MAEA
MAEA
TMEM154
WFS1
ARL15
ANKRD55
ZBED3-AS1
CDKAL1
POU5F1-TCF19
58
Alleles
Risk Ref/Alt
T
G
G
T
C
C
A
A
C
C
T
A
A
C
T
G
C
C
C
C
C
C
C
T
A
G
G
C
G
T/C
G/A
T/G
A/G
C/T
C/T
T/C
A/G
A/G
C/G
T/G
G/A
C/T
C/A
C/T
C/T
A/G
G/A
C/G
G/A
Beta
SE
-0.14
-1.08
0.35
-0.44
-0.26
-0.75
0.13
-0.02
-1.17
0.34
-0.95
-0.48
0.42
0.36
0.03
0.21
-0.86
-0.94
-0.28
-0.15
0.56
0.88
0.52
0.39
0.43
0.36
0.72
0.35
0.40
0.55
0.38
0.37
0.43
0.69
0.61
0.37
0.45
0.36
0.37
0.42
Heterogeneity
P-value
Additive
P-value
0.064
0.59
0.11
0.36
0.60
1.00
0.044
0.75
0.46
0.0016
0.29
0.043
0.31
0.71
0.41
0.67
0.30
0.043
0.012
0.094
0.69
0.94
0.87
0.033
1.82E-04
0.98
0.94
0.53
0.095
0.84
0.023
0.49
0.50
0.022
0.24
0.17
0.71
0.50
0.016
0.31
Page 95 of 127
rs9470794
rs1535500
rs1048886
rs9505118
rs6467136
rs10229583
rs972283
rs17168486
rs864745
rs10278336
rs13266634
rs515071
rs896854
rs10811661
rs7018475
rs7041847
rs13292136
rs2796441
rs17584499
rs7903146
rs10886471
rs12779790
rs1802295
rs12571751
rs1111875
rs2334499
rs5219
rs231362
rs2237892
rs1552224
rs1387153
rs7305618
rs7957197
rs4275659
rs10842994
rs11063069
Diabetes
8
rs3800364
0.83
8
15
28
8
16
5
29
1
rs1635852
1.00
29
11
9
5
rs508419
rs4735337
1.00
0.81
6
18
8
5
33
20
22
19
1
4
33
11
35
6
5
24
5
5
17
5
28
33
34
rs10882101
1.00
6:38121211
6:39284050
6:71289189
6:7290437
7:127164958
7:127246903
7:130466854
7:14898282
7:28189411
7:44211888
8:118184783
8:41522991
8:95973465
9:22134094
9:22137685
9:4287466
9:81952128
9:84308948
9:8879118
10:114758349
10:121149403
10:12328010
10:70931474
10:80612637
10:94462427
11:1696849
11:17409572
11:2691471
11:2839751
11:72433098
11:92673828
12:121402932
12:121460686
12:123447928
12:27965150
12:4374373
ZFAND3
KCNK16
C6orf57
SSR1-RREB1
ZNF800 / GCC1
FSCN3 / PAX4
KLF14 / MIR29A
DGKB
JAZF1
GCK
SLC30A8
ANK1
TP53INP1
CDKN2B-AS1 / DMRTA1
CDKN2B-AS1 / DMRTA1
GLIS3
KRT18P24 / CHCHD2P9
TLE1
PTPRD
TCF7L2
GRK5
CDC123 / MIR4480
VPS26A
ZMIZ1
HHEX / EXOC6
DUSP8
KCNJ11
KCNQ1;KCNQ1OT1
KCNQ1
ARAP1
FAT3 / MTNR1B
RPL12P33 / HNF1A-AS1
OASL
MPHOSPH9
KLHDC5
CCND2
59
C
T
G
A
G
G
G
T
T
A
C
C
T
T
T
A
C
G
T
T
C
G
A
A
C
T
T
G
C
A
T
C
T
C
C
G
G/A
G/A
A/G
G/A
G/A
T/C
T/C
C/T
G/A
T/C
T/G
G/A
T/C
T/C
C/T
A/G
C/T
T/C
T/C
G/A
C/T
A/C
T/C
C/T
C/T
C/T
G/A
1.40
-0.11
0.03
-0.85
-0.67
-0.37
-0.49
-0.77
-0.07
-0.21
1.32
-0.01
-0.58
-1.06
0.12
0.13
0.32
-0.49
-0.29
0.71
-0.88
-1.65
-2.69
-0.46
0.06
-0.91
-0.79
0.79
0.45
0.36
0.50
0.36
0.36
0.44
0.40
0.44
0.35
0.37
0.34
0.42
0.40
0.37
0.41
0.36
0.35
0.35
0.37
0.41
0.71
0.42
0.50
0.35
0.50
0.56
0.92
0.27
0.071
0.60
0.27
0.17
0.89
0.79
0.92
0.95
0.17
0.36
0.70
0.08
0.66
0.55
0.51
0.07
0.23
0.12
0.0007
0.50
0.0046
0.98
0.82
0.70
0.69
0.10
0.85
0.79
0.064
0.033
0.74
0.28
0.018
0.79
0.43
3.9E-04
0.63
0.33
5.8E-05
0.90
0.99
0.49
0.39
0.18
0.19
0.0035
0.016
5.7E-09
0.26
0.96
0.21
0.40
Diabetes
rs1531343
rs2261181
rs7961581
rs9552911
rs1359790
rs7403531
rs7172432
rs7178572
rs11634397
rs2028299
rs8042680
rs8050136
rs7202877
rs391300
rs13342232
rs4430796
rs12970134
rs8090011
rs10401969
rs3786897
rs6017317
rs4812829
rs12010175
rs5945326
5
rs2612067
1.00
5
1
26
23
19
27
4
rs11857294
0.86
5
4
5
12
33
20
36
19
33
14
33
8
8
4
rs2144908
19
5
1.00
12:66170163
12:66212318
12:71663102
13:23864657
13:80717156
15:38822905
15:62396389
15:77596725
15:80432222
15:90374257
15:91521337
16:53816275
16:75247245
17:2216258
17:6945940
17:36098040
18:57884750
18:7068462
19:19407718
19:33893008
20:42946966
20:42985717
X:152862638
X:152899922
RPSAP52
HMGA2
TSPAN8 / LGR5
SGCG
NDFIP2 / SPRY2
RASGRP1
C2CD4A / C2CD4B
HMG20A
ZFAND6 / FAH
AP3S2;C15orf38-AP3S2
PRC1
FTO
BCAR1
SRR
SLC16A11
HNF1B
MC4R
LAMA1
CILP2
PEPD
FITM2 / R3HDML
HNF4A
FAM58A
KRT18P48 / DUSP9
60
Page 96 of 127
C
T
C
G
G
T
A
G
G
C
A
A
T
G
G
G
A
G
C
A
G
A
G
A
G/T
T/C
C/T
T/C
C/T
G/A
C/A
A/C
A/C
T/G
G/A
G/A
A/G
C/T
A/G
A/G
-
0.19
0.08
-0.36
-0.08
-0.33
0.51
0.14
-0.24
-0.21
-0.51
0.01
-0.72
-0.08
2.02
0.29
0.02
-
0.68
0.72
0.45
0.35
0.36
0.36
0.44
0.36
0.39
0.72
0.37
0.35
0.50
0.92
0.38
0.34
-
0.15
0.14
0.94
0.61
0.16
0.80
0.014
0.68
0.86
0.48
0.96
0.038
0.68
0.12
0.68
0.59
-
0.68
0.85
0.31
0.81
0.28
0.052
0.72
0.64
0.51
0.48
0.90
0.20
0.91
0.008
0.86
0.96
-
Page 97 of 127
Diabetes
Supplementary Table 5G. Association with reported type 2 diabetes (T2D) susceptibility loci with SG in GUARDIAN Hispanic Americans (nmax=2,542). Index SNPs reaching genome‐wide significance (P<5.0E‐08) for association with T2D were selected from the NHGRI GWAS catalog (http://www.genome.gov/gwastudies). When the index variable was unavailable in GUARDIAN, a suitable proxy was selected using the HapMap 3 MEX (Mexican ancestry in Los Angeles, California) population. Index
SNP
rs10923931
rs2075423
rs17106184
rs6723108
rs7560163
rs7593730
rs3923113
rs7578326
rs2943641
rs780094
rs7578597
rs243021
rs11708067
rs1801282
rs4402960
rs16861329
rs6808574
rs7612463
rs831571
rs4607103
rs7656416
rs6815464
rs6813195
rs1801214
rs702634
rs459193
rs4457053
rs10946398
rs3130501
Ref
1
Proxy
rs2793831
r2
(MEX)
1.00
29
28
rs1278516
1.00
30
2
3
4
5
rs13405357
0.90
rs16861317
1.00
rs35837
0.92
31
29
1
5
29
6
4
28
32
8
1
9
8
28
5
28
33
5
12
28
rs7754840
0.96
Position
(hg19)
Gene(s)
Alleles
Risk
Ref/Alt
1:120523902
1:212221342
1:50900021
2:135479980
2:151637936
2:161171454
2:165501849
2:227022036
2:227093745
2:27741237
2:43732823
2:60584819
3:123065778
3:12393125
3:185511687
3:186664728
3:187740523
3:23336450
3:64013249
3:64711904
4:1254535
4:1309901
4:153739925
4:6303022
5:53271420
5:55842508
5:76424949
6:20661250
6:31136453
NOTCH2
PROX1
FAF1
TMEM163
RND3 / FABP5P10
RBMS1
EIF3EP3 / SNORA70F
LOC646736
IRS1
GCKR
THADA
BCL11A
ADCY5
PPARG
IGF2BP2
ST6GAL1
LPP
UBE2E2
PSMD6 / PRICKLE2-AS1
ADAMTS9-AS2
CTBP1-AS1 / MAEA
MAEA
TMEM154
WFS1
ARL15
ANKRD55
ZBED3-AS1
CDKAL1
POU5F1-TCF19
61
T
G
G
T
C
C
A
A
C
C
T
A
A
C
T
G
C
C
C
C
C
C
C
T
A
G
G
C
G
T/C
G/A
T/G
A/G
C/T
C/T
T/C
A/G
A/G
C/G
T/G
G/A
C/T
C/A
C/T
C/T
A/G
G/A
C/G
G/A
Beta
SE
-0.01
-0.07
0.03
-0.04
-0.05
-0.14
0.06
-0.03
-0.05
0.03
-0.07
-0.01
-0.02
0.02
0.07
-0.05
-0.04
-0.05
-0.02
0.03
0.04
0.07
0.04
0.03
0.03
0.03
0.05
0.03
0.03
0.04
0.03
0.03
0.03
0.05
0.04
0.03
0.03
0.03
0.03
0.03
Heterogeneity
P-value
0.23
0.34
0.18
0.86
0.18
0.29
0.79
0.17
0.97
0.96
0.048
0.47
0.28
0.11
0.019
0.92
0.51
0.72
0.33
0.98
Additive
P-value
0.67
0.063
0.20
0.28
0.12
1.97E-06
0.13
0.076
0.12
0.51
0.0075
0.65
0.58
0.99
0.26
0.054
0.28
0.046
0.29
0.36
Diabetes
rs9470794
rs1535500
rs1048886
rs9505118
rs6467136
rs10229583
rs972283
rs17168486
rs864745
rs10278336
rs13266634
rs515071
rs896854
rs10811661
rs7018475
rs7041847
rs13292136
rs2796441
rs17584499
rs7903146
rs10886471
rs12779790
rs1802295
rs12571751
rs1111875
rs2334499
rs5219
rs231362
rs2237892
rs1552224
rs1387153
rs7305618
rs7957197
rs4275659
rs10842994
rs11063069
8
rs3800364
0.83
8
15
28
8
16
5
29
1
rs1635852
1.00
29
11
9
5
rs508419
rs4735337
1.00
0.81
6
18
8
5
33
20
22
19
1
4
33
11
35
6
5
24
5
5
17
5
28
33
34
rs10882101
1.00
6:38121211
6:39284050
6:71289189
6:7290437
7:127164958
7:127246903
7:130466854
7:14898282
7:28189411
7:44211888
8:118184783
8:41522991
8:95973465
9:22134094
9:22137685
9:4287466
9:81952128
9:84308948
9:8879118
10:114758349
10:121149403
10:12328010
10:70931474
10:80612637
10:94462427
11:1696849
11:17409572
11:2691471
11:2839751
11:72433098
11:92673828
12:121402932
12:121460686
12:123447928
12:27965150
12:4374373
ZFAND3
KCNK16
C6orf57
SSR1-RREB1
ZNF800 / GCC1
FSCN3 / PAX4
KLF14 / MIR29A
DGKB
JAZF1
GCK
SLC30A8
ANK1
TP53INP1
CDKN2B-AS1 / DMRTA1
CDKN2B-AS1 / DMRTA1
GLIS3
KRT18P24 / CHCHD2P9
TLE1
PTPRD
TCF7L2
GRK5
CDC123 / MIR4480
VPS26A
ZMIZ1
HHEX / EXOC6
DUSP8
KCNJ11
KCNQ1;KCNQ1OT1
KCNQ1
ARAP1
FAT3 / MTNR1B
RPL12P33 / HNF1A-AS1
OASL
MPHOSPH9
KLHDC5
CCND2
62
Page 98 of 127
C
T
G
A
G
G
G
T
T
A
C
C
T
T
T
A
C
G
T
T
C
G
A
A
C
T
T
G
C
A
T
C
T
C
C
G
G/A
G/A
A/G
G/A
G/A
T/C
T/C
C/T
G/A
T/C
T/G
G/A
T/C
T/C
C/T
A/G
C/T
T/C
T/C
G/A
C/T
A/C
T/C
C/T
C/T
C/T
G/A
0.04
0.04
-0.05
0.00
-0.02
-0.03
0.03
-0.04
0.00
0.00
0.04
-0.01
0.00
0.01
-0.04
-0.02
-0.01
-0.04
-0.06
0.04
0.00
0.02
-0.12
-0.08
0.00
-0.02
-0.04
0.06
0.04
0.03
0.04
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.05
0.03
0.04
0.03
0.04
0.04
0.67
-
0.58
-
0.21
0.15
-
0.48
0.20
-
0.88
0.062
0.80
0.33
0.16
0.41
0.28
0.24
0.20
0.91
0.20
0.91
0.44
0.51
0.59
0.29
0.66
0.44
0.98
0.39
0.71
0.45
0.29
0.31
0.98
0.44
0.22
0.29
0.070
0.67
0.93
0.41
0.93
0.85
0.96
0.19
0.44
0.62
0.10
0.0076
0.15
0.95
0.75
3.0E-04
0.049
1.00
0.86
0.47
Page 99 of 127
rs1531343
rs2261181
rs7961581
rs9552911
rs1359790
rs7403531
rs7172432
rs7178572
rs11634397
rs2028299
rs8042680
rs8050136
rs7202877
rs391300
rs13342232
rs4430796
rs12970134
rs8090011
rs10401969
rs3786897
rs6017317
rs4812829
rs12010175
rs5945326
Diabetes
5
rs2612067
1.00
5
1
26
23
19
27
4
rs11857294
0.86
5
4
5
12
33
20
36
19
33
14
33
8
8
4
rs2144908
1.00
19
5
12:66170163
12:66212318
12:71663102
13:23864657
13:80717156
15:38822905
15:62396389
15:77596725
15:80432222
15:90374257
15:91521337
16:53816275
16:75247245
17:2216258
17:6945940
17:36098040
18:57884750
18:7068462
19:19407718
19:33893008
20:42946966
20:42985717
X:152862638
X:152899922
RPSAP52
HMGA2
TSPAN8 / LGR5
SGCG
NDFIP2 / SPRY2
RASGRP1
C2CD4A / C2CD4B
HMG20A
ZFAND6 / FAH
AP3S2;C15orf38-AP3S2
PRC1
FTO
BCAR1
SRR
SLC16A11
HNF1B
MC4R
LAMA1
CILP2
PEPD
FITM2 / R3HDML
HNF4A
FAM58A
KRT18P48 / DUSP9
63
C
T
C
G
G
T
A
G
G
C
A
A
T
G
G
G
A
G
C
A
G
A
G
A
G/T
T/C
C/T
T/C
C/T
G/A
C/A
A/C
A/C
T/G
G/A
G/A
A/G
C/T
A/G
A/G
-
-0.04
-0.05
-0.01
0.02
-0.04
0.01
-0.01
-0.01
-0.02
0.07
0.01
-0.04
-0.03
0.06
0.02
-0.02
-
0.05
0.05
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.05
0.03
0.03
0.04
0.07
0.03
0.03
-
0.25
0.33
0.78
-
0.56
0.33
0.93
-
0.12
-
0.94
-
0.29
0.35
0.0055
0.73
0.21
0.24
0.67
-
0.42
0.32
0.93
0.78
0.48
0.23
0.52
-
0.26
0.76
-
0.14
0.51
-
0.13
0.40
-
0.27
0.83
-
0.49
-
0.57
-
Diabetes
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REFERENCES 1. Zeggini et al. Meta‐analysis of genome‐wide association data and large‐scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 40:638‐645, 2008 2. Palmer et al. A genome‐wide association search for type 2 diabetes genes in African Americans. PLoS One 7:e29202, 2012 3. Qi et al. Genetic variants at 2q24 are associated with susceptibility to type 2 diabetes. Hum Mol Genet 19:2706‐2715, 2010 4. Kooner et al. Genome‐wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci. Nat Genet 43:984‐989, 2011 5. Voight et al. Twelve type 2 diabetes susceptibility loci identified through large‐scale association analysis. Nat Genet 42:579‐589, 2010 6. Scott et al. A genome‐wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316:1341‐1345, 2007 7. Unoki et al. SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nat Genet 40:1098‐1102, 2008 8. Cho et al. Meta‐analysis of genome‐wide association studies identifies eight new loci for type 2 diabetes in east Asians. Nat Genet 44:67‐72, 2012 9. Imamura et al. A single‐nucleotide polymorphism in ANK1 is associated with susceptibility to type 2 diabetes in Japanese populations. Hum Mol Genet 21:3042‐3049, 2012 10. Takeuchi et al. Confirmation of multiple risk Loci and genetic impacts by a genome‐wide association study of type 2 diabetes in the Japanese population. Diabetes 58:1690‐1699, 2009 11. Saxena et al. Genome‐wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331‐1336, 2007 12. Zeggini et al. Replication of genome‐wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316:1336‐1341, 2007 13. Steinthorsdottir et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 39:770‐775, 2007 14. Perry et al. Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases. PLoS Genet 8:e1002741, 2012 15. Sim et al. Transferability of type 2 diabetes implicated loci in multi‐ethnic cohorts from Southeast Asia. PLoS Genet 7:e1001363, 2011 16. Ma et al. Genome‐wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4. Diabetologia 56:1291‐1305, 2013 17. Parra et al. Genome‐wide association study of type 2 diabetes in a sample from Mexico City and a meta‐analysis of a Mexican‐American sample from Starr County, Texas. Diabetologia 54:2038‐2046, 2011 18. Huang et al. 1000 Genomes‐based imputation identifies novel and refined associations for the Wellcome Trust Case Control Consortium phase 1 Data. Eur J Hum Genet 20:801‐805, 2012 19. Li et al. A genome‐wide association study identifies GRK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans. Diabetes 62:291‐298, 2013 20. Tsai et al. A genome‐wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese. PLoS Genet 6:e1000847, 2010 21. WTCCC Genome‐wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661‐678, 2007 22. Sladek at al. A genome‐wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881‐885, 2007 23. Shu et al. Identification of new genetic risk variants for type 2 diabetes. PLoS Genet 6:e1001127, 2010 24. Yasuda et al. Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nat Genet 40:1092‐1097, 2008 25. Cui et al. A genome‐wide association study confirms previously reported loci for type 2 diabetes in Han Chinese. PLoS One 6:e22353, 2011 26. Saxena et al. Genome‐wide association study identifies a novel locus contributing to type 2 diabetes susceptibility in Sikhs of Punjabi origin from India. Diabetes 62:1746‐1755, 2013 27. Yamauchi et al. A genome‐wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A‐C2CD4B. Nat Genet 42:864‐868, 2010 64
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Diabetes
Supplementary Table 6. All SNPs from GWAS of T2D-related quantitative traits with Translation to T2D in Mexican-origin cohorts
ordered by trait from the Discovery stage.
Discovery Cohort Marker Chr Position rs4350219 rs11247954 rs2278979 rs3790645 rs1064196 rs282177 rs7549785 rs12742834 rs6697598 rs6718111 rs1044280 rs7572039 rs10197417 rs6745880 rs13024014 rs11688831 rs12373582 rs6741187 rs6798029 rs13321674 rs381062 rs726737 rs13064954 rs13325944 rs9830704 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 19858807 26741285 26877708 26884864 26887592 26899125 159277868 240107121 241105515 8201262 8871342 31061392 70881592 171105318 173530946 199299078 209069303 222065721 10763460 51704721 55267391 142860107 156854742 157057390 187222367 Gene LIN28A RPS6KA1 RPS6KA1 RPS6KA1 RPS6KA1 FCER1A RGS7 LINC00299 KIDINS220 ADD2 MYO3B VEPH1 Trait Beta P‐value MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI 0.24 0.26 0.31 0.34 0.34 0.34 0.34 0.22 ‐0.60 ‐0.19 0.19 0.36 ‐0.15 ‐0.30 ‐0.62 ‐0.14 0.37 2.15 ‐0.29 ‐1.57 0.43 ‐0.15 0.23 0.19 0.21 7.45E‐05 9.76E‐05 3.16E‐05 6.07E‐06 9.75E‐06 3.30E‐05 7.92E‐04 1.94E‐04 1.88E‐05 9.33E‐05 6.97E‐05 2.74E‐05 7.00E‐04 7.34E‐05 9.17E‐05 7.08E‐05 1.80E‐04 8.62E‐05 5.17E‐04 7.70E‐05 3.11E‐04 7.83E‐04 6.36E‐04 9.82E‐04 3.06E‐04 65
Translational Cohort RA/ RA Nonref Frequency
T/C A/G A/G A/G C/T T/C A/G C/T C/T C/T A/C T/G T/C G/A T/C A/G G/A T/C A/G C/T A/G A/G A/G A/G T/C 0.244 0.179 0.405 0.421 0.424 0.451 0.163 0.245 0.042 0.487 0.287 0.078 0.411 0.138 0.023 0.384 0.084 0.010 0.254 0.009 0.061 0.320 0.107 0.145 0.164 OR (95%CI) P‐value 0.93 (0.86‐1.00) 1.03 (0.93‐1.14) 1.06 (0.99‐1.13) 1.05 (0.98‐1.12) 1.04 (0.97‐1.11) 1.07 (1.00‐1.15) 1.22 (1.11‐1.35) 1.06 (0.98‐1.16) 0.99 (0.82‐1.19) 0.99 (0.92‐1.06) 0.99 (0.92‐1.07) 1.10 (0.97‐1.24) 0.98 (0.91‐1.05) 0.97 (0.88‐1.07) 0.96 (0.77‐1.20) 1.01 (0.94‐1.09) 0.94 (0.81‐1.08) 1.06 (0.54‐2.08) 0.90 (0.84‐0.98) 0.60 (0.35‐1.01) 1.11 (0.98‐1.26) 0.90 (0.83‐0.97) 1.08 (0.96‐1.22) 1.06 (0.96‐1.17) 1.04 (0.95‐1.14) 1.40E‐01 4.97E‐01 4.33E‐01 8.57E‐01 7.54E‐01 3.62E‐01 1.66E‐03 8.27E‐01 3.16E‐01 2.49E‐01 8.72E‐01 1.59E‐01 4.51E‐01 6.61E‐01 4.36E‐01 7.27E‐01 7.64E‐01 9.35E‐01 2.33E‐02 1.96E‐01 2.56E‐01 7.54E‐03 7.68E‐02 6.37E‐02 8.69E‐01 Discovery and Translational Meta‐Analysis P‐value 1.21E‐04 2.29E‐02 1.69E‐02 2.13E‐03 3.66E‐03 2.20E‐02 8.82E‐01 1.31E‐02 2.05E‐02 5.14E‐02 3.43E‐03 4.88E‐02 6.23E‐02 1.84E‐03 2.67E‐02 2.24E‐03 4.22E‐03 6.54E‐03 3.95E‐01 5.99E‐02 8.07E‐02 6.27E‐01 2.44E‐01 3.08E‐01 7.61E‐03 Diabetes
rs16835397 rs2124794 rs6822279 rs7726659 rs6874765 rs523848 rs220933 rs9370836 rs3749855 rs6938736 rs9295552 rs9449095 rs13219760 rs723685 rs17166951 rs4629751 rs10251809 rs10246021 rs11136431 rs6651438 rs13258014 rs17128106 rs4434590 rs13253073 rs12544943 rs13257834 rs7851513 rs10960561 rs7025024 rs16923334 rs6602203 rs10825203 4 4 4 5 5 6 6 6 6 6 6 6 6 6 7 7 7 7 8 8 8 8 8 8 8 8 9 9 9 9 10 10 4268642 62290634 99745705 74478078 147298847 15830025 15845797 15856619 17283321 22441270 22540765 81313076 110761189 110763875 13302054 16825580 32044030 100692680 1791433 1794023 4165460 19146926 100860657 100897383 100903890 122322450 9842176 12275924 25816219 106556113 17596121 55798117 LPHN3 ANKRD31 RBM24 SLC22A16 SLC22A16 PDE1C MUC17 ARHGEF10 ARHGEF10 CSMD1 VPS13B COX6C COX6C PTPRD PCDH15 MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI ‐0.71 ‐0.15 ‐0.21 ‐0.90 ‐4.50 0.20 ‐0.19 0.23 ‐0.52 0.22 ‐0.28 0.44 0.35 0.33 0.42 0.26 ‐0.25 0.29 0.14 0.20 0.26 2.97 ‐0.29 ‐0.35 ‐0.34 ‐0.22 0.38 ‐0.19 ‐0.18 ‐0.54 ‐0.32 0.23 1.85E‐05 5.27E‐05 2.33E‐05 4.58E‐05 2.02E‐04 3.48E‐05 9.83E‐05 1.19E‐04 5.04E‐06 7.64E‐05 7.11E‐04 3.88E‐04 3.15E‐06 8.04E‐06 8.25E‐05 9.58E‐05 4.28E‐05 2.01E‐04 6.90E‐05 9.10E‐05 7.99E‐05 1.37E‐04 8.09E‐05 5.89E‐06 6.90E‐06 9.10E‐04 2.72E‐05 4.19E‐04 8.33E‐05 6.75E‐04 4.80E‐06 5.80E‐05 66
Page 102 of 127
T/C A/G C/A G/A A/G A/G C/T C/T G/T C/T T/C G/A G/A G/A A/C G/T T/C T/G T/C C/T T/C A/G T/C A/C G/A G/A A/C A/G G/A C/T T/C A/C 0.018 0.437 0.406 0.015 0.005 0.467 0.421 0.442 0.057 0.469 0.300 0.046 0.111 0.114 0.060 0.284 0.180 0.470 0.383 0.377 0.392 0.003 0.161 0.129 0.129 0.248 0.129 0.256 0.342 0.028 0.403 0.268 0.83 (0.64‐1.06) 0.98 (0.92‐1.06) 0.93 (0.87‐0.99) 0.97 (0.75‐1.26) 1.16 (0.34‐4.01) 0.96 (0.90‐1.03) 1.07 (0.99‐1.14) 0.94 (0.88‐1.00) 0.96 (0.82‐1.11) 0.96 (0.90‐1.03) 1.04 (0.97‐1.12) 0.97 (0.84‐1.12) 0.94 (0.84‐1.05) 1.04 (0.94‐1.15) 0.93 (0.79‐1.10) 0.97 (0.90‐1.05) 0.95 (0.86‐1.04) 0.96 (0.90‐1.03) 0.99 (0.93‐1.07) 0.90 (0.84‐0.96) 0.98 (0.91‐1.05) 0.53 (0.25‐1.13) 1.00 (0.92‐1.09) 0.93 (0.85‐1.02) 0.91 (0.83‐1.00) 1.01 (0.94‐1.08) 0.98 (0.89‐1.07) 1.03 (0.90‐1.17) 0.94 (0.87‐1.01) 0.94 (0.77‐1.14) 1.02 (0.95‐1.09) 0.94 (0.87‐1.01) 5.52E‐01 9.53E‐01 1.50E‐02 6.08E‐01 6.09E‐01 3.56E‐01 3.83E‐01 2.19E‐01 6.94E‐01 1.42E‐01 2.64E‐01 2.04E‐01 8.13E‐01 2.54E‐01 7.71E‐01 4.80E‐01 4.06E‐01 3.36E‐02 2.65E‐01 3.40E‐02 5.32E‐01 1.00E‐01 5.65E‐01 2.08E‐01 1.44E‐01 4.27E‐01 3.41E‐01 8.23E‐02 4.12E‐01 3.16E‐01 5.86E‐01 5.86E‐02 9.12E‐03 3.73E‐03 2.04E‐01 1.17E‐02 2.79E‐03 3.44E‐04 7.51E‐04 3.30E‐04 4.56E‐04 1.26E‐04 1.45E‐03 6.58E‐04 5.34E‐04 1.88E‐02 2.79E‐03 1.12E‐03 2.12E‐02 3.60E‐05 3.16E‐04 1.98E‐05 1.23E‐03 1.14E‐04 1.73E‐02 2.07E‐02 3.19E‐02 3.65E‐03 2.72E‐04 1.97E‐04 2.76E‐02 9.01E‐02 2.96E‐04 2.91E‐05 Page 103 of 127
rs1911409 rs716594 rs11016332 rs7944706 rs2449501 rs16918932 rs10400279 rs2510094 rs7131741 rs2059765 rs17075764 rs1334870 rs9530368 rs1930224 rs6576136 rs1680727 rs2031271 rs8003026 rs8014528 rs10147864 rs637568 rs10518808 rs11853158 rs2718934 rs8032549 rs2244373 rs12441883 rs3784334 rs7172809 rs2701405 rs4843249 rs781856 Diabetes
10 10 10 11 11 11 11 11 12 12 13 13 13 13 14 14 14 14 14 14 15 15 15 15 15 15 15 15 15 15 16 17 55806316 112006311 130363802 10331311 20044696 29309078 36270057 102981300 78251906 115030724 52100949 54838415 75270057 96897559 28737460 34507353 42344822 72482760 91305899 97919601 29692391 55562142 56364902 56557418 56572176 57622887 58456850 68610384 77819676 87539918 87652026 3950224 PCDH15 MXI1 NAV2 DYNC2H1 NAV3 HS6ST3 LRFN5 RGS6 FAM189A1 RAB27A ALDH1A2 ITGA11 AGBL1 JPH3 ZZEF1 MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI MCRI 0.23 ‐0.65 2.07 0.31 ‐0.22 3.45 ‐0.31 0.45 0.25 ‐0.29 0.37 ‐0.26 ‐0.22 0.25 0.18 0.19 0.23 3.07 ‐0.20 3.27 ‐0.46 0.22 ‐0.18 ‐0.17 ‐0.18 ‐0.15 0.23 0.25 0.18 ‐0.23 0.18 0.94 5.05E‐05 3.84E‐05 4.72E‐05 4.70E‐05 1.27E‐05 4.38E‐05 8.87E‐05 5.69E‐05 4.30E‐04 4.19E‐04 5.41E‐04 8.31E‐05 6.37E‐05 3.69E‐04 9.18E‐05 5.13E‐04 3.73E‐05 4.04E‐05 3.03E‐04 6.21E‐05 8.96E‐05 4.70E‐04 6.96E‐05 2.50E‐05 7.52E‐05 4.42E‐04 3.60E‐05 4.38E‐04 9.20E‐06 2.15E‐05 5.22E‐04 7.06E‐06 67
G/A A/G G/A A/G G/A G/T G/A C/T G/T A/G G/A A/C C/A T/C C/T C/T C/A G/T C/T C/T G/A A/G A/G G/A G/A C/T A/G G/T A/G A/C G/A A/G 0.243 0.019 0.008 0.285 0.198 0.003 0.058 0.044 0.211 0.228 0.042 0.309 0.358 0.131 0.381 0.336 0.158 0.003 0.348 0.005 0.027 0.215 0.320 0.466 0.328 0.212 0.370 0.183 0.484 0.486 0.465 0.014 1.00 (0.93‐1.08) 0.74 (0.57‐0.96) 0.74 (0.37‐1.50) 1.04 (0.97‐1.11) 0.97 (0.89‐1.07) 0.43 (0.11‐1.70) 1.06 (0.93‐1.20) 0.88 (0.74‐1.05) 0.97 (0.89‐1.07) 1.07 (0.98‐1.17) 1.10 (0.83‐1.45) 0.98 (0.90‐1.06) 0.92 (0.86‐0.99) 0.99 (0.88‐1.10) 1.01 (0.94‐1.08) 1.06 (0.98‐1.14) 1.10 (1.00‐1.21) 1.84 (0.85‐3.97) 1.04 (0.96‐1.12) 0.76 (0.12‐4.83) 1.17 (0.92‐1.48) 0.94 (0.86‐1.02) 0.91 (0.84‐0.98) 0.94 (0.88‐1.01) 0.92 (0.86‐0.99) 1.06 (0.97‐1.15) 1.00 (0.93‐1.08) 1.03 (0.94‐1.13) 1.12 (1.04‐1.20) 1.02 (0.95‐1.09) 0.98 (0.91‐1.06) 1.09 (0.83‐1.43) 2.89E‐01 7.50E‐02 7.84E‐01 9.33E‐02 7.91E‐01 6.30E‐01 6.57E‐01 4.90E‐01 6.72E‐01 1.25E‐01 4.00E‐01 4.44E‐01 2.43E‐01 4.38E‐01 5.90E‐01 6.13E‐01 6.74E‐02 1.17E‐01 5.45E‐02 5.88E‐01 6.61E‐01 2.73E‐01 1.79E‐02 2.44E‐01 1.65E‐02 3.65E‐01 9.40E‐01 7.62E‐01 1.49E‐02 8.93E‐01 2.90E‐01 7.79E‐01 3.00E‐04 9.85E‐02 7.30E‐03 9.07E‐02 1.06E‐03 1.23E‐03 2.03E‐03 8.54E‐04 2.85E‐02 3.44E‐04 2.35E‐03 8.86E‐04 4.54E‐02 2.16E‐03 1.71E‐02 3.58E‐02 1.05E‐01 7.25E‐02 9.07E‐05 1.31E‐03 2.07E‐03 1.16E‐03 2.55E‐01 3.11E‐02 2.70E‐01 1.78E‐03 2.93E‐03 2.31E‐02 1.57E‐01 1.94E‐03 8.83E‐02 2.91E‐03 Diabetes
rs4790177 rs8065822 rs2325989 rs1986507 rs2274892 rs9911767 rs9912528 rs2339345 rs1008632 rs11872993 rs2276210 rs3786947 rs7247790 rs6013784 rs9983598 rs6685355 rs1507290 rs896232 rs13411840 rs7581057 rs207910 rs6767721 rs9853442 rs10007938 rs10023791 rs6815953 rs16894006 rs7724522 rs29848 rs2001097 rs2227138 rs3135376 17 17 17 17 17 17 17 18 18 18 18 19 19 20 21 1 1 2 2 2 2 3 3 4 4 4 5 5 5 6 6 6 4067900 4171848 4199320 10082301 16852027 70376204 77387550 49957255 58869249 71104519 74587458 3114229 5311412 52365120 17903973 79458347 86684713 2732877 29973281 115958079 217018422 87630433 177191797 32452973 99425353 183109012 24833120 142081559 151449400 32383858 32384500 32385470 ANKFY1 UBE2G1 GAS7 TNFRSF13B RBFOX3 DCC ZNF236 GNA11 PTPRS LINC00478 ELTD1 ALK DPP10 XRCC5 TSPAN5 ODZ3 AK001582 MCRI 0.95 4.21E‐05 MCRI 1.21 2.19E‐04 MCRI 1.10 5.63E‐05 MCRI ‐0.26 9.92E‐05 MCRI ‐0.16 7.67E‐05 MCRI 0.12 6.78E‐04 MCRI 0.27 1.65E‐05 MCRI ‐0.25 7.80E‐06 MCRI 0.22 4.19E‐04 MCRI ‐1.74 8.65E‐05 MCRI ‐0.89 9.92E‐05 MCRI ‐0.28 1.21E‐05 MCRI ‐0.28 6.88E‐05 MCRI 0.18 9.56E‐04 MCRI 3.86 1.06E‐04 SI+M ‐7.81 6.27E‐05 SI+M 5.01 6.54E‐05 SI+M ‐5.28 1.26E‐06 SI+M ‐14.39 2.69E‐06 SI+M ‐5.47 1.74E‐04 SI+M 7.26 4.51E‐05 SI+M 6.37 5.90E‐05 SI+M ‐5.68 4.21E‐04 SI+M 6.76 4.74E‐05 SI+M 4.03 4.31E‐05 SI+M 4.10 3.14E‐05 SI+M ‐12.02 4.38E‐05 SI+M ‐7.09 5.11E‐05 SI+M 6.61 5.08E‐05 SI+M 10.04 3.69E‐05 SI+M 10.62 7.04E‐05 SI+M 10.04 3.69E‐05 68
Page 104 of 127
T/C C/A G/A A/G G/T A/G C/T A/C T/C T/C A/G A/G G/T T/C T/C C/A G/A T/C C/A G/A G/A G/T A/G G/A A/G T/G C/T C/T T/G T/G T/C G/A 0.012 0.009 0.015 0.152 0.372 0.386 0.150 0.343 0.312 0.006 0.015 0.222 0.185 0.167 0.002 0.326 0.206 0.282 0.046 0.056 0.150 0.071 0.485 0.241 0.426 0.431 0.020 0.038 0.328 0.128 0.110 0.128 1.26 (0.77‐2.06) 1.42 (0.83‐2.43) 1.09 (0.85‐1.41) 1.02 (0.93‐1.12) 0.92 (0.86‐0.98) 0.99 (0.92‐1.07) 1.05 (0.95‐1.15) 1.05 (0.99‐1.13) 0.99 (0.92‐1.07) 0.44 (0.21‐0.90) 0.90 (0.70‐1.17) 1.05 (0.95‐1.16) 0.95 (0.86‐1.06) 1.04 (0.95‐1.14) 0.51 (0.04‐6.14) 0.97 (0.91‐1.05) 0.98 (0.90‐1.07) 1.00 (0.92‐1.08) 0.87 (0.75‐1.00) 1.29 (1.10‐1.50) 0.95 (0.85‐1.07) 1.08 (0.95‐1.23) 1.00 (0.94‐1.08) 1.00 (0.92‐1.08) 1.02 (0.96‐1.10) 0.92 (0.86‐0.99) 0.91 (0.68‐1.22) 1.14 (0.94‐1.37) 1.06 (0.98‐1.13) 1.04 (0.75‐1.42) 0.92 (0.62‐1.38) 1.04 (0.75‐1.42) 3.52E‐01 4.18E‐01 3.55E‐01 8.68E‐01 1.30E‐02 3.38E‐01 4.48E‐01 3.75E‐01 6.36E‐01 1.88E‐01 7.25E‐01 2.42E‐01 5.34E‐01 7.29E‐01 7.20E‐01 4.28E‐01 8.85E‐01 4.05E‐01 6.03E‐02 6.67E‐03 7.04E‐01 5.94E‐01 8.47E‐01 9.48E‐01 3.04E‐01 1.25E‐02 4.62E‐01 1.10E‐01 3.27E‐01 8.29E‐01 3.55E‐01 8.32E‐01 2.53E‐02 4.13E‐02 2.82E‐02 8.41E‐03 2.99E‐01 8.44E‐02 1.21E‐02 1.52E‐04 3.08E‐02 6.51E‐02 1.23E‐02 8.79E‐05 1.76E‐02 3.66E‐02 2.76E‐03 2.32E‐02 6.51E‐03 4.54E‐03 4.66E‐02 4.82E‐06 8.90E‐03 1.38E‐02 1.84E‐02 3.47E‐03 3.03E‐02 2.47E‐06 1.78E‐02 6.51E‐05 2.99E‐02 5.70E‐03 5.31E‐04 5.65E‐03 Page 105 of 127
rs2395161 rs3135366 rs558015 rs24003 rs2726051 rs17141982 rs10268984 rs3177186 rs7799219 rs12675420 rs6475448 rs10966384 rs4817 rs10739874 rs1176191 rs2688789 rs12413935 rs948178 rs3781827 rs11180162 rs10860482 rs7974375 rs17512574 rs673078 rs884844 rs7305647 rs4772128 rs12717423 rs10129385 rs2617235 rs10851411 rs2241998 Diabetes
6 6 6 7 7 7 7 7 7 8 9 9 9 9 9 10 10 11 11 12 12 12 12 12 12 12 13 14 14 15 15 15 32387752 32388709 137899792 30748323 36155071 70133502 98963340 98984399 123895098 62924308 20497142 24672959 33917498 105991203 105993267 17733014 85453920 113195595 121411041 75081042 100038835 118585698 118788003 118791441 118814838 118855566 99385553 52940827 52959478 42758738 42859235 42869028 INMT AUTS2 ARPC1A ARPC1A EU233817 MLLT3 UBE2R2 BC035187 BC035187 STAM TTC12 SORL1 ANKS1B TAOK3 TAOK3 SUDS3 SUDS3 SLC15A1 TXNDC16 TXNDC16 ZFP106 HAUS2 STARD9 SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M 10.04 9.96 ‐4.84 ‐4.83 6.17 3.95 ‐7.02 ‐7.04 6.38 10.10 ‐6.91 ‐9.96 ‐3.47 10.13 10.03 ‐6.25 ‐10.34 5.63 3.38 3.44 5.67 ‐10.14 ‐12.38 ‐12.79 ‐12.12 ‐12.32 ‐7.87 ‐4.35 ‐4.30 6.10 5.46 5.10 3.79E‐05 3.61E‐05 1.45E‐04 6.24E‐05 5.27E‐05 9.89E‐05 5.59E‐05 6.58E‐05 6.95E‐05 8.87E‐05 3.31E‐05 9.06E‐05 7.96E‐05 1.00E‐04 1.77E‐04 9.47E‐05 4.11E‐05 9.43E‐05 6.12E‐05 8.30E‐05 9.80E‐05 8.96E‐05 3.19E‐05 4.71E‐06 6.71E‐05 5.90E‐05 5.57E‐05 3.87E‐05 5.48E‐05 9.05E‐05 5.64E‐06 7.70E‐05 69
C/A C/T A/G C/T C/A T/C T/C T/C T/C T/C G/A C/T C/T C/T T/C G/A G/T A/G G/A C/T C/T T/G T/C C/A T/C A/G A/G G/A C/T C/T T/G A/G 0.128 0.129 0.470 0.471 0.223 0.340 0.103 0.105 0.228 0.069 0.303 0.057 0.314 0.092 0.090 0.419 0.020 0.337 0.434 0.189 0.372 0.104 0.110 0.125 0.113 0.105 0.029 0.253 0.253 0.366 0.428 0.417 1.04 (0.75‐1.42) 0.95 (0.76‐1.18) 0.98 (0.92‐1.05) 1.02 (0.95‐1.09) 1.07 (0.98‐1.16) 0.99 (0.92‐1.06) 1.09 (0.99‐1.20) 1.03 (0.73‐1.47) 0.94 (0.86‐1.04) 1.10 (0.96‐1.27) 0.98 (0.91‐1.06) 0.86 (0.74‐1.01) 0.93 (0.86‐1.00) 1.05 (0.95‐1.17) 1.05 (0.95‐1.15) 1.00 (0.93‐1.07) 0.95 (0.75‐1.21) 1.04 (0.96‐1.12) 0.97 (0.91‐1.04) 1.05 (0.97‐1.15) 1.07 (1.00‐1.15) 0.91 (0.82‐1.03) 0.96 (0.87‐1.07) 0.88 (0.80‐0.98) 0.90 (0.81‐1.01) 0.96 (0.86‐1.06) 0.81 (0.58‐1.14) 1.02 (0.94‐1.10) 1.03 (0.96‐1.11) 0.95 (0.88‐1.02) 0.96 (0.89‐1.03) 1.00 (0.94‐1.07) 8.29E‐01 7.76E‐01 8.86E‐01 2.81E‐01 1.77E‐01 2.23E‐01 1.96E‐01 8.64E‐01 1.41E‐01 7.17E‐01 5.97E‐01 7.07E‐02 8.88E‐02 5.58E‐01 5.46E‐01 4.65E‐01 6.14E‐01 6.89E‐01 5.36E‐01 4.38E‐01 2.30E‐01 1.93E‐01 2.92E‐01 6.71E‐02 1.84E‐02 2.40E‐01 5.32E‐01 7.64E‐01 3.47E‐01 5.46E‐01 7.23E‐01 4.71E‐01 5.77E‐03 1.80E‐03 9.73E‐03 3.27E‐04 5.68E‐02 3.01E‐04 1.67E‐04 3.24E‐03 1.17E‐04 1.19E‐02 9.37E‐04 1.36E‐01 1.13E‐01 1.95E‐02 2.62E‐02 1.05E‐03 1.13E‐03 2.33E‐03 1.07E‐03 2.55E‐02 5.68E‐02 6.45E‐02 2.81E‐02 5.21E‐02 2.50E‐01 4.45E‐02 1.60E‐02 1.79E‐03 4.35E‐04 1.40E‐03 5.40E‐04 2.23E‐02 Diabetes
rs7497796 rs12438945 rs884202 rs7178383 rs4624233 rs7219451 rs10558 rs9303297 rs3760333 rs2291447 rs6133145 rs6139486 rs6075733 rs1061325 rs17385225 rs6719442 rs12620694 rs1978648 rs4952971 rs10167465 rs1044710 rs6782551 rs1872552 rs716975 rs7690543 rs1848056 rs9997902 rs1602084 rs11943562 rs17069175 rs6868526 rs16875556 15 15 15 15 17 17 17 17 17 17 20 20 20 22 1 2 2 2 2 2 2 3 3 4 4 4 4 4 4 4 5 5 55136506 55226570 68054388 99159956 38955961 38957002 38991003 39005990 39023875 43212963 4576230 4578080 20856254 19184095 164475201 2722295 2763051 43371542 43373119 43397176 211297355 74922055 85049088 38349236 68056613 125755019 125763629 128843480 167652786 181226698 5399472 5402163 MAP2K5 KRT28 TMEM99 ACBD4 CLTCL1 LANCL1 CADM2 MFSD8 SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI+M SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI 9.33 10.00 ‐3.79 ‐8.34 ‐7.61 ‐6.80 ‐7.00 ‐7.40 ‐5.83 ‐4.56 6.23 5.16 ‐7.74 ‐3.28 0.28 ‐0.29 ‐0.38 0.20 0.18 0.19 ‐0.20 0.57 ‐0.20 ‐0.27 0.28 0.09 0.10 0.43 ‐0.25 ‐0.27 0.27 0.26 2.63E‐05 5.38E‐05 9.64E‐05 8.42E‐05 2.46E‐05 3.92E‐06 1.48E‐05 9.98E‐06 2.09E‐05 7.95E‐05 4.52E‐05 7.29E‐05 3.40E‐05 9.96E‐05 4.87E‐05 1.53E‐05 3.42E‐05 5.31E‐07 2.31E‐05 9.30E‐05 8.93E‐05 9.04E‐05 8.59E‐05 9.86E‐06 2.34E‐06 3.21E‐05 2.29E‐05 3.10E‐06 6.27E‐05 7.04E‐05 2.22E‐05 3.47E‐05 70
Page 106 of 127
A/C C/A A/G C/T A/G C/T C/T T/C C/T T/G A/C A/G C/T C/T A/G A/G A/G T/C A/G G/A A/G A/G A/G T/C T/C T/C A/G G/A C/T A/G C/T A/G 0.376 0.230 0.381 0.332 0.137 0.380 0.138 0.138 0.173 0.346 0.400 0.366 0.346 0.451 0.134 0.180 0.162 0.328 0.438 0.419 0.395 0.014 0.444 0.226 0.177 0.484 0.490 0.038 0.130 0.241 0.188 0.167 0.99 (0.92‐1.06) 1.01 (0.93‐1.10) 0.97 (0.90‐1.04) 1.00 (0.93‐1.09) 1.02 (0.92‐1.14) 1.08 (1.00‐1.16) 1.06 (0.96‐1.17) 1.06 (0.96‐1.16) 1.05 (0.96‐1.15) 1.00 (0.93‐1.07) 0.99 (0.92‐1.07) 0.96 (0.89‐1.03) 0.99 (0.92‐1.06) 1.02 (0.95‐1.09) 0.99 (0.84‐1.17) 1.05 (0.96‐1.15) 1.03 (0.95‐1.13) 1.03 (0.96‐1.11) 1.00 (0.93‐1.07) 0.98 (0.91‐1.06) 1.03 (0.96‐1.11) 0.80 (0.42‐1.54) 1.01 (0.95‐1.07) 1.03 (0.95‐1.12) 1.05 (0.96‐1.15) 0.98 (0.91‐1.05) 0.95 (0.89‐1.00) 1.05 (0.85‐1.29) 0.96 (0.86‐1.07) 0.99 (0.91‐1.07) 1.05 (0.96‐1.14) 1.01 (0.92‐1.12) 7.74E‐01 3.51E‐01 5.72E‐01 5.91E‐01 4.08E‐01 1.06E‐02 1.18E‐01 1.73E‐01 9.73E‐02 8.85E‐01 4.24E‐01 4.80E‐01 9.15E‐01 5.01E‐01 5.60E‐01 4.33E‐01 7.09E‐01 3.08E‐01 8.08E‐01 8.93E‐01 5.43E‐01 7.97E‐02 6.62E‐01 8.57E‐01 3.76E‐01 3.41E‐01 1.15E‐01 5.78E‐01 2.49E‐01 4.28E‐01 6.91E‐01 7.85E‐01 5.61E‐03 2.81E‐02 1.84E‐02 1.64E‐02 3.60E‐04 3.97E‐07 3.08E‐05 4.34E‐05 2.90E‐05 3.82E‐03 5.60E‐04 9.53E‐04 2.65E‐03 1.25E‐03 1.39E‐02 3.03E‐04 1.40E‐03 4.72E‐03 1.55E‐03 4.25E‐03 1.37E‐03 6.14E‐05 2.03E‐03 2.71E‐03 6.67E‐03 3.02E‐04 3.98E‐05 3.68E‐03 4.39E‐02 7.49E‐04 6.56E‐03 1.81E‐03 Page 107 of 127
rs7717247 rs462647 rs6880017 rs17155849 rs1898910 rs1042711 rs12194985 rs10080664 rs4716224 rs724941 rs943086 rs196701 rs7803642 rs9406428 rs10964496 rs10811340 rs1581979 rs10780305 rs1885984 rs2819042 rs359297 rs12256421 rs1223629 rs10870301 rs4443996 rs10870302 rs10870303 rs4568920 rs7117567 rs121704 rs10160242 rs2368785 Diabetes
5 5 5 5 5 5 6 6 6 6 6 6 7 9 9 9 9 9 9 10 10 10 10 10 10 10 10 10 11 11 11 12 27839258 81080808 81185254 103142399 124555847 148206348 6892411 15864284 18161563 76723011 76755221 80147187 21641629 11463799 20248264 20283406 23407435 81978708 119078249 10230151 17333680 17614097 95906315 134186772 134191005 134191738 134191811 134324451 7715079 17904634 108498885 260682 SH3TC2 KDM1B IMPG1 IMPG1 DNAH11 PAPPA PLCE1 LRRC27 LRRC27 LRRC27 LRRC27 OVCH2 SERGEF IQSEC3 SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI ‐0.33 0.32 ‐0.17 ‐0.29 ‐0.38 0.31 ‐0.40 0.15 ‐0.19 0.17 0.15 ‐0.35 ‐0.18 0.33 0.34 0.27 ‐0.18 0.15 ‐0.79 ‐0.18 ‐0.28 ‐0.20 ‐0.74 ‐0.12 ‐0.11 ‐0.13 ‐0.13 ‐0.29 ‐0.21 0.15 0.41 0.19 4.16E‐05 8.79E‐05 7.51E‐05 7.13E‐05 6.60E‐06 9.07E‐05 8.50E‐05 9.95E‐05 9.37E‐05 9.34E‐05 6.49E‐05 1.37E‐06 9.92E‐05 7.63E‐05 5.14E‐05 7.35E‐05 8.14E‐05 8.69E‐06 9.14E‐05 1.38E‐05 5.10E‐05 9.07E‐05 4.72E‐06 7.93E‐05 9.70E‐05 9.64E‐05 6.94E‐05 7.13E‐05 8.87E‐05 5.97E‐05 4.33E‐06 4.51E‐05 71
C/A C/T G/A T/C A/C C/T T/G A/G A/G C/T G/A C/T T/C C/T A/G G/A C/A A/G T/C A/C A/G A/G A/G C/T C/A T/G G/A T/C G/A G/A C/T C/T 0.136 0.334 0.314 0.290 0.161 0.212 0.032 0.384 0.306 0.446 0.449 0.128 0.321 0.132 0.091 0.098 0.310 0.431 0.009 0.455 0.213 0.387 0.038 0.435 0.441 0.436 0.436 0.077 0.356 0.474 0.060 0.150 0.99 (0.89‐1.10) 1.07 (0.99‐1.15) 0.97 (0.90‐1.04) 1.02 (0.94‐1.10) 1.02 (0.93‐1.12) 1.04 (0.97‐1.11) 1.17 (0.97‐1.43) 0.95 (0.89‐1.02) 1.00 (0.93‐1.07) 0.93 (0.87‐1.00) 1.00 (0.93‐1.07) 0.93 (0.84‐1.03) 1.05 (0.98‐1.13) 0.96 (0.86‐1.06) 0.95 (0.85‐1.06) 0.93 (0.83‐1.03) 0.95 (0.89‐1.03) 0.97 (0.91‐1.04) 0.64 (0.35‐1.19) 0.99 (0.92‐1.06) 1.03 (0.95‐1.12) 1.00 (0.94‐1.08) 0.98 (0.83‐1.16) 0.98 (0.92‐1.05) 0.97 (0.91‐1.04) 0.98 (0.92‐1.05) 0.99 (0.92‐1.06) 0.98 (0.86‐1.11) 1.02 (0.93‐1.11) 1.06 (0.98‐1.13) 1.11 (0.93‐1.33) 1.03 (0.93‐1.13) 7.57E‐01 4.37E‐02 5.61E‐01 5.96E‐01 7.04E‐01 6.40E‐01 3.04E‐01 3.04E‐01 8.23E‐01 7.11E‐01 3.15E‐01 5.03E‐02 9.62E‐01 7.62E‐02 9.58E‐01 8.57E‐01 4.25E‐01 5.95E‐01 1.90E‐01 8.34E‐01 8.39E‐01 5.42E‐01 4.29E‐01 4.49E‐01 3.22E‐01 4.06E‐01 8.09E‐01 2.63E‐01 7.59E‐01 5.16E‐02 7.79E‐01 9.50E‐02 1.83E‐03 1.78E‐01 1.69E‐02 1.46E‐03 3.52E‐03 1.48E‐02 4.55E‐04 5.04E‐04 9.20E‐03 2.49E‐03 3.46E‐02 4.23E‐02 6.55E‐03 5.10E‐05 3.73E‐03 3.38E‐03 2.63E‐02 4.31E‐04 6.57E‐02 1.27E‐03 6.51E‐03 1.95E‐02 7.44E‐03 2.41E‐02 3.98E‐02 3.01E‐02 8.24E‐03 4.36E‐02 2.80E‐03 1.44E‐01 2.29E‐03 8.83E‐02 Diabetes
rs1947234 rs10785139 rs9554019 rs17376318 rs9559508 rs10129961 rs17123946 rs10498430 rs17123969 rs4901281 rs11631474 rs896598 rs4887140 rs2415230 rs27230 rs16530 rs691336 rs6139479 rs6100794 rs2235438 rs2744761 rs11209072 rs12135476 rs10493454 rs4650135 rs1886644 rs6665426 rs17047682 rs10926618 rs7558483 rs17031893 rs7595513 12 12 13 13 13 14 14 14 14 14 15 15 15 15 16 17 17 20 20 1 1 1 1 1 1 1 1 1 1 2 2 2 39450491 75089475 27951711 108013050 109805793 34767305 51929722 51942961 51946458 52980190 67934167 74036629 74046663 74059081 3434699 37357034 76518426 4566415 58799036 4849384 26040514 67908644 69649328 69659840 69684997 85350658 200148319 218523025 242251696 11537452 44283172 46687867 FAM155A MYO16 TXNDC16 MAP2K5 C15orf59 ZNF434 RPL19 DNAH17 AX747739 BC037321 MAN1C1 LPAR3 TGFB2 PLD5 SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI SI M M M M M M M M M M M M M 0.13 0.19 ‐0.36 ‐0.41 ‐0.17 0.33 ‐0.29 ‐0.30 ‐0.30 ‐0.29 ‐0.24 0.37 0.31 0.26 ‐0.23 ‐0.33 ‐0.27 0.23 ‐0.63 15.45 ‐21.75 ‐22.54 ‐31.54 ‐29.41 ‐29.56 ‐22.90 ‐19.74 ‐31.01 ‐23.32 ‐19.51 27.41 ‐22.09 7.83E‐05 5.31E‐05 2.76E‐05 4.00E‐05 9.54E‐05 2.25E‐05 9.17E‐05 4.05E‐05 5.36E‐05 5.98E‐05 3.36E‐05 5.83E‐07 6.91E‐08 7.20E‐06 5.85E‐05 2.97E‐05 2.91E‐05 9.73E‐05 4.80E‐06 3.95E‐05 5.54E‐05 7.60E‐05 3.75E‐06 6.08E‐06 2.31E‐06 6.28E‐06 8.31E‐05 1.19E‐05 8.79E‐05 7.39E‐05 9.83E‐05 6.66E‐05 72
Page 108 of 127
A/C C/T A/G C/T T/C A/G G/A T/C G/A A/C G/A A/G G/T A/G G/A T/C T/C A/G T/C T/C G/T G/A A/G G/A C/T C/A A/G G/A T/C T/C G/A G/A 0.197 0.307 0.061 0.119 0.240 0.146 0.251 0.243 0.245 0.148 0.272 0.119 0.143 0.171 0.107 0.102 0.261 0.308 0.012 0.357 0.229 0.393 0.118 0.136 0.157 0.295 0.309 0.078 0.386 0.244 0.101 0.198 1.02 (0.93‐1.11) 1.04 (0.96‐1.12) 1.02 (0.80‐1.30) 0.98 (0.87‐1.11) 0.95 (0.88‐1.03) 1.07 (0.97‐1.18) 1.09 (1.00‐1.18) 1.11 (1.02‐1.20) 1.11 (1.02‐1.21) 1.03 (0.94‐1.14) 0.98 (0.91‐1.06) 1.07 (0.96‐1.19) 0.97 (0.88‐1.07) 1.07 (0.98‐1.17) 0.94 (0.84‐1.04) 0.97 (0.86‐1.10) 0.98 (0.91‐1.06) 0.94 (0.87‐1.02) 1.10 (0.60‐2.02) 1.09 (1.01‐1.18) 1.06 (0.97‐1.16) 1.05 (0.98‐1.12) 0.99 (0.89‐1.10) 1.00 (0.91‐1.09) 1.01 (0.92‐1.11) 0.93 (0.86‐1.00) 0.94 (0.87‐1.03) 1.09 (0.90‐1.31) 1.02 (0.95‐1.10) 0.98 (0.91‐1.07) 0.93 (0.84‐1.03) 0.94 (0.86‐1.02) 8.21E‐01 6.92E‐01 7.86E‐01 7.08E‐01 5.34E‐01 2.02E‐01 1.50E‐01 7.37E‐02 2.37E‐01 4.55E‐01 8.76E‐01 9.72E‐02 2.93E‐01 2.01E‐01 6.25E‐01 7.24E‐01 6.97E‐01 3.82E‐01 8.27E‐01 7.53E‐02 8.04E‐01 2.03E‐01 9.13E‐01 7.50E‐01 8.17E‐01 5.01E‐02 3.54E‐01 1.11E‐01 8.50E‐01 9.67E‐01 3.59E‐01 4.35E‐01 8.47E‐03 9.95E‐03 5.56E‐03 8.30E‐03 2.04E‐02 3.62E‐02 1.54E‐04 3.08E‐05 2.22E‐04 7.63E‐04 4.77E‐03 1.83E‐02 2.14E‐03 2.33E‐02 1.26E‐02 1.36E‐03 7.36E‐03 7.41E‐04 7.02E‐04 9.92E‐02 7.47E‐03 2.18E‐04 1.41E‐03 6.16E‐04 4.57E‐04 7.05E‐02 3.34E‐02 2.39E‐05 3.65E‐03 4.63E‐03 6.67E‐04 2.33E‐02 Page 109 of 127
rs2138397 rs2889323 rs10179986 rs1996589 rs4953902 rs1111961 rs13030335 rs10178963 rs1546676 rs1429411 rs2178704 rs11683087 rs2251692 rs10205233 rs2596937 rs2279440 rs17050395 rs3806667 rs13106 rs635787 rs9682976 rs17062321 rs9854367 rs12493716 rs12487584 rs13094259 rs9824464 rs1426260 rs10937355 rs12511127 rs6448852 rs1025877 Diabetes
2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 86974049 RMND5A 105039687 134864344 134865196 134876049 134880830 142231898 LRP1B 142349495 LRP1B 154509239 198144002 ANKRD44 227579207 227586606 227589780 227614005 IRS1 9480906 SETD5 9518511 SETD5 9533974 9860880 ARPC4‐TTLL3 12624580 MKRN2 32466487 CMTM7 60118879 FHIT 60122156 FHIT 102259425 106777359 LOC100302640 132300293 ACAD11 142444625 TRPC1 167635899 LOC646168 188260703 LPP 188289697 LPP 5142212 STK32B 12017993 12074137 M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M ‐24.39 ‐14.31 ‐17.78 ‐21.95 ‐25.81 ‐25.37 ‐33.45 24.53 23.62 21.71 25.31 20.54 17.31 23.19 ‐17.41 ‐21.57 ‐17.84 ‐20.45 126.46 ‐22.82 ‐24.49 ‐24.84 27.76 ‐16.30 19.13 ‐29.40 27.97 27.98 ‐23.26 ‐16.49 15.04 ‐14.32 3.71E‐05 3.60E‐04 7.95E‐06 3.97E‐05 1.41E‐05 1.40E‐05 4.13E‐05 9.64E‐05 8.00E‐06 4.09E‐04 8.83E‐05 7.42E‐07 1.98E‐05 2.35E‐05 9.76E‐05 3.31E‐06 8.31E‐05 2.79E‐05 3.41E‐05 1.24E‐05 5.93E‐05 2.39E‐05 3.04E‐04 9.21E‐05 2.87E‐05 9.10E‐05 8.41E‐05 4.25E‐06 4.12E‐05 6.59E‐05 5.55E‐05 9.65E‐05 73
A/G C/A G/A C/T C/A G/A A/G C/A A/G G/A G/A G/A A/G T/C C/T T/C G/A G/T A/G A/G T/C T/C C/T G/A T/C T/G T/C T/C T/C G/A C/T G/A 0.442 0.436 0.467 0.230 0.140 0.158 0.382 0.446 0.325 0.436 0.244 0.412 0.483 0.185 0.238 0.203 0.235 0.272 0.028 0.453 0.152 0.163 0.092 0.253 0.284 0.091 0.468 0.501 0.306 0.325 0.468 0.455 1.00 (0.93‐1.07) 1.01 (0.94‐1.09) 1.00 (0.93‐1.07) 0.95 (0.88‐1.03) 0.95 (0.86‐1.05) 0.96 (0.87‐1.05) 0.89 (0.83‐0.96) 1.12 (1.04‐1.20) 1.02 (0.95‐1.10) 1.07 (1.00‐1.14) 0.94 (0.87‐1.03) 1.02 (0.94‐1.11) 1.04 (0.97‐1.11) 0.97 (0.89‐1.06) 1.00 (0.93‐1.08) 1.04 (0.96‐1.13) 0.96 (0.89‐1.03) 1.03 (0.95‐1.11) 0.90 (0.50‐1.62) 0.98 (0.91‐1.06) 1.02 (0.93‐1.13) 1.03 (0.94‐1.14) 0.94 (0.84‐1.05) 0.96 (0.88‐1.04) 1.06 (0.98‐1.15) 1.05 (0.94‐1.17) 0.98 (0.91‐1.04) 1.01 (0.94‐1.08) 0.97 (0.90‐1.05) 1.04 (0.97‐1.12) 0.95 (0.89‐1.02) 1.02 (0.96‐1.08) 9.03E‐01 7.85E‐01 8.77E‐01 7.90E‐01 7.10E‐01 6.47E‐01 9.78E‐04 6.83E‐03 5.20E‐01 1.19E‐01 1.39E‐01 8.38E‐01 6.73E‐01 2.18E‐01 2.32E‐01 9.13E‐01 5.60E‐02 3.99E‐01 3.16E‐01 2.10E‐01 7.28E‐01 6.51E‐01 6.85E‐01 3.71E‐01 2.27E‐01 5.03E‐02 9.28E‐01 7.67E‐01 9.71E‐01 6.18E‐01 2.39E‐01 9.44E‐01 4.64E‐03 6.61E‐03 2.30E‐03 6.58E‐03 4.99E‐03 5.99E‐03 5.70E‐01 3.98E‐01 6.88E‐03 1.62E‐01 1.34E‐04 7.92E‐04 6.56E‐03 1.13E‐04 5.60E‐02 1.32E‐03 1.52E‐01 3.71E‐04 2.74E‐04 2.75E‐02 2.03E‐03 9.42E‐04 4.50E‐03 3.30E‐02 3.53E‐02 3.31E‐05 4.45E‐03 2.35E‐03 4.05E‐03 1.50E‐03 2.31E‐04 5.00E‐03 Diabetes
rs4834882 rs9997603 rs4320186 rs1023514 rs11930824 rs4627838 rs4695784 rs6877846 rs4835696 rs13361457 rs1019507 rs1465417 rs322394 rs241439 rs16884633 rs987672 rs665791 rs484621 rs490010 rs510432 rs4134409 rs10267935 rs11768415 rs11764734 rs296307 rs296316 rs2188256 rs1588422 rs2968865 rs441606 rs17197236 rs13267838 4 4 4 4 4 4 4 5 5 5 5 5 5 6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 8 8 8 12108239 66438114 66483593 108239396 161451545 175602762 175608905 81160103 137972584 152797679 152798614 153790531 172157768 32797537 53902171 77410315 106674850 106734408 106740458 106774030 170279658 34885503 52347667 52356515 52432938 52439967 88213062 97329406 124810399 17903046 25193338 25196710 EPHA5 EPHA5 GLRA3 GLRA3 GALNT10 TAP2 MLIP ATG5 ATG5 ATG5 AAA1 AX746567 DOCK5 DOCK5 M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M 18.23 ‐31.75 ‐30.58 7.76 29.13 19.97 19.97 20.99 35.18 23.81 ‐18.01 ‐20.39 ‐15.83 18.67 ‐23.78 ‐17.03 18.17 18.89 18.72 16.93 19.26 ‐26.04 ‐17.74 ‐18.43 ‐15.67 ‐16.72 ‐21.95 44.15 29.85 26.11 54.29 54.96 2.08E‐05 1.54E‐05 2.41E‐05 5.36E‐02 7.46E‐05 7.25E‐05 7.25E‐05 5.27E‐05 1.74E‐05 9.63E‐06 2.10E‐05 7.72E‐05 3.38E‐05 9.23E‐05 3.67E‐05 9.05E‐05 8.39E‐06 4.12E‐06 5.91E‐06 2.61E‐05 3.79E‐05 3.55E‐04 2.80E‐05 1.41E‐05 8.25E‐05 9.52E‐05 6.79E‐05 3.19E‐05 1.40E‐05 9.48E‐05 7.13E‐06 4.03E‐06 74
Page 110 of 127
T/C T/G A/G A/G A/G A/C T/C A/G A/G T/C C/A T/C C/T G/T A/G G/A G/A T/C A/G T/C A/G A/C A/G T/C T/C T/C C/T T/C G/A A/G G/A T/G 0.314 0.080 0.079 0.413 0.445 0.427 0.426 0.328 0.383 0.477 0.409 0.198 0.360 0.426 0.234 0.358 0.328 0.323 0.316 0.341 0.245 0.105 0.519 0.520 0.470 0.369 0.179 0.278 0.459 0.462 0.034 0.035 1.00 (0.93‐1.08) 1.01 (0.90‐1.13) 1.08 (0.95‐1.23) 1.07 (1.00‐1.15) 0.99 (0.93‐1.06) 1.02 (0.95‐1.09) 1.01 (0.94‐1.07) 1.02 (0.95‐1.10) 0.95 (0.88‐1.02) 1.04 (0.97‐1.12) 0.99 (0.93‐1.07) 0.98 (0.90‐1.06) 1.17 (1.09‐1.26) 0.94 (0.87‐1.00) 0.97 (0.89‐1.06) 1.03 (0.96‐1.11) 0.88 (0.82‐0.94) 0.95 (0.88‐1.02) 0.88 (0.82‐0.94) 0.94 (0.88‐1.01) 0.89 (0.80‐0.99) 0.99 (0.90‐1.10) 1.00 (0.93‐1.06) 0.97 (0.91‐1.05) 0.97 (0.91‐1.04) 0.93 (0.86‐1.00) 0.97 (0.89‐1.06) 1.00 (0.93‐1.07) 0.99 (0.93‐1.06) 0.92 (0.86‐0.99) 0.89 (0.73‐1.08) 0.90 (0.75‐1.08) 9.93E‐01 9.81E‐01 3.57E‐01 1.22E‐01 3.48E‐01 5.38E‐01 7.84E‐01 3.16E‐01 2.35E‐01 1.18E‐01 4.74E‐01 4.60E‐01 7.87E‐04 6.69E‐01 6.21E‐01 7.05E‐01 5.92E‐02 3.23E‐01 9.35E‐02 1.47E‐01 3.50E‐01 7.77E‐01 6.10E‐01 3.22E‐01 4.34E‐01 2.59E‐02 8.44E‐01 9.93E‐01 8.79E‐01 8.73E‐02 1.64E‐01 1.45E‐01 2.57E‐03 2.36E‐03 2.76E‐04 7.86E‐01 5.30E‐04 1.78E‐02 8.99E‐03 3.16E‐02 1.06E‐04 4.31E‐02 1.24E‐02 2.30E‐02 1.12E‐07 2.16E‐03 1.08E‐03 1.24E‐02 7.32E‐06 7.64E‐05 1.14E‐05 6.38E‐05 3.51E‐04 2.01E‐02 9.28E‐03 1.78E‐02 2.57E‐02 2.37E‐01 3.11E‐03 3.20E‐03 3.04E‐03 7.21E‐05 3.21E‐05 1.78E‐05 Page 111 of 127
rs13252932 rs11780263 rs9650426 rs1715350 rs4737430 rs633142 rs618854 rs4333664 rs17781302 rs17060946 rs7030420 rs1888221 rs17099236 rs4564313 rs1488933 rs10841497 rs7964191 rs10770655 rs7311799 rs11059101 rs4760067 rs2874868 rs7329452 rs4520736 rs4885169 rs1041515 rs7992923 rs1331765 rs10492494 rs2325622 rs9554374 rs2389751 Diabetes
8 8 8 8 8 8 8 9 9 9 9 9 10 11 11 12 12 12 12 12 12 13 13 13 13 13 13 13 13 13 13 13 25198091 27823832 27827391 50396852 57303823 102466767 102467706 6556948 24142314 77808519 77809075 117778355 92484110 6083952 17267029 20524202 20551038 20574060 84718394 127874250 130611682 36356679 39000963 59174647 74900793 74905950 74907043 74907933 74920186 74932425 97580064 97584304 DOCK5 SCARA5 SCARA5 GLDC PDE3A PDE3A PDE3A MAB21L1 M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M 47.71 ‐16.34 15.63 ‐19.15 17.90 ‐16.14 ‐16.61 16.94 21.35 37.86 29.63 19.08 28.87 ‐13.19 30.81 17.05 24.85 23.56 ‐27.14 ‐25.34 ‐23.40 16.78 ‐23.70 ‐21.75 ‐23.04 ‐21.78 ‐13.94 ‐15.35 ‐22.02 ‐21.66 20.73 15.52 5.17E‐06 6.64E‐05 6.38E‐05 7.31E‐05 6.71E‐05 8.10E‐05 5.04E‐05 1.15E‐05 6.10E‐05 2.56E‐06 5.75E‐05 2.52E‐06 5.13E‐05 1.49E‐03 2.76E‐05 3.17E‐05 5.20E‐05 9.20E‐05 9.33E‐05 9.30E‐05 2.54E‐05 6.40E‐05 3.64E‐05 2.56E‐05 5.31E‐06 5.14E‐07 7.86E‐05 2.15E‐05 5.04E‐07 5.61E‐07 4.37E‐04 2.13E‐04 75
T/C A/G C/T T/G A/G T/G T/C T/C C/A G/A G/A A/G A/G A/G T/C G/T C/T C/A A/C C/T T/C G/T G/T C/T A/G C/T A/G G/A A/C A/C T/G A/G 0.049 0.210 0.334 0.258 0.404 0.337 0.343 0.432 0.178 0.068 0.080 0.310 0.114 0.489 0.448 0.356 0.150 0.180 0.469 0.100 0.432 0.233 0.498 0.415 0.239 0.243 0.427 0.372 0.240 0.247 0.387 0.411 0.89 (0.75‐1.04) 0.92 (0.84‐1.00) 0.97 (0.90‐1.05) 1.08 (1.00‐1.17) 0.98 (0.91‐1.05) 0.93 (0.87‐0.99) 0.93 (0.87‐1.00) 0.99 (0.92‐1.06) 1.09 (0.93‐1.27) 0.87 (0.75‐1.01) 0.95 (0.83‐1.09) 0.97 (0.90‐1.05) 0.96 (0.86‐1.07) 0.94 (0.88‐1.00) 1.08 (1.01‐1.16) 1.05 (0.91‐1.22) 1.12 (1.02‐1.24) 1.12 (1.02‐1.23) 1.00 (0.93‐1.07) 0.99 (0.75‐1.31) 0.94 (0.88‐1.01) 0.94 (0.87‐1.02) 0.97 (0.92‐1.03) 0.99 (0.92‐1.07) 1.10 (1.01‐1.19) 1.08 (1.00‐1.18) 1.05 (0.99‐1.13) 1.06 (0.99‐1.14) 1.11 (1.02‐1.20) 1.07 (0.99‐1.16) 1.07 (0.99‐1.15) 1.02 (0.95‐1.09) 6.61E‐02 1.21E‐02 2.58E‐01 2.91E‐01 7.97E‐01 3.99E‐02 4.21E‐02 7.79E‐01 3.36E‐01 6.89E‐02 5.25E‐01 8.52E‐01 6.47E‐01 2.72E‐02 8.21E‐02 9.35E‐02 3.05E‐02 2.71E‐02 7.60E‐01 8.71E‐01 2.16E‐01 7.78E‐01 8.55E‐01 8.42E‐01 6.90E‐01 7.18E‐01 6.37E‐01 6.38E‐01 4.22E‐01 9.52E‐01 8.82E‐01 4.73E‐01 6.11E‐06 2.95E‐01 2.87E‐04 3.84E‐04 2.69E‐03 1.82E‐01 1.53E‐01 3.70E‐03 3.12E‐02 3.99E‐06 9.87E‐04 5.40E‐04 1.44E‐03 4.94E‐01 8.27E‐02 7.90E‐02 1.83E‐01 2.29E‐01 2.89E‐03 8.07E‐03 3.55E‐02 2.48E‐03 2.30E‐03 4.57E‐03 4.64E‐04 1.41E‐04 1.78E‐03 8.46E‐04 3.77E‐05 3.42E‐04 1.72E‐02 1.77E‐03 Diabetes
rs555647 rs6572117 rs17120327 rs7165441 rs17818867 rs11637842 rs17238052 rs3826347 rs6501303 rs626410 rs12961613 rs10408924 rs892024 rs913555 rs911112 rs11907984 rs4813402 rs6137217 rs6047982 rs6113604 rs4815102 rs1028444 rs4813452 rs17192831 rs6018406 rs155004 rs1573708 rs763040 rs2784739 rs11121182 rs10492966 rs11121203 13 14 14 15 15 15 15 17 17 18 18 19 19 20 20 20 20 20 20 20 20 20 20 20 20 20 22 22 1 1 1 1 98632349 IPO5 M 42360633 LRFN5 M 49073392 M 27828539 M 55175350 M 55200927 M 55259099 M 64970002 CACNG4 M 77430593 RBFOX3 M 65855591 M 66309996 M 9253139 ZNF317 M 33399344 CEP89 M 3090124 LOC100134015 M 3144664 ProSAPiP1 M 20862068 M 20889803 M 20997702 M 22246450 M 22252275 M 22255173 CR627206 M 22267058 M 22276813 M 22281954 M 45941326 ZMYND8 M 57870356 M 36427484 M 44763606 M 8497558 RERE AIRg
AIRg 8522553 RERE AIRg 8598005 RERE AIRg 8648240 RERE 20.89 ‐29.20 ‐22.43 22.79 19.09 20.78 22.68 25.26 33.30 16.55 ‐22.84 22.59 ‐23.28 21.80 22.86 ‐16.12 ‐16.68 24.96 12.85 22.01 21.95 26.33 24.54 24.83 18.51 ‐24.33 14.69 22.54 ‐1.98 ‐1.92 ‐1.96 ‐1.86 8.65E‐05 9.45E‐05 3.06E‐05 6.52E‐05 1.24E‐05 1.43E‐05 9.39E‐05 4.44E‐05 4.32E‐05 2.88E‐05 6.23E‐05 9.94E‐05 8.92E‐05 6.92E‐05 6.70E‐05 9.28E‐05 5.21E‐05 9.01E‐06 6.23E‐04 1.22E‐04 1.39E‐04 5.22E‐06 2.16E‐05 1.64E‐05 5.91E‐05 2.48E‐05 2.25E‐03 6.91E‐05 1.91E‐05 5.01E‐05 4.70E‐05 4.42E‐05 76
Page 112 of 127
G/A T/C A/G G/A C/T A/G G/A G/A A/G A/C T/C G/T A/G A/G T/C T/C C/T T/C G/T T/C T/G C/T G/T T/C C/A G/A T/C A/G G/T A/C T/C C/T 0.403 0.374 0.199 0.408 0.255 0.225 0.235 0.424 0.046 0.398 0.229 0.370 0.168 0.295 0.254 0.370 0.366 0.349 0.419 0.369 0.371 0.404 0.382 0.386 0.247 0.283 0.488 0.205 0.243 0.270 0.273 0.286 1.00 (0.93‐1.07) 0.98 (0.91‐1.05) 1.03 (0.95‐1.12) 1.01 (0.94‐1.08) 1.01 (0.93‐1.09) 1.01 (0.93‐1.09) 1.03 (0.95‐1.11) 1.00 (0.93‐1.07) 0.95 (0.80‐1.12) 0.96 (0.90‐1.03) 1.07 (0.94‐1.21) 0.97 (0.90‐1.04) 1.00 (0.92‐1.10) 1.01 (0.94‐1.09) 1.00 (0.93‐1.09) 0.99 (0.92‐1.07) 0.99 (0.92‐1.06) 0.96 (0.89‐1.03) 0.98 (0.92‐1.06) 1.03 (0.96‐1.10) 0.99 (0.92‐1.06) 1.02 (0.96‐1.10) 1.03 (0.96‐1.11) 0.98 (0.91‐1.05) 0.88 (0.79‐0.97) 0.95 (0.87‐1.04) 0.95 (0.89‐1.03) 1.04 (0.96‐1.13) 1.01 (0.93‐1.10) 0.87 (0.81‐0.94) 0.87 (0.81‐0.94) 0.96 (0.88‐1.03) 4.15E‐01 2.70E‐01 8.15E‐01 4.83E‐01 5.38E‐01 6.06E‐01 1.65E‐01 9.15E‐01 1.30E‐01 6.99E‐01 1.26E‐01 4.57E‐01 8.53E‐01 8.91E‐01 7.46E‐01 7.18E‐01 8.26E‐01 6.94E‐01 4.66E‐01 6.89E‐01 3.79E‐01 8.62E‐01 7.51E‐01 2.33E‐01 1.06E‐01 2.50E‐01 6.46E‐01 8.50E‐01 2.97E‐01 4.40E‐03 3.27E‐03 5.20E‐02 8.00E‐04 4.76E‐02 1.85E‐03 2.00E‐02 7.94E‐03 6.86E‐03 7.52E‐02 4.92E‐03 7.43E‐05 1.23E‐03 9.10E‐05 1.05E‐03 3.71E‐03 6.59E‐03 2.31E‐03 2.53E‐03 2.56E‐03 6.31E‐04 3.34E‐03 2.69E‐03 9.13E‐04 8.26E‐04 1.25E‐03 9.99E‐05 6.84E‐05 3.01E‐02 1.30E‐02 7.36E‐03 2.23E‐02 3.93E‐01 4.25E‐01 1.30E‐01 Page 113 of 127
rs12061717 rs13375344 rs7537721 rs11185362 rs17018659 rs2053797 rs4953320 rs1345516 rs6756027 rs13002043 rs9809000 rs6803803 rs17013808 rs3893856 rs10041174 rs11750248 rs6887101 rs193541 rs17149748 rs6891052 rs10476419 rs10078423 rs10051450 rs4712523 rs6456369 rs7754840 rs9368222 rs2206734 rs1040558 rs6935599 rs10946403 rs9358357 Diabetes
1 1 1 1 2 2 2 2 2 2 3 3 4 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 6 55024928 73500168 88514479 104561488 4211781 46370892 46374529 64703286 64720254 64726449 154268934 180116563 89004957 111163 11710193 52153066 122109207 122253304 122267367 122358015 162296335 162312823 162378040 20657564 20660365 20661250 20686996 20694884 20713706 20717095 20717404 20719145 ACOT11 PRKCE PRKCE CTNND2 ITGA1 SNX24 SNX24 CDKAL1 CDKAL1 CDKAL1 CDKAL1 CDKAL1 CDKAL1 CDKAL1 CDKAL1 CDKAL1 AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg ‐2.10 16.86 8.45 ‐1.65 10.57 1.89 2.13 1.04 1.09 1.07 2.17 17.53 ‐3.15 2.09 ‐2.59 2.43 ‐1.70 ‐1.71 ‐2.14 ‐2.31 4.71 7.29 7.39 ‐1.17 ‐0.98 ‐1.26 ‐1.46 ‐2.05 ‐1.92 ‐1.73 ‐1.74 ‐1.77 2.66E‐05 3.10E‐05 2.92E‐05 3.21E‐05 5.39E‐05 5.02E‐05 8.13E‐05 4.11E‐05 6.05E‐05 7.92E‐05 2.76E‐05 1.64E‐06 4.05E‐05 7.21E‐05 2.36E‐05 2.88E‐05 1.24E‐05 7.64E‐06 5.70E‐05 2.32E‐05 8.86E‐05 4.94E‐05 3.14E‐05 1.60E‐05 5.17E‐05 3.83E‐06 1.28E‐06 1.02E‐06 5.52E‐06 5.83E‐05 5.56E‐05 3.60E‐05 77
T/C A/C A/G G/A G/A A/G C/T A/C A/G A/G G/A C/T A/G A/G G/A T/C A/G C/T G/A T/G G/A G/A T/C G/A C/T C/G A/C T/C G/A G/A G/A G/A 0.080 0.002 0.010 0.309 0.004 0.162 0.099 0.420 0.432 0.437 0.080 0.002 0.056 0.096 0.080 0.068 0.270 0.253 0.093 0.092 0.010 0.005 0.005 0.315 0.350 0.310 0.262 0.194 0.218 0.245 0.242 0.247 0.95 (0.84‐1.08) 2.77 (0.48‐16.12) 0.79 (0.33‐1.90) 1.06 (0.98‐1.14) 1.35 (0.45‐4.06) 0.91 (0.83‐1.00) 0.95 (0.84‐1.07) 0.95 (0.88‐1.02) 0.95 (0.88‐1.02) 0.99 (0.93‐1.05) 0.99 (0.89‐1.11) 0.63 (0.25‐1.59) 1.03 (0.88‐1.20) 0.95 (0.85‐1.05) 1.07 (0.95‐1.21) 1.22 (1.07‐1.39) 0.98 (0.91‐1.05) 0.98 (0.91‐1.06) 0.94 (0.84‐1.06) 0.92 (0.82‐1.04) 1.23 (0.61‐2.47) 0.87 (0.38‐1.97) 1.20 (0.50‐2.91) 1.03 (0.96‐1.11) 1.09 (1.01‐1.17) 1.10 (1.02‐1.18) 1.12 (1.00‐1.25) 1.19 (1.09‐1.30) 1.15 (1.05‐1.24) 1.03 (0.96‐1.11) 1.09 (1.01‐1.18) 1.16 (1.07‐1.26) 1.96E‐01 2.69E‐01 1.72E‐01 4.67E‐01 4.11E‐01 1.42E‐02 1.71E‐01 2.04E‐01 3.87E‐01 9.29E‐01 6.97E‐01 4.23E‐01 6.78E‐01 5.26E‐01 5.16E‐01 1.75E‐02 4.56E‐01 4.08E‐01 3.63E‐01 2.39E‐01 3.66E‐01 7.94E‐01 5.10E‐01 2.64E‐01 2.97E‐02 9.77E‐03 3.31E‐03 1.41E‐03 5.05E‐03 2.01E‐01 5.25E‐03 2.64E‐03 3.97E‐02 3.04E‐02 8.85E‐05 5.50E‐04 2.30E‐02 4.21E‐06 1.74E‐04 1.46E‐04 5.65E‐04 4.32E‐03 1.20E‐03 7.64E‐05 1.39E‐03 1.14E‐03 5.62E‐04 2.02E‐01 1.04E‐02 9.90E‐03 2.76E‐02 3.08E‐02 3.29E‐02 7.26E‐03 1.32E‐02 1.23E‐04 1.09E‐05 3.50E‐07 3.78E‐08 1.11E‐08 2.04E‐07 1.80E‐04 1.41E‐06 4.46E‐07 Diabetes
rs9356746 rs3873380 rs35473403 rs7750450 rs11963462 rs9321207 rs4897370 rs2038586 rs9295206 rs7779074 rs10232215 rs2111200 rs10237822 rs10242768 rs11779094 rs7000560 rs4922265 rs6988635 rs7018475 rs13301551 rs2295926 rs7341705 rs1602111 rs2287005 rs7036846 rs10870202 rs7919192 rs6584696 rs2129969 rs510398 rs11227856 rs10898909 6 6 6 6 6 6 6 6 6 7 7 7 7 7 8 8 8 8 9 9 9 9 9 9 9 9 10 10 11 11 11 11 20720279 31262438 43480822 55714563 121021878 130397238 130466676 158091108 163326692 22986107 92097166 92140397 93760001 93784157 10666813 16993943 16996435 95744466 22137685 25683697 101593825 107651348 109277184 113791313 119798885 139257411 93660727 107578214 45586169 66054823 67377758 72952496 CDKAL1 HLA‐B YIPF3 BMP5 L3MBTL3 SAMD3 ZDHHC14 PACRG FAM126A PEX1 SOX7 DPY19L4 GALNT12 ABCA1 BC017988 LPAR1 ASTN2 DNLZ YIF1A NDUFV1 AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg ‐1.73 1.55 16.32 1.40 1.60 ‐0.97 1.43 1.97 ‐1.18 2.13 1.96 1.96 3.94 3.94 ‐2.18 2.00 2.11 1.18 ‐1.64 2.39 ‐1.61 13.32 ‐1.53 2.61 10.86 ‐1.04 ‐1.45 4.14 1.14 12.63 6.51 1.41 3.29E‐05 4.50E‐05 7.58E‐05 6.21E‐05 6.06E‐05 7.43E‐05 3.80E‐05 1.49E‐05 4.78E‐05 9.56E‐05 4.41E‐05 3.21E‐05 3.53E‐05 6.87E‐05 8.16E‐05 3.35E‐05 6.61E‐06 7.73E‐05 4.90E‐06 8.39E‐05 2.21E‐05 1.77E‐05 2.16E‐05 6.49E‐05 9.25E‐06 5.37E‐05 5.00E‐05 2.66E‐05 2.10E‐05 4.37E‐06 5.34E‐05 4.03E‐06 78
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C/T T/C T/C C/T C/T A/G G/A T/C G/A A/G G/A T/C G/T C/T A/G C/A A/C G/A G/T T/C C/T C/T C/A C/T C/T T/C C/T C/T G/A C/T T/C A/G 0.193 0.408 0.002 0.322 0.232 0.365 0.346 0.184 0.400 0.101 0.248 0.251 0.025 0.022 0.075 0.476 0.469 0.444 0.323 0.075 0.348 0.003 0.233 0.068 0.005 0.430 0.216 0.026 0.477 0.003 0.005 0.404 1.16 (1.06‐1.27) 0.89 (0.70‐1.12) 1.02 (0.32‐3.29) 0.92 (0.86‐0.99) 1.09 (1.00‐1.19) 0.97 (0.90‐1.04) 0.97 (0.90‐1.04) 0.92 (0.81‐1.05) 1.00 (0.93‐1.07) 1.17 (1.05‐1.32) 0.95 (0.88‐1.03) 0.96 (0.88‐1.05) 1.03 (0.81‐1.31) 1.10 (0.84‐1.46) 1.10 (0.94‐1.27) 1.04 (0.97‐1.12) 1.00 (0.93‐1.07) 0.96 (0.89‐1.03) 1.09 (1.02‐1.17) 0.97 (0.85‐1.11) 0.92 (0.82‐1.04) 1.02 (0.49‐2.10) 1.00 (0.93‐1.08) 1.08 (0.92‐1.26) 1.11 (0.57‐2.17) 1.12 (1.05‐1.20) 0.92 (0.84‐1.01) 0.82 (0.66‐1.02) 0.91 (0.85‐0.98) 1.89 (0.65‐5.53) 1.77 (0.88‐3.55) 0.94 (0.86‐1.02) 8.95E‐03 3.21E‐01 9.73E‐01 4.67E‐02 1.72E‐01 5.05E‐01 8.71E‐01 6.47E‐02 9.75E‐01 2.90E‐02 7.07E‐01 4.02E‐01 3.89E‐01 1.60E‐01 7.19E‐01 8.77E‐01 8.54E‐01 5.33E‐01 2.34E‐03 1.80E‐01 1.08E‐01 3.82E‐01 9.49E‐01 7.63E‐01 6.67E‐01 2.08E‐02 6.01E‐01 2.70E‐01 2.38E‐02 6.85E‐01 4.86E‐01 9.27E‐02 1.71E‐06 3.35E‐04 5.53E‐03 2.26E‐05 6.13E‐02 1.98E‐02 2.46E‐03 1.26E‐05 3.76E‐03 2.24E‐01 1.61E‐03 1.89E‐02 2.06E‐02 6.87E‐02 2.36E‐03 4.74E‐03 9.11E‐04 1.21E‐03 7.31E‐08 1.92E‐04 6.23E‐02 1.56E‐02 3.09E‐03 9.03E‐03 5.82E‐04 7.10E‐06 1.25E‐02 1.77E‐04 4.10E‐06 3.07E‐03 1.81E‐02 8.64E‐06 Page 115 of 127
rs3847554 rs1387153 rs2166706 rs10830961 rs10830963 rs686413 rs12292105 rs7927108 rs7962050 rs247352 rs12816878 rs3847896 rs1489076 rs11049971 rs1489078 rs11113214 rs3026485 rs16940879 rs10774579 rs10744163 rs9553849 rs9670049 rs9585660 rs7158254 rs1690356 rs2570133 rs9935964 rs7192071 rs16953087 rs1006703 rs2619996 rs899596 Diabetes
11 11 11 11 11 11 11 11 12 12 12 12 12 12 12 12 12 12 12 12 13 13 13 14 15 15 16 16 17 17 17 17 92668826 92673828 92691532 92694757 92708710 117537710 117983479 134038949 1031454 14900457 23155705 23159966 29129874 29130200 29141413 107588082 110782027 110928719 121405210 124383950 27082326 31692454 101962642 37264674 55301874 87604296 66216144 78953857 420033 3865399 71703758 71735485 MTNR1B DSCAML1 TMPRSS4 NCAPD3 RAD52 AK094733 AK094733 ATP2A2 DNAH10 NALCN SLC25A21 WWOX VPS53 ATP2A3 AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg ‐1.64 ‐2.55 ‐1.70 ‐1.59 ‐2.76 ‐1.19 3.77 10.54 1.20 4.42 1.31 1.12 ‐1.37 ‐1.37 ‐1.34 ‐1.93 15.24 11.03 1.59 1.75 1.57 1.81 8.29 7.18 13.41 ‐1.00 28.14 4.34 ‐1.81 2.13 3.15 2.20 1.08E‐06 2.21E‐09 1.24E‐06 1.91E‐06 5.23E‐12 5.67E‐05 3.77E‐05 4.35E‐05 7.67E‐05 9.24E‐05 9.69E‐05 6.47E‐05 1.97E‐05 1.78E‐05 2.48E‐05 6.21E‐05 6.78E‐06 6.21E‐05 7.01E‐05 2.66E‐05 6.70E‐05 9.20E‐05 2.60E‐05 3.91E‐05 1.47E‐05 6.64E‐05 9.57E‐08 7.30E‐05 3.26E‐05 2.65E‐06 7.69E‐05 2.64E‐06 79
T/C T/C C/T G/A G/C A/G G/T T/G G/A C/T T/C C/T T/C T/C G/A G/A C/T G/A C/T T/C A/G C/T A/G C/T A/C C/T A/G G/A C/T T/C T/C G/A 0.343 0.220 0.308 0.331 0.220 0.327 0.024 0.004 0.323 0.013 0.283 0.453 0.377 0.376 0.376 0.219 0.002 0.003 0.252 0.200 0.199 0.176 0.006 0.007 0.003 0.416 0.001 0.024 0.130 0.087 0.042 0.230 1.07 (1.00‐1.15) 1.07 (0.98‐1.16) 1.07 (0.99‐1.15) 1.07 (0.99‐1.15) 1.08 (1.00‐1.18) 0.94 (0.88‐1.00) 0.92 (0.73‐1.16) 0.82 (0.35‐1.93) 0.96 (0.89‐1.03) 1.20 (0.94‐1.52) 0.98 (0.91‐1.05) 0.94 (0.88‐1.01) 0.97 (0.91‐1.04) 0.98 (0.91‐1.05) 0.98 (0.92‐1.06) 1.08 (0.99‐1.17) 2.54 (0.96‐6.73) 1.51 (0.68‐3.37) 0.97 (0.89‐1.06) 0.97 (0.89‐1.06) 0.86 (0.79‐0.94) 1.02 (0.94‐1.10) 1.55 (0.82‐2.94) 1.22 (0.74‐2.01) 0.95 (0.29‐3.07) 1.03 (0.95‐1.10) 2.15 (0.21‐22.37) 0.94 (0.77‐1.15) 1.02 (0.93‐1.13) 0.92 (0.81‐1.05) 0.97 (0.81‐1.17) 0.98 (0.90‐1.06) 1.96E‐01 1.97E‐01 2.47E‐01 2.41E‐01 1.83E‐01 1.03E‐01 9.00E‐01 5.25E‐01 2.74E‐01 5.40E‐01 8.61E‐01 1.16E‐01 4.26E‐01 3.78E‐01 6.42E‐01 6.07E‐01 4.64E‐02 3.93E‐01 1.46E‐01 2.32E‐01 1.29E‐02 3.81E‐01 6.36E‐02 5.50E‐01 9.94E‐01 6.31E‐01 5.63E‐01 6.35E‐01 9.47E‐01 8.38E‐01 8.86E‐01 5.32E‐01 1.29E‐05 2.72E‐07 2.17E‐05 2.70E‐05 5.86E‐09 9.00E‐02 2.68E‐03 8.36E‐04 3.56E‐04 1.98E‐02 3.97E‐03 8.32E‐05 1.41E‐02 1.59E‐02 7.97E‐03 1.40E‐03 7.61E‐02 2.59E‐02 1.24E‐04 1.36E‐04 4.70E‐06 3.19E‐02 9.64E‐02 1.29E‐02 2.14E‐03 1.58E‐03 7.71E‐04 1.69E‐03 3.84E‐03 5.30E‐04 7.06E‐03 1.67E‐04 Diabetes
rs9955097 rs9950590 rs2068732 rs12608167 rs33845 rs6030572 rs17646111 rs1892700 rs5752933 rs2985125 rs16866049 rs513553 rs185580 rs266549 rs474939 rs10919851 rs6427807 rs7603311 rs4482537 rs17492567 rs12986646 rs881952 rs6753918 rs7560169 rs684428 rs7559293 rs28415051 rs9832209 rs602149 rs612304 rs1520323 rs467650 18 18 18 18 19 20 21 21 22 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 3 3 3 3 4 5 7965469 8043661 26236729 71893294 34014316 41598995 34954782 35016137 29902192 17004186 35836440 182494063 182519861 182528269 182538615 200187504 200189305 49041322 49052255 50212116 52372389 60888202 137214258 142148511 220505265 236422975 66008918 96825782 185244569 185251001 125146503 97969453 PTPRM PTPRM PTPRT DONSON DONSON ZMYM4 RGSL1 RGSL1 RGSL1 NRXN1 LRP1B SLC4A3 AGAP1 MAGI1 EPHA6 LIPH LIPH AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg AIRg DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI 11.62 11.99 2.42 1.36 1.00 ‐1.96 ‐1.57 ‐1.52 2.11 3.11 21.17 ‐1.83 ‐1.47 ‐1.59 ‐1.69 ‐1.16 1.15 1.44 1.38 2.54 2.64 ‐2.30 6.77 1.57 1.61 1.95 15.79 2.00 ‐2.95 ‐3.25 ‐3.68 1.94 3.10E‐05 5.19E‐06 6.85E‐05 2.48E‐05 7.03E‐05 8.83E‐05 3.16E‐05 5.02E‐05 1.36E‐05 3.02E‐05 3.08E‐05 8.14E‐05 9.30E‐05 6.29E‐05 3.59E‐05 5.29E‐05 6.79E‐05 2.30E‐05 5.52E‐05 4.51E‐05 8.76E‐05 4.59E‐06 2.54E‐05 8.79E‐05 8.27E‐05 6.75E‐05 5.80E‐05 5.13E‐05 4.20E‐05 3.31E‐05 6.82E‐05 3.33E‐05 80
Page 116 of 127
C/A T/C C/A G/A A/G C/A A/G A/G C/A G/A G/A G/A A/G T/C A/G C/T A/C C/T T/C C/T A/G C/T C/T T/C T/C A/G G/A A/G T/G C/T T/C C/T 0.004 0.005 0.120 0.264 0.361 0.175 0.237 0.236 0.230 0.052 0.002 0.262 0.227 0.229 0.239 0.442 0.462 0.441 0.404 0.089 0.044 0.477 0.012 0.388 0.170 0.408 0.003 0.356 0.059 0.059 0.021 0.271 0.64 (0.19‐2.10) 0.48 (0.19‐1.19) 1.08 (0.97‐1.19) 1.01 (0.93‐1.09) 1.03 (0.96‐1.11) 0.96 (0.88‐1.05) 1.07 (0.99‐1.16) 1.01 (0.93‐1.09) 1.00 (0.91‐1.10) 1.01 (0.70‐1.45) 1.18 (0.38‐3.65) 1.08 (1.00‐1.17) 1.04 (0.95‐1.13) 0.99 (0.91‐1.08) 1.06 (0.97‐1.15) 0.98 (0.91‐1.05) 1.05 (0.98‐1.12) 1.04 (0.97‐1.12) 1.05 (0.98‐1.12) 0.99 (0.89‐1.10) 0.90 (0.75‐1.08) 0.94 (0.88‐1.01) 0.96 (0.77‐1.19) 1.02 (0.95‐1.10) 0.97 (0.88‐1.06) 1.03 (0.96‐1.11) 0.79 (0.44‐1.40) 1.07 (1.00‐1.15) 1.10 (0.95‐1.28) 1.07 (0.92‐1.25) 0.99 (0.78‐1.25) 1.01 (0.93‐1.09) 4.54E‐01 1.47E‐01 9.87E‐02 8.70E‐01 7.03E‐01 4.28E‐01 7.21E‐01 2.99E‐01 9.23E‐01 9.82E‐01 7.18E‐01 7.92E‐02 3.41E‐01 4.60E‐01 2.15E‐01 7.31E‐01 6.41E‐01 2.94E‐01 2.62E‐01 3.21E‐01 8.01E‐01 1.17E‐01 8.94E‐01 6.30E‐01 9.15E‐01 2.65E‐01 7.93E‐01 5.20E‐02 6.29E‐01 9.49E‐01 9.94E‐01 8.86E‐01 5.11E‐04 2.15E‐05 9.94E‐02 1.95E‐03 1.11E‐02 2.70E‐02 1.40E‐03 3.29E‐02 1.66E‐03 3.02E‐03 7.10E‐03 5.64E‐05 5.89E‐04 8.02E‐04 1.45E‐04 1.92E‐03 1.29E‐02 2.44E‐02 3.95E‐02 2.90E‐02 9.44E‐03 3.30E‐02 3.93E‐03 1.50E‐02 6.76E‐03 4.25E‐02 2.46E‐03 1.36E‐01 1.20E‐03 3.85E‐03 4.95E‐03 4.61E‐03 Page 117 of 127
rs6902991 rs13193467 rs1510292 rs17086954 rs10225719 rs10267836 rs1346111 rs10278107 rs12539028 rs1077489 rs12546336 rs2891781 rs13253406 rs2382470 rs2020927 rs10121901 rs2066720 rs11145750 rs10781499 rs4077515 rs3812560 rs3812570 rs4266763 rs8413 rs10870194 rs10781542 rs1148233 rs1414894 rs2488069 rs7081634 rs7068036 rs2237896 Diabetes
6 6 6 6 7 7 7 7 7 8 8 8 8 9 9 9 9 9 9 9 9 9 9 9 9 9 10 10 10 10 10 11 78060981 85211681 124371914 156337304 12691988 30755583 49742459 125278195 154812950 6635669 39620015 124608162 143200557 14387817 107553185 107553524 107554069 139259249 139266405 139266496 139269905 139275204 139289825 139323311 139327034 139327439 31461599 89785190 94505421 94685886 95315193 2858440 NKAIN2 SCIN INMT ADAM2 NFIB ABCA1 ABCA1 ABCA1 CARD9 CARD9 CARD9 SNAPC4 SNAPC4 INPP5E INPP5E INPP5E EXOC6 KCNQ1 DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI ‐0.52 ‐2.10 ‐3.05 2.02 ‐2.17 3.20 ‐2.04 ‐1.90 ‐1.74 ‐2.37 1.65 ‐1.38 ‐1.77 ‐1.59 ‐1.74 ‐1.74 ‐1.74 ‐1.69 ‐0.97 ‐0.89 ‐1.83 ‐1.87 ‐2.00 ‐1.77 ‐1.58 ‐1.59 8.86 1.67 ‐18.48 ‐22.06 1.94 1.64 1.58E‐01 4.66E‐05 5.10E‐05 2.71E‐05 3.17E‐05 6.27E‐06 2.28E‐05 5.14E‐05 8.46E‐05 9.47E‐05 9.24E‐05 4.34E‐03 6.65E‐05 2.02E‐05 5.74E‐05 5.63E‐05 5.74E‐05 2.71E‐05 4.13E‐02 5.71E‐02 6.16E‐06 1.72E‐06 3.46E‐06 2.83E‐05 5.86E‐05 5.77E‐05 9.09E‐06 4.62E‐05 5.73E‐05 2.62E‐05 6.79E‐05 1.57E‐05 81
T/C T/C A/G G/A T/C T/C C/T C/T A/G T/C A/G T/C G/T A/G G/A G/A T/C A/G G/A C/T T/C A/C A/G T/C A/G A/G T/C C/T G/T G/A T/C A/G 0.534 0.132 0.060 0.220 0.418 0.041 0.226 0.477 0.435 0.072 0.333 0.537 0.390 0.255 0.161 0.161 0.161 0.474 0.491 0.491 0.465 0.461 0.489 0.470 0.446 0.446 0.008 0.286 0.002 0.002 0.156 0.247 1.03 (0.96‐1.10) 1.02 (0.92‐1.13) 0.90 (0.78‐1.03) 0.92 (0.85‐1.00) 1.01 (0.94‐1.08) 0.95 (0.81‐1.12) 1.00 (0.92‐1.08) 1.05 (0.99‐1.11) 1.03 (0.96‐1.11) 1.06 (0.91‐1.23) 1.06 (0.99‐1.14) 0.97 (0.90‐1.04) 1.01 (0.95‐1.07) 0.95 (0.88‐1.02) 0.95 (0.87‐1.03) 0.96 (0.87‐1.05) 0.95 (0.87‐1.04) 1.11 (1.04‐1.18) 1.07 (1.01‐1.15) 1.08 (1.01‐1.15) 1.09 (1.02‐1.16) 1.07 (0.99‐1.14) 1.10 (1.03‐1.18) 1.07 (1.00‐1.15) 1.07 (1.01‐1.14) 1.06 (0.99‐1.14) 1.29 (0.70‐2.38) 1.02 (0.95‐1.10) 2.34 (0.90‐6.07) 2.24 (0.87‐5.80) 0.99 (0.88‐1.11) 0.75 (0.69‐0.82) 1.47E‐01 5.99E‐01 1.69E‐01 1.77E‐01 5.45E‐01 9.93E‐01 1.49E‐01 2.10E‐01 5.08E‐01 5.84E‐01 2.26E‐01 1.06E‐01 9.75E‐01 7.38E‐01 4.55E‐01 6.85E‐01 5.79E‐01 2.77E‐02 1.53E‐01 1.48E‐01 1.89E‐01 4.93E‐02 1.23E‐02 3.83E‐02 3.40E‐01 7.76E‐02 8.19E‐01 9.05E‐01 2.63E‐01 1.40E‐01 9.89E‐01 2.90E‐13 4.30E‐02 1.15E‐03 5.85E‐02 8.74E‐05 7.52E‐04 1.37E‐03 4.83E‐02 1.76E‐04 1.16E‐03 1.76E‐02 5.63E‐02 3.82E‐01 5.14E‐03 5.48E‐03 2.05E‐02 1.04E‐02 1.42E‐02 6.06E‐06 1.42E‐02 1.79E‐02 3.71E‐05 1.81E‐06 4.34E‐07 9.62E‐06 4.38E‐04 4.28E‐05 2.92E‐03 5.17E‐03 2.76E‐04 5.87E‐05 5.01E‐03 2.13E‐16 Diabetes
rs2237897 rs5241 rs4756016 rs744434 rs1351571 rs17108749 rs7971324 rs17107718 rs7304911 rs1537435 rs17085484 rs870767 rs2764026 rs9575437 rs9575445 rs1328641 rs2149423 rs2054715 rs11073891 rs4238710 rs2326274 rs9891963 rs654136 rs4073064 rs2541872 rs2587374 rs4802566 rs219628 rs2833555 rs133937 rs1674879 rs1572823 11 2858546 11 14990543 11 45699134 11 65847982 11 98408860 11 108796817 12 3098924 12 70488764 12 129705400 13 27909319 13 27930039 13 27938560 13 36291051 13 36731208 13 36731586 13 36745029 13 36772381 15 59607007 15 90363995 16 84546021 16 84546108 17 2875114 18 48464204 18 59532727 18 63632952 18 63638807 19 49632309 21 27865420 21 33285149 22 33395851 1 4497217 1 19889959 KCNQ1 CALCA PACS1 DDX10 TEAD4 TMEM132D MAB21L1 SOHLH2 SOHLH2 MYO1E RAP1GAP2 ME2 RNF152 PPFIA3 CYYR1 HUNK SYN3 DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI DI SG
SG 1.75 5.81 1.50 15.07 ‐1.31 ‐9.79 3.44 2.52 ‐1.40 1.61 1.52 1.53 ‐1.77 2.02 1.88 1.96 2.18 ‐1.35 1.37 ‐2.08 ‐2.10 ‐3.23 ‐1.43 ‐10.09 ‐1.93 ‐2.07 1.77 1.40 ‐2.93 1.65 0.19 ‐0.14 7.04E‐06 9.58E‐05 4.61E‐05 5.45E‐05 4.20E‐05 7.57E‐05 5.00E‐05 6.92E‐05 2.69E‐05 5.12E‐05 8.64E‐05 5.87E‐05 6.43E‐05 2.08E‐05 1.48E‐05 1.96E‐05 3.67E‐07 6.02E‐05 9.68E‐05 3.68E‐05 3.97E‐05 8.32E‐05 9.26E‐05 7.42E‐05 9.90E‐05 5.93E‐05 2.84E‐05 5.01E‐05 6.09E‐05 6.74E‐05 5.99E‐05 6.36E‐05 82
Page 118 of 127
T/C T/G G/A G/T T/C G/T C/A T/C T/C T/C C/T G/A G/A G/A A/G T/C G/A C/T C/A A/G T/G T/C T/C C/T A/G A/G T/C C/T T/C C/A T/C T/C 0.251 0.016 0.416 0.003 0.472 0.009 0.056 0.054 0.223 0.316 0.318 0.233 0.282 0.296 0.285 0.227 0.315 0.172 0.274 0.310 0.308 0.038 0.359 0.010 0.385 0.250 0.392 0.255 0.079 0.335 0.079 0.125 0.73 (0.68‐0.79) 1.22 (0.74‐2.01) 1.00 (0.94‐1.07) 0.82 (0.38‐1.77) 1.02 (0.95‐1.09) 2.10 (0.91‐4.88) 0.81 (0.70‐0.94) 1.05 (0.92‐1.21) 1.04 (0.96‐1.14) 0.97 (0.91‐1.04) 0.97 (0.90‐1.04) 1.02 (0.90‐1.15) 0.93 (0.86‐1.00) 1.08 (1.00‐1.16) 1.01 (0.93‐1.10) 1.10 (1.02‐1.20) 1.01 (0.94‐1.09) 1.06 (0.96‐1.16) 1.03 (0.94‐1.13) 0.98 (0.91‐1.06) 1.03 (0.96‐1.11) 0.99 (0.84‐1.15) 0.95 (0.88‐1.02) 1.18 (0.37‐3.73) 0.97 (0.91‐1.05) 0.95 (0.88‐1.04) 0.95 (0.88‐1.03) 0.98 (0.91‐1.06) 1.02 (0.90‐1.14) 0.94 (0.87‐1.01) 1.00 (0.88‐1.14) 1.07 (0.97‐1.18) 1.89E‐19 3.22E‐01 8.85E‐01 8.63E‐01 7.58E‐01 1.31E‐01 6.09E‐02 9.50E‐01 4.63E‐01 4.77E‐01 5.01E‐01 6.17E‐01 3.26E‐01 1.46E‐01 2.58E‐01 5.84E‐02 2.95E‐01 6.85E‐01 4.94E‐01 8.69E‐01 5.31E‐01 5.55E‐01 9.87E‐02 9.68E‐01 9.18E‐01 6.46E‐01 2.25E‐01 5.33E‐01 1.18E‐01 7.94E‐01 9.07E‐01 5.69E‐01 1.24E‐21 3.97E‐02 2.85E‐03 2.93E‐03 1.84E‐03 1.11E‐04 2.75E‐05 5.61E‐03 4.88E‐04 7.61E‐04 1.15E‐03 1.40E‐03 3.31E‐02 4.76E‐02 2.36E‐02 9.28E‐02 4.30E‐03 1.79E‐03 1.19E‐03 2.41E‐03 8.11E‐04 1.80E‐02 1.10E‐01 5.55E‐03 7.37E‐03 1.19E‐02 1.34E‐04 9.37E‐04 8.16E‐05 2.67E‐03 5.86E‐03 1.23E‐03 Page 119 of 127
rs11805807 rs563988 rs471910 rs7570259 rs11684134 rs4665969 rs6716894 rs7586601 rs11695549 rs7602534 rs13472 rs4803 rs11126999 rs704795 rs1260320 rs2293571 rs1260326 rs780093 rs11681351 rs4852424 rs3755388 rs6743318 rs14234 rs9816690 rs11927192 rs523079 rs13059988 rs10000105 rs3775781 rs1011631 rs6871313 rs6885718 Diabetes
1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 4 4 4 5 5 155064844 182474160 182474704 23202248 27558252 27574953 27583273 27584666 27586155 27592423 27600239 27667297 27670307 27716494 27722416 27729480 27730940 27742603 27743423 70283210 70310878 70373677 70524142 82046207 183730657 187615862 187624906 53623677 70595637 82440730 2397617 31657655 RGSL1 RGSL1 GTF3C2 GTF3C2 EIF2B4 ZNF513 KRTCAP3 IFT172 FNDC4 GCKR GCKR GCKR GCKR GCKR PCBP1‐AS1 PCBP1‐AS1 FAM136A BC031255 ABCC5 SULT1B1 PDZD2 S G SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG S G SG SG SG SG SG 1.14 ‐0.11 ‐0.11 1.59 0.10 0.11 0.11 0.11 ‐0.11 0.11 0.11 0.11 0.11 0.11 0.11 0.12 0.13 0.14 0.11 ‐0.15 ‐0.15 ‐0.15 0.10 0.23 0.77 0.25 0.22 1.32 ‐0.38 0.09 0.10 0.22 2.89E‐05 9.29E‐05 5.55E‐05 5.51E‐06 5.99E‐05 1.44E‐05 3.40E‐05 3.20E‐05 3.21E‐05 5.06E‐05 4.28E‐05 8.09E‐05 3.09E‐05 7.12E‐05 9.73E‐05 1.98E‐05 4.04E‐06 1.12E‐06 3.35E‐05 5.50E‐05 6.51E‐05 4.91E‐05 2.34E‐05 7.44E‐05 5.32E‐05 1.53E‐07 3.40E‐07 7.67E‐05 3.26E‐05 9.08E‐05 4.12E‐05 4.62E‐05 83
T/C C/T C/T A/C A/G T/C A/G A/G C/A C/T G/A A/G G/A G/A G/A G/A T/C T/C G/A G/A G/A G/T A/G A/G A/G T/C T/G A/G T/C T/C G/A G/A 0.004 0.268 0.269 0.002 0.436 0.468 0.468 0.425 0.479 0.465 0.469 0.459 0.474 0.460 0.467 0.476 0.335 0.341 0.479 0.382 0.388 0.392 0.412 0.055 0.004 0.069 0.063 0.002 0.027 0.328 0.372 0.081 0.55 (0.16‐1.91) 1.07 (0.99‐1.16) 1.05 (0.98‐1.14) 0.79 (0.29‐2.17) 0.93 (0.87‐1.00) 0.96 (0.89‐1.02) 0.96 (0.91‐1.02) 0.94 (0.88‐1.01) 1.04 (0.97‐1.11) 0.97 (0.91‐1.04) 0.97 (0.91‐1.04) 0.98 (0.91‐1.05) 0.98 (0.92‐1.05) 0.98 (0.91‐1.05) 0.98 (0.92‐1.05) 0.94 (0.86‐1.02) 0.96 (0.89‐1.03) 0.96 (0.90‐1.03) 0.96 (0.90‐1.03) 1.00 (0.93‐1.07) 1.07 (1.00‐1.15) 1.01 (0.93‐1.10) 0.98 (0.91‐1.05) 1.09 (0.94‐1.26) 1.03 (0.39‐2.78) 0.92 (0.81‐1.05) 1.01 (0.86‐1.17) 0.95 (0.12‐7.74) 0.88 (0.71‐1.08) 1.06 (0.99‐1.14) 1.12 (1.05‐1.21) 1.06 (0.90‐1.26) 3.20E‐01 6.42E‐02 2.59E‐01 8.19E‐01 1.05E‐01 2.08E‐01 1.99E‐01 5.98E‐02 2.41E‐01 3.37E‐01 2.44E‐01 3.46E‐01 3.41E‐01 3.23E‐01 3.80E‐01 1.61E‐01 5.58E‐02 2.07E‐01 2.83E‐01 7.39E‐01 2.45E‐01 5.35E‐01 5.66E‐01 8.23E‐01 4.88E‐01 3.39E‐01 6.78E‐01 3.83E‐01 1.58E‐01 3.84E‐01 3.04E‐02 2.68E‐01 2.52E‐04 4.65E‐05 2.63E‐04 2.28E‐03 6.77E‐05 7.58E‐05 1.23E‐04 1.94E‐05 1.63E‐04 3.93E‐04 2.01E‐04 5.54E‐04 2.95E‐04 4.51E‐04 7.32E‐04 6.09E‐05 3.99E‐06 1.46E‐05 2.22E‐04 2.02E‐03 2.67E‐04 9.33E‐04 6.84E‐04 8.22E‐03 1.79E‐02 1.14E‐05 9.62E‐05 6.41E‐04 5.25E‐02 3.14E‐02 1.71E‐01 3.60E‐02 Diabetes
rs17165293 rs7708035 rs28011 rs4700708 rs2064197 rs367274 rs7744034 rs11752655 rs16876733 rs539518 rs1421221 rs883952 rs12313180 rs4931283 rs909013 rs17518256 rs10843647 rs11837387 rs11104268 rs7296900 rs11113179 rs7319628 rs17081477 rs1748124 rs9550193 rs2145516 rs12432901 rs7140895 rs1429751 rs1115936 rs4783122 rs7202949 5 5 5 5 6 6 6 6 7 7 8 9 12 12 12 12 12 12 12 12 12 13 13 13 13 14 14 14 15 16 16 16 126183502 161834699 179407229 179529895 8998811 90622187 135143748 135160309 10945193 73753250 97004203 71514651 30308868 30334071 30334754 30339648 30341934 73467487 76627445 104177668 107452785 34502705 35134265 52455098 113324324 26129412 26494469 49724328 34116858 7171923 82535037 82593560 RNF130 RASGEF1C CLIP2 PIP5K1B NT5DC3 CRY1 RFC3 C13orf35 RYR3 RBFOX1 S G S G SG SG SG SG S G S G SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG 0.28 1.71 ‐0.08 ‐0.08 ‐0.19 0.12 0.13 0.19 ‐0.17 0.09 ‐0.11 0.10 0.14 0.16 0.16 0.17 0.17 2.02 0.33 0.12 ‐0.12 0.95 0.44 ‐0.11 ‐0.12 0.09 ‐0.18 0.17 0.14 ‐0.13 ‐0.16 ‐0.09 8.94E‐05 1.99E‐05 8.59E‐05 6.82E‐05 7.23E‐06 2.51E‐05 5.45E‐05 1.12E‐05 5.24E‐05 9.40E‐05 9.91E‐05 5.56E‐05 5.88E‐06 1.34E‐05 1.75E‐05 1.32E‐05 4.13E‐06 2.22E‐05 6.74E‐06 4.05E‐05 1.28E‐05 2.21E‐05 3.83E‐05 8.53E‐05 3.19E‐05 8.88E‐05 4.44E‐05 9.31E‐05 9.22E‐05 5.22E‐05 3.56E‐05 9.47E‐05 84
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A/G A/G C/T A/G G/A T/C A/G G/A C/A T/C C/T G/A T/C G/A G/A C/A T/G C/T G/A T/C T/C A/G C/T C/T T/G A/G A/G C/T C/T G/A G/A G/A 0.041 0.003 0.325 0.419 0.164 0.418 0.253 0.081 0.129 0.366 0.385 0.478 0.336 0.322 0.317 0.295 0.331 0.001 0.042 0.453 0.286 0.006 0.013 0.480 0.351 0.457 0.105 0.123 0.253 0.363 0.243 0.474 1.01 (0.82‐1.24) 1.71 (0.64‐4.56) 1.05 (0.97‐1.13) 1.03 (0.96‐1.10) 1.18 (1.08‐1.30) 1.07 (1.00‐1.15) 0.95 (0.88‐1.03) 0.91 (0.81‐1.02) 1.02 (0.92‐1.13) 0.99 (0.93‐1.07) 1.00 (0.94‐1.07) 1.02 (0.95‐1.09) 0.98 (0.91‐1.07) 1.02 (0.95‐1.09) 1.02 (0.95‐1.09) 0.99 (0.92‐1.07) 1.00 (0.93‐1.07) 2.96 (1.26‐6.92) 1.04 (0.87‐1.25) 0.97 (0.91‐1.04) 0.99 (0.91‐1.07) 1.35 (0.56‐3.25) 1.23 (0.81‐1.85) 0.96 (0.90‐1.03) 1.07 (0.99‐1.17) 0.94 (0.87‐1.01) 0.97 (0.87‐1.09) 0.98 (0.89‐1.08) 1.03 (0.95‐1.11) 1.02 (0.95‐1.10) 1.01 (0.93‐1.09) 1.01 (0.95‐1.09) 6.68E‐01 1.98E‐01 5.41E‐01 5.13E‐01 7.01E‐04 4.86E‐02 2.32E‐01 6.90E‐02 9.52E‐01 7.40E‐01 6.75E‐01 7.38E‐01 7.41E‐01 9.22E‐01 9.82E‐01 6.30E‐01 6.81E‐01 5.74E‐02 8.66E‐01 9.58E‐02 5.74E‐01 3.94E‐01 2.62E‐01 3.35E‐01 1.16E‐01 2.91E‐02 5.37E‐01 5.29E‐01 7.11E‐01 7.93E‐01 9.90E‐01 5.97E‐01 1.36E‐02 3.52E‐02 1.33E‐03 1.04E‐03 2.56E‐08 1.13E‐01 2.17E‐04 1.13E‐05 3.71E‐03 2.73E‐03 1.41E‐02 8.95E‐03 2.98E‐03 2.61E‐03 2.26E‐03 6.14E‐03 3.03E‐03 9.78E‐02 9.58E‐04 4.50E‐05 7.19E‐03 1.66E‐02 3.42E‐02 3.60E‐02 5.03E‐05 1.60E‐05 1.43E‐02 1.33E‐03 1.23E‐02 7.47E‐03 3.37E‐03 1.72E‐03 Page 121 of 127
rs4299147 rs1559310 rs11150514 rs12933472 rs11150519 rs1559438 rs16947417 rs9896748 rs94312 rs2048132 rs6566045 rs2291004 rs788338 rs788332 rs2004423 rs4802723 rs4802724 rs2825882 rs9984764 rs9974077 Diabetes
16 16 16 16 16 16 17 17 18 18 18 19 19 19 19 19 19 21 21 21 82883338 82918371 82923464 82924685 82934307 83308559 13143819 64939574 7806492 73694904 75650801 37997952 50778543 50782462 50939867 51172786 51173218 21283010 27497497 43835771 CDH13 CDH13 CDH13 CDH13 CDH13 CDH13 PTPRM ZNF793 MYH14 MYH14 MYBPC2 SHANK1 SHANK1 APP UBASH3A SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG SG 0.10 ‐0.11 0.10 ‐0.12 ‐0.11 0.09 0.26 0.27 ‐0.27 0.16 0.14 0.16 ‐0.17 ‐0.16 0.12 ‐0.16 ‐0.16 ‐0.10 0.81 0.13 8.86E‐05 4.08E‐05 4.41E‐05 8.16E‐06 4.32E‐05 6.67E‐05 2.24E‐05 2.37E‐05 8.39E‐05 2.16E‐05 4.52E‐05 3.82E‐05 1.66E‐06 1.77E‐05 4.51E‐05 1.90E‐05 1.81E‐05 9.16E‐05 2.06E‐05 3.44E‐05 85
T/C G/T G/T A/G G/A C/T G/T T/G G/A T/G C/T A/C C/T A/C A/G G/A C/A C/T A/G T/G 0.410 0.437 0.414 0.435 0.441 0.476 0.053 0.070 0.049 0.225 0.289 0.153 0.287 0.264 0.325 0.150 0.151 0.474 0.997 0.259 0.96 (0.89‐1.03) 1.04 (0.97‐1.11) 0.94 (0.88‐1.01) 1.06 (0.99‐1.14) 1.05 (0.98‐1.12) 1.04 (0.95‐1.13) 1.07 (0.90‐1.27) 0.91 (0.80‐1.03) 0.97 (0.82‐1.16) 1.01 (0.93‐1.11) 0.96 (0.89‐1.04) 0.89 (0.82‐0.97) 0.97 (0.89‐1.05) 0.98 (0.86‐1.13) 0.97 (0.89‐1.05) 1.03 (0.94‐1.14) 1.01 (0.89‐1.13) 1.06 (0.99‐1.14) 0.82 (0.29‐2.28) 1.02 (0.94‐1.10) 2.05E‐01 3.11E‐01 4.40E‐01 9.55E‐02 1.37E‐01 8.39E‐01 9.35E‐02 1.60E‐01 3.68E‐01 9.16E‐01 2.42E‐01 9.88E‐03 7.42E‐01 8.03E‐01 2.63E‐01 9.26E‐01 8.80E‐01 9.78E‐01 5.58E‐01 9.59E‐01 2.44E‐04 2.98E‐04 5.93E‐04 1.47E‐05 7.99E‐05 3.04E‐03 7.00E‐02 6.82E‐05 3.20E‐02 3.40E‐03 2.05E‐04 2.18E‐06 1.61E‐03 4.26E‐03 2.36E‐04 2.00E‐03 3.44E‐03 5.34E‐03 6.13E‐04 3.02E‐03 Diabetes
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Supplementary Table 7. Top regions from GWAS of T2D-related quantitative traits with translation to T2D in Mexican-origin
cohorts ordered by trait from the Discovery stage.
§
Marker
rs7219451
rs6815953
rs7581057
rs322394
rs17060946
rs13252932
rs10830963
rs2206734
rs7018475
rs1387153
rs2129969
rs2053797
rs9553849
rs10870202
rs10898909
rs2237897
rs4266763
rs2064197
rs2291004
rs1260326
Chr
17
4
2
5
9
8
11
6
9
11
11
2
13
9
11
11
9
6
19
2
Position*
38957002
183109012
115958079
172157768
77808519
25198091
92708710
20694884
22137685
92673828
45586169
46370892
27082326
139257411
72952496
2858546
139289825
8998811
37997952
27730940
Gene
KRT28 / KRT10
TENM3
DPP10
NEURL1B / DUSP1
OSTF1 / PCSK5
DOCK5
MTNR1B¶
#
CDKAL1
CDKN2B-AS1 / DMRTA1**
MTNR1B††
PRDN11 / CHST1
PRKCE
CDK8 / WASF3
DNLZ
P2RY2
KCNQ1‡‡
SNAPC4
SLC35B3 / TFAP2A
ZNF793
GCKR§§
Trait
SI +M
SI +M
SI +M
M
M
M
AIRg
AIRg
AIRg
AIRg
AIRg
AIRg
AIRg
AIRg
AIRg
DI
DI
SG
SG
SG
RA†
C
T
G
C
G
T
G
T
G
T
G
A
A
T
A
A
A
G
A
T
RAF‡
0.38
0.431
0.056
0.36
0.068
0.049
0.22
0.194
0.323
0.22
0.477
0.162
0.199
0.43
0.404
0.251
0.489
0.164
0.153
0.335
Model 1
Beta
P-value
-6.8
3.92E-06
4.10
3.14E-05
-5.47
1.74E-04
-15.8
3.38E-05
37.86
2.56E-06
47.71
5.17E-06
-2.76
5.23E-12
-2.05
1.02E-06
-1.64
4.90E-06
-2.55
2.21E-09
1.14
2.10E-05
1.89
5.02E-05
1.57
6.70E-05
-1.04
5.37E-05
1.41
4.03E-06
1.75
7.04E-06
-2.00
3.46E-06
-0.19
7.23E-06
0.16
3.82E-05
0.13
4.04E-06
||
Model 2
Beta
P-value
-5.86
1.43E-04
3.59
3.53E-04
-4.52
9.35E-03
-13.94
8.64E-05
31.94
2.94E-05
39.14
5.93E-05
-2.81
3.22E-13
-1.90
5.03E-06
-1.60
8.24E-06
-2.62
2.16E-10
1.21
4.56E-06
1.81
6.75E-05
1.54
6.07E-05
-1.06
2.09E-05
1.31
7.78E-06
1.82
1.59E-06
-1.93
3.35E-06
-0.19
7.31E-06
0.15
1.97E-05
0.13
1.43E-05
SNPs with evidence of association with the nearest annotated RefSeq gene(s) listed. *Build hg19, †Reference Allele, ‡Reference Allele
Frequency, §Model 1 covariates included age, gender, study site (in multi-center recruitment studies), and admixture proportions,
||
Model 2 covariates included age, gender, study site (in multi-center recruitment studies), admixture proportions, and BMI,
¶
Previously identified T2D locus (MTNR1B rs1387153, r2=0.69), #Previously identified T2D locus (CDKAL1 rs7754840, r2=0.42),
**
Previously identified T2D locus (CDKN2B rs7018475), ††Previously identified T2D locus (MTNR1B rs1387153), ‡‡Previously
identified T2D locus (KCNQ1 rs2237892, r2=0.90; and KCNQ1 rs231362, r2=0.038), §§Previously identified T2D locus (GCKR
rs780094, r2=0.91).
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Supplementary Table 8. Top regions from GWAS of T2D-related quantitative traits with translation to T2D in Mexican-origin cohorts ordered by
trait from the Discovery stage with conditional analyses performed at loci with multiple signals of association or in close proximity to previously
identified T2D loci.
Discovery Cohorts
Marker
Chr:Position*
Gene
Trait
RAF‡
Translation Cohorts
Conditional Analysis
Beta
P-value
r2||
SNP
P-value
rs7219451
17:38957002
KRT28 / KRT10
SI+M
0.380 (C)
-6.80
3.92E-06
rs6815953
4:183109012
TENM3
SI+M
0.431 (T)
4.10
3.14E-05
rs7581057
2:115958079
DPP10
SI+M
0.056 (G)
-5.47
1.74E-04
rs322394
5:172157768
NEURL1B / DUSP1
M
0.360 (C)
-15.83
3.38E-05
rs17060946
9:77808519
OSTF1 / PCSK5
M
0.068 (G)
37.86
2.56E-06
rs13252932
8:25198091
DOCK5
M
0.049 (T)
47.71
5.17E-06
rs10830963
11:92708710
MTNR1B
AIRg
0.220 (G)
-2.76
5.23E-12
rs1387153¶
0.69
8.67E-05
rs2206734
6:20694884
CDKAL1
AIRg
0.194 (T)
-2.05
1.02E-06
rs7754840¶
0.42
9.37E-03
rs7018475
9:22137685
CDKN2B-AS1 /
DMRTA1
AIRg
0.323 (G)
-1.64
4.90E-06
rs1387153
11:92673828
MTNR1B
AIRg
0.220 (T)
-2.55
2.21E-09
rs2129969
11:45586169
PRDN11 / CHST1
AIRg
0.477 (G)
1.14
2.10E-05
rs2053797
2:46370892
PRKCE
AIRg
0.162 (A)
1.89
5.02E-05
rs9553849
13:27082326
CDK8 / WASF3
AIRg
0.199 (A)
1.57
6.70E-05
rs10870202
9:139257411
DNLZ
AIRg
0.430 (T)
-1.04
5.37E-05
rs10898909
11:72952496
P2RY2
AIRg
0.404 (A)
1.41
4.03E-06
¶
rs2237897
11:2858546
KCNQ1††
DI
0.251 (A)
1.75
7.04E-06
rs4266763
9:139289825
SNAPC4
DI
0.489 (A)
-2.00
3.46E-06
rs2064197
6:8998811
SLC35B3 / TFAP2A
SG
0.164 (G)
-0.19
7.23E-06
rs2291004
19:37997952
ZNF793
SG
0.153 (A)
0.16
3.82E-05
rs1260326
2:27730940
GCKR
SG
0.335 (T)
0.13
4.04E-06
87
rs2237892
rs231362¶
rs780094¶
0.90
0.038
0.91
1.57E-04
1.06E-05
9.62E-01
OR
(95% CI)§
1.08 (1.00‐1.16) 0.92 (0.86‐0.99) 1.29 (1.10‐1.50) 1.17 (1.09‐1.26) 0.87 (0.75‐1.01) 0.89 (0.75‐1.04) 1.08 (1.00‐1.18) 1.19 (1.09‐1.30) 1.09 (1.02‐1.17) 1.07 (0.98‐1.16) 0.91 (0.85‐0.98) 0.91 (0.83‐1.00) 0.86 (0.79‐0.94) 1.12 (1.05‐1.20) 0.94 (0.86‐1.02) 0.73 (0.68‐0.79) 1.10 (1.03‐1.18) 0.94 (0.87‐1.01) 0.89 (0.82‐0.97) 0.96 (0.89‐1.03) P-value
Discovery and
Translation
Meta-Analysis
P-value
1.06E-02
3.97E-07
1.25E-02
2.47E-06
6.67E-03
4.82E-06
7.87E-04
1.12E-07
6.89E-02
3.99E-06
6.61E-02
6.11E-06
1.83E-01
5.86E-09
1.41E-03
1.11E-08
2.34E-03
7.31E-08
1.97E-01
2.72E-07
2.38E-02
4.10E-06
1.42E-02
4.21E-06
1.29E-02
4.70E-06
2.08E-02
7.10E-06
9.27E-02
8.64E-06
1.89E-19
1.24E-21
1.23E-02
4.34E-07
7.01E-04
2.56E-08
9.88E-03
2.18E-06
5.58E-02
3.99E-06
Diabetes
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SNPs with evidence of association with the nearest annotated RefSeq gene(s) listed. *Build hg19, †Reference Allele, ‡Reference Allele Frequency,
§
Odds Ratio (OR) and 95% Confidence Interval (95% CI), ||Correlation from the largest set of unrelated individuals from BetaGene ¶Previously
identified T2D locus
88
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Supplementary Figure 1. Power to detect association with T2D (n=6,463 T2D cases and 9,232
controls) with an α of 5.00x10-8 at minor allele frequencies (MAF) ranging from 0.05-0.45.
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Supplementary Figure 2. Regional plots of loci with evidence of association (P<2.00x10-6) in
the Discovery meta-analysis. A) GNA15 rs2302063 with MCRI/T2D, B) MFSD8 rs1602084 with
SI+M/T2D, C) MYT1L/TSSC1 rs896232 with SI+M/T2D, D) HAAO/SFP36L2/THADA
rs1978648 with SI/T2D, E) C15orf59 rs4887140 with SI/T2D, F) HMGN3/LCA5 rs196701 with
SI/T2D, G) KLF12/LINC00347 rs10492494 with M/T2D, H) LOC646736/IRS1 rs11683087 with
M/T2D, I) MTNR1B rs10830963 with AIRg/T2D, J) CDKAL1 rs2206734 with AIRg/T2D, K)
PEX5L/TTC14 rs6803803 with AIRg/T2D, L) SOHLH2 rs2149423 with DI/T2D, M) SNAPC4
rs3812570 with DI/T2D, N) BCL6/LPP rs523079 with SG/T2D, O) GCKR rs780093 with
SG/T2D, and P) MYH14 rs788338 with SG. Genotyped SNPs passing quality control measures
across all Discovery cohorts are plotted with their Discovery meta-analysis p-values (as -log10
values) as a function of genomic position (hg19). In each panel, the index variant is represented
by a diamond, with the discovery results denoted in red and the discovery and translational metaanalysis denoted in purple. Estimated recombination rates (taken from HapMap) are plotted to
reflect the local LD structure. Color of additional variants indicates correlation with the index
SNP (red, r2≥0.80; orange, 0.60≤r2<0.80; green, 0.40≤r2<0.60; blue, 0.20≤r2<0.40; white,
r2<0.20; gray no r2 value available) based on pairwise r2 values from HapMap. Gene annotations
were taken from the University of California Santa Cruz genome browser.
91
Diabetes
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A)
B)
C)
D)
E)
F)
G)
H)
I)
J)
K)
L)
92
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M)
Diabetes
N)
O)
P)
93