Glycans and age
Dealing with non-linear correlations
Lucija Klarić
Genos Ltd.
Lucija Klarić
Relationship between age and glycans
KOR
ORCA
TWINS
VIS
30
GP4
20
10
8
GP6
6
4
Sex
2
Female
Male
20
GP14
Percentage of Glycan Group
10
15
10
5
2.0
GP15
1.6
1.2
0.8
25
50
75
100
25
50
75
100
Age
40
60
80
20
40
60
80
Local correction for age and sex
- linear age/sex correction vs local age/sex correction
- local age/sex correction – general additive models with smooth function
(R package: mgcv)
Local correction for age and sex
Residuals after age and sex correction in Korcula cohort
Local correction for age and sex
Residuals after age and sex correction in Korcula cohort
Materials and methods
• 2 cohorts:
– Korcula
• 851 individuals
• 316751 SNPs (typed)
• 77 glycans (UPLC)
– Vis
• 808 individuals
• 308996 SNPs (typed)
• 77 glycans (UPLC)
• GWAS – GenABEL package for R
• Meta analysis – MetABEL package for R
Comparison GWAS Korcula:
Linear vs Local Correction
SNP
rs6764279
rs6764279
rs6764279
rs6764279
rs12366899
rs12366899
rs6444193
rs6939603
rs6764279
rs6939603
rs6764279
rs11621121
rs12366899
glycan p (Linear) p (Local)
IGP29
4.68E-31
2.59E-31
IGP35
5.49E-19
7.30E-19
IGP32
3.10E-17
2.39E-17
IGP15
9.69E-17
2.05E-16
IGP41
2.80E-16
2.40E-16
IGP1
3.09E-15
3.38E-15
IGP29
2.09E-14
3.92E-14
IGP41
3.28E-14
1.56E-14
IGP28
3.73E-14
5.77E-14
IGP1
9.47E-14
3.68E-14
IGP24
2.93E-13
3.95E-13
IGP42
1.02E-12
2.07E-11
IGP19
1.38E-12
2.15E-13
Comparison Meta analysis:
Linear vs Local Correction
SNP
glycan
rs6764279 IGP29
rs6764279 IGP15
rs6764279 IGP35
rs6764279 IGP32
rs6764279 IGP28
rs6444193 IGP29
rs6764279 IGP24
rs4686837 IGP29
rs909674 IGP39
rs909674 IGP40
rs11621121 IGP59
rs12366899 IGP41
p (Linear) p (Local) chi (Linear) chi (Local) chi Lin/Loc
9.07E-59 1.46E-58
261.27
260.32
1.004
2.24E-36 5.10E-35
158.65
152.43
1.041
9.90E-35 9.00E-35
151.11
151.30
0.999
1.78E-29 2.63E-30
127.09
130.88
0.971
4.34E-29 2.02E-28
125.31
122.26
1.025
2.49E-25 6.23E-25
108.15
106.33
1.017
6.00E-24 4.76E-23
101.85
97.74
1.042
1.04E-19 7.36E-20
82.53
83.22
0.992
2.52E-18 6.64E-18
76.24
74.32
1.026
3.84E-18 9.26E-18
75.40
73.66
1.024
1.29E-16 5.09E-15
68.47
61.22
1.118
3.19E-16 2.60E-16
66.69
67.08
0.994
Concluding remarks
• Most p-values are lower in linear correction than
local correction for age
• Linear age correction outperformes local age
correction
– possible reason: local correction corrects better only
few people (~50 people from 40-50 years of age)
• Associations of SNPs and glycans are quite robust
• Residuals of local correction for age and sex are
not related to age
Monogalactosylated IgG glycans in aging
β4GalT-I (Beta-1,4-galactosyltransferase 1)
• adds galactose to GlcNAc residues
• interacts preferentially with 1,6-arm
FA2[6]G1
FA2[3]G1
FA2B[6]G1
FA2B[3]G1
Monogalactosylated IgG glycans in aging
Monogalactosylated structures with Gal on 1,6 arm decrease with age.
Monogalactosylated structures with bisecting GlcNAc with Gal on 1,3 or 1,6 arm increase
with age.
Monogalactosylated IgG glycans in aging
Monogalactosylated structures with Gal on 1,6 arm decrease with age.
Monogalactosylated structures with bisecting GlcNAc with Gal on 1,3 or 1,6 arm increase with age.
Table 1. Associations of glycans with age (UPLC)
Glycan
FA2[6]G1
FA2[3]G1
FA2B[6]G1
FA2B[3]G1
KOR (n=915)
ORCADES (n=2035)
R
p
R
p
-0.193 6.49E-08 -0.171 1.92E-12
0.010 3.91E-01 0.024 3.89E-08
0.141 2.33E-07 0.335 4.69E-46
0.264 1.05E-17 0.481 4.31E-113
Twins (n=1261)
VIS (n=906)
R
p
R
p
-0.028 6.86E-03 -0.231 2.71E-11
0.008 2.30E-03 -0.061 9.06E-02
0.183 2.79E-10 0.043 1.69E-01
0.314 3.77E-27 0.247 5.36E-14
Monogalactosylated IgG glycans in aging
Table 2. Correlation of age and glycans measured by different methods in Vis population
(500 subjects).
Glycan
FA2[6]G1
FA2[3]G1
FA2B[6]G1
FA2B[3]G1
Glycan
FA2[6]G1
FA2[3]G1
FA2B[6]G1
FA2B[3]G1
UPLC
(Total IgG)
R
p
-0,303 8,19E-11
-0,094 4,91E-02
-0,021 6,63E-01
0,254 6,37E-08
MALDI-TOF-MS
IgG1
IgG2&3
R
p
R
p
xCGE-LIF
(Total IgG)
R
p
-0,218
3,69E-06
-0,026
5,79E-01
0,012
8,01E-01
0,302
8,86E-11
LC-ESI-MS
IgG1
R
p
IgG2&3
R
p
-0,506 4,64E-30 -0,568
4,35E-39 -0,088 6,50E-02 -0,390 1,58E-17
-0,154 1,15E-03 -0,412
1,49E-19 -0,008 8,72E-01 -0,247 1,48E-07