CONTROVERSIES IN
HYPERTENSION
Genome-Wide Association Studies Will Unlock
the Genetic Basis of Hypertension
Con Side of the Argument
Theodore W. Kurtz
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Abstract—Over the past few years, it has been asserted that genome-wide association studies would open the door to
identifying primary genetic mechanisms underlying a variety of common clinical disorders, including essential
hypertension. Great hope was expressed that such research would ultimately lead to improved clinical outcomes
by facilitating the discovery of novel targets for therapy and by spawning a new era of personalized medicine in
which the results of genetic tests would be useful for guiding customized risk assessment and individual patient
management. In this Controversies in Hypertension series, I contend that genome-wide association studies have
failed, and will continue to fail, to unlock the genetic basis of essential hypertension and the research dollars being
devoted to genome-wide association studies should be shifted to other strategies and technologies that may hold
greater chance for advancing our understanding of the genetic factors that influence population variation in blood
pressure and risk for hypertension. (Hypertension. 2010;56:1021-1025.)
Key Words: genetics 䡲 hypertension 䡲 genome 䡲 association studies 䡲 blood pressure
The proponents of genome-wide association (GWA) studies
assert that such research has already provided initial insights
into the genetic basis of hypertension and that larger genomewide studies are warranted in the future.1,2 I disagree with
both assertions. To see that we have learned very little about
the genetic basis of hypertension from the large genome-wide
association studies conducted to date, it is helpful to consider
what the results of GWA studies have actually shown so far
and what was known about the genetic architecture of
hypertension before the advent of GWA studies. I then
discuss why little is expected to be gained by more GWA
studies of hypertension in the future.
involved analysis of 2.5 million genetic markers in ⬇30 000
individuals.1,2 In both cases, only a few loci (chromosome
regions) were found to be associated with effects on blood
pressure (BP) at a genome-wide level of statistical significance. The implicated loci had only tiny effects on BP
(⬍1 mm Hg or so) and typically accounted for ⬍0.2% of the
overall BP variation in the study populations. In the Gobal
BPgen consortium study, investigators selected genetic markers for ⬇10 of their loci and subjected them to analysis in
other study populations.1 This culminated in a meta-analysis
that included results in ⱕ134 258 subjects from ⬎35 studies.
The results of this effort yielded 8 loci that met criteria for
genome-wide significance. Again, each of these loci was
associated with miniscule effects on BP, with each accounting for ⬍0.1% of the total variation in BP.
Disappointing Results From the Largest GWA
Studies Relevant to Hypertension
Did These GWA Studies Lead to Any Surprising
Conclusions About the Genetics of Hypertension?
Recently, the results of several large GWA studies relevant to
hypertension have been reported, including 2 that each
Unfortunately, the results from these GWA studies have told
us little if anything new about the genetic architecture of
What Have We Learned So Far About the Genetic
Basis of Hypertension From Genome-Wide
Association Studies?
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
From the Department of Laboratory Medicine, University of California, San Francisco, Calif.
Correspondence to Theodore W. Kurtz, Department of Laboratory Medicine, University of California, San Francisco, 185 Berry St, Suite 290, San
Francisco, CA 94107. E-mail [email protected]
© 2010 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.110.156190
1021
1022
Table.
Hypertension
December 2010
Major Limitations of GWA Studies of Hypertension
Will not clarify the genetic architecture of hypertension
Cannot definitively identify causal genetic variants for hypertension
Have not revealed any surprising new mechanisms of hypertension
Have not identified any useful new targets for therapy of hypertension
Have failed to uncover any clinically useful risk markers for hypertension
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hypertension (Table). They have not unlocked the genetic
basis of hypertension, nor are such studies likely to do so in
the future. Based on the results of the main GWA studies of
hypertension conducted to date, the authors merely concluded
what everyone already knew about the genetics of hypertension before the advent of GWA studies, that essential hypertension is a polygenic disorder in which multiple genetic
variants are involved in the regulation of BP. Specifically, the
investigators of the Cohorts for Heart and Ageing Research in
Genome Epidemiology consortium concluded that, “The
findings are consistent with the hypothesis that variation in
scores, if not hundreds, of genes contribute to BP variation”2;
the Global BPgen investigators concluded that, “Given the
modest effects observed here and the limited power of this
study to detect such effects, it is likely that many more
common variants exist with weak effects on blood pressure.”1
GWA Studies Have Not Addressed and Cannot
Address the Key Question Regarding the Genetic
Architecture of Hypertension
It has long been accepted that essential hypertension is a
polygenic disorder. What has been unclear is whether genetic
risk for essential hypertension is determined to a greater
extent by many common gene variants with individually
small effects on BP (the common disease⫺common variant
model) or by many different rare gene variants with individually large effects on BP (the common disease⫺rare variant
model).3 The GWA studies conducted to date have shed little
light on the relative roles of these 2 models in the pathogenesis of hypertension, and more GWA studies will not be able
to clarify this issue much further in the future.
By nature of their design, GWA studies are intended to
detect the effects of common gene variants on BP and have
limited ability to detect rare variants affecting BP.4 Gene
variants with minor allele frequencies between 5% and 50%
are considered common, those with minor allele frequencies
of 1% to 5% are considered less common, and those with
minor allele frequencies of ⬍1% are considered rare.5 The
fact that GWA studies have turned up so few candidates in the
search for common gene variants influencing risk for hypertension might suggest that rare gene variants are playing a
greater role than common gene variants in the genetic
architecture of hypertension.6,7 To the extent that this ultimately proves to be true, investigators involved in GWA
studies of hypertension have been “barking up the wrong tree.”
Recently, prominent geneticists have begun to argue that rare
variants might play a much more important role than common
variants in the pathogenesis of a wide range of common clinical
disorders, including essential hypertension.5,7
Should More GWA Studies of Hypertension Be
Conducted in the Future?
Although one might suspect that the anemic results from
GWA studies of hypertension reflect the fact that the proponents of this approach have indeed been barking up the wrong
tree (ie, focusing on the common gene variant model and not
the rare gene variant model), other explanations have also
been offered for the poor showing of the GWA studies
conducted to date. Some of the alternative explanations
offered are that (1) the studies used insufficient sample sizes
and were underpowered to detect common variants with very
tiny effects on BP and (2) only tested for BP effects of
common single nucleotide polymorphisms with minor allele
frequencies ⬎5% and did not test for effects of somewhat less
common variants (minor allele frequencies of 1% to 5%) or
for types of genetic variants other than just single nucleotide
polymorphisms.3 Indeed, these kinds of explanations were
invoked by the investigators in the Global BPgen consortium
when they concluded that, “Given the modest effects observed here and the limited power of this study to detect such
effects, it is likely that many more common variants exist
with weak effects on blood pressure.”1
Even if the proponents of GWA studies are correct in their
speculative conclusion that “many more common variants
exist with weak effects on blood pressure,”1 I contend that,
because the variant effects will be so small or perhaps not
even real, it is not worth the effort and expense to search for
them. Some prominent geneticists strongly suspect that many
if not most of the genetic variants that have been found to be
associated with common disorders in GWA studies are in fact
spurious associations caused by subtle differences in ancestry
between the populations being studied (“cryptic population
stratification”).7 But for purposes of discussion, let us assume
that the weak genetic associations with BP being reported in
GWA studies of hypertension are real. What are the justifications for searching for common gene variants with tiny
effects on BP, and are those claims valid?
Claim 1: Small Effects on BP Can Have
Meaningful Effects on Cardiovascular Risk
The largest GWA studies conducted to date identified common genetic variants that appeared to impart only tiny effects
on BP.1,2 However, the study investigators emphasized that
even very small changes in BP can “produce meaningful
population changes in cardiovascular and stroke risk.”1 It may
well be true that, if a reduction in systolic BP of 1 to 2 mm Hg
could be achieved across the entire population, it would
translate into a meaningful reduction in coronary heart
disease and stroke in the population. However, this has no
relevance to the potential clinical importance of genetic
variants implicated in GWA studies, because no one is going
to manipulate genetic variants across the entire population.8
Imagine if a clinical trial demonstrated that a new antihypertensive drug could reduce BP by only 1 mm Hg. In the
context of such a clinical trial result, it would make no sense
to note that a 1-mm Hg reduction in BP across the entire
population could translate into a meaningful reduction in
cardiovascular risk in the population, nor does it make sense
to note this issue in the context of a GWA study of
hypertension. The fact that a 1-mm Hg reduction in BP across
Kurtz
GWAS Will Not Unlock the Genetics of Hypertension
the population can have a meaningful impact on population
cardiovascular risk does not mean that discovery of an antihypertensive drug that lowers BP by 1 mm Hg, or discovery of a
group of genetic variants that affect BP by 1 mm Hg, holds any
clinical significance.
Claim 2: GWA Studies Can Yield Mechanistic
Insights Into the Regulation of BP By Identifying
Causal Genetic Variants for Hypertension
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Proponents of GWA studies of hypertension have claimed
that, “These associations between common variants and BP
and hypertension can offer mechanistic insights into the
regulation of BP.”1 However, mechanistic insights can be
gained only by identification of the true culprit gene variants
influencing risk for hypertension and not by identification of
candidate genes. GWA studies can suggest candidate genes
for hypertension but they do not prove identity of the true
causal genetic variants that are required for investigators to
gain mechanistic insights into regulation of BP. The Global
BPgen investigators admit that GWA studies of hypertension
only identify candidate genes and that they do not pinpoint
the true causal genetic variants: “Although we describe
promising candidates at each locus identified, the causal
genes could be any of the genes around the association signal
in each locus.”1 Even higher-resolution GWA studies cannot
establish proof of causation for a specific gene variant in
hypertension. Moreover, even if GWA studies succeed in
identifying valid candidate genes as opposed to false candidates implicated by spurious association results,7 one need
only peruse a few issues of Hypertension to realize that there
is hardly a shortage of candidate genetic pathways for BP
regulation in the field of hypertension research.
Claim 3: GWA Studies Will Lead to Identification
of Important New Targets for Treatment
of Hypertension
This claim stems from the idea that, by identifying candidate
genes that affect risk for hypertension, GWA studies will help
uncover new pathways influencing BP and “serve as a basis
for the development of novel therapies for the prevention and
treatment of hypertension.”2 While recognizing that many if
not most of the candidates implicated in GWA studies of
common disorders like hypertension could represent spurious
associations,7 let us again assume for purposes of discussion
that the candidates identified by the Cohorts for Heart and
Ageing Research in Genome Epidemiology and Global BPgen
investigators are valid.1,2 Proponents of GWA studies note that a
common variant in the gene encoding 3-hydroxy-3-methylglutarylcoenzyme A reductase was found to be associated with only a
modest effect on fasting lipid levels, yet statin therapy, which
inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity and lowers cholesterol levels, is effective in lowering the
risk for cardiovascular disease.1 Of course, GWA studies were
not required to discover the important role of 3-hydroxy-3methylglutaryl-coenzyme A reductase and statins in regulating
cholesterol levels. The GWA studies of lipid levels are cited to
support the possibility that other GWA studies might lead to a
therapeutic target for hypertension that is as important as
3-hydroxy-3-methylglutaryl-coenzyme A reductase has been for
hypercholesterolemia. However, given that the very large GWA
1023
studies relevant to hypertension have failed to show associations
with any of the known targets used for treating hypertension in
the clinic today, there seems little reason to expect that GWA
studies will be useful for detecting any important therapeutic
targets in the future. Moreover, the field of hypertension is not
lacking in candidate targets for therapy, and there is no evidence
that candidate targets for therapy identified in GWA studies will
be any more useful than candidate targets identified through
other approaches.
It is unquestioned that a focus on rare gene variants
promoting mendelian forms of cardiovascular disease is of
value in understanding mechanistic pathways that serve as
useful targets for therapeutic intervention. The genetic studies
of mendelian forms of disordered BP regulation readily
turned up targets that are of known relevance to the treatment
of hypertension.9,10 The same cannot be said for the focus on
common gene variants that are reported to be associated with
tiny effects on BP. Judging from failure of the large GWA
studies to uncover associations with most if not all of the
target pathways for antihypertensive therapy that have already been established, why should we bet on this approach
to discover any special target pathways for antihypertensive
therapy in the future?
Claim 4: The Results of GWA Studies Will Lead
to Development of Genetic Profiles That Are
Useful for Predicting an Individual’s Risk
for Hypertension
The simplistic concept of using the results from GWA studies
to develop genetic profiles to predict an individual’s risk for
developing complex disorders like hypertension is going out
of favor. These kinds of results have very limited value for
personalized risk prediction, because in complex multifactorial disorders like essential hypertension, the relationship
between genotype and phenotype (BP) is very weak. Nevertheless, some investigators continue to suggest that the results
of GWA studies of hypertension “can serve as a basis for
future approaches to early detection of high risk individuals.”2 For example, the Cohorts for Heart and Ageing Research in Genome Epidemiology investigators created BP
“risk scores” by aggregating the effects of the top 10 genetic
markers implicated in their GWA studies and showed that
subgroups with the highest risk scores had the highest odds
ratios for hypertension.2 It should be noted, however, that the
odds ratio for hypertension in the group with the highest risk
score was at best ⬇1.5. From the perspective of predictive
testing in an individual, an odds ratio of 1.5 is of practically
no value.11 In fact, even if every genetic factor involved in
hypertension could be identified and analyzed, the accuracy
of genetic profiling would not be any better than simple
clinical risk scores in predicting who will and who will not
get hypertension.12 This is because of the fact that a very large
fraction of BP variation is determined by nongenetic factors.
Some might suggest that we should attempt to unravel the BP
impact of gene-gene interaction and gene-environment interaction in hopes of further improving the discriminative ability
of risk profiling based on common variants with apparently
small effects on BP. However, assuming such studies were
technically feasible to begin with, they would be extremely
1024
Hypertension
December 2010
expensive and not worth the effort for the reasons discussed
below.
Even if one could develop a better risk score with high
discriminative ability, there is little rationale for early detection of individuals at high risk for essential hypertension. It is
unclear whether patients who are given information on their
genetic risk for hypertension will be any more likely to adopt
appropriate lifestyle changes and reduce their risk for hypertension than patients not given such information. Moreover,
recommendations for preventing essential hypertension, including control of body weight, dietary habits, stress, physical
exercise, alcohol intake, and tobacco intake can be helpful for
everyone, not just people with increased risk for hypertension. Such recommendations can and should be made regardless of an individual’s estimated risk for hypertension.
Given the Limited Value of GWA Studies for
Unlocking the Genetics of Hypertension, Is There
a Better Way Forward?
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Although considerable effort has been expended on GWA
studies to search for common genetic variants with individually small effects on BP, the attention of geneticists has
recently begun to shift to the “rare gene variant” hypothesis
for common disorders like hypertension.5,7 The fact that
GWA studies have identified common genetic variants that
together account for only a tiny fraction of complex trait
variation in the population has stimulated some to suspect
that the so-called “missing heritability” may be traceable to
effects of rare variants that cannot be detected by GWA
studies. As mentioned previously, the rare gene variant
hypothesis holds that much (but not necessarily all) of the
genetically determined BP variation in the population stems
from a large number of different gene variants, each of which
is rare in the population and each of which can individually
exert relatively substantial effects on BP.3,6 Thus, although
each individual variant itself may be rare, such rare variants
could still play important roles in common disorders like
hypertension because, throughout the population, there could
be many different types of rare variants with individually
strong effects on BP.
The best illustration of the potential role of rare gene
variants in the pathogenesis of essential hypertension is found
in a study of 3125 participants from the Framingham study
performed by Lifton and colleagues13 in which they carefully
sequenced 3 genes known to be involved in renal electrolyte
transport and BP regulation. Previous studies by Lifton and
colleagues had uncovered mutations in these genes that
caused rare recessive diseases characterized by very large
reductions in BP. Remarkably, 1 of every 64 subjects in this
Framingham cohort was found to carry a mutation of potential functional significance in 1 of these 3 genes.13 Very few
of the carriers shared the same variant in common (the
tendency was for each person to carry his or her own
particular mutation so that each specific mutation was rare).
On average, the systolic BP at age 60 in those carrying one of
these rare mutations was 9 mm Hg lower than in the noncarriers, and having one of these rare mutations reduced the risk
for hypertension at the age of 60 years by ⬇60%. It is
important to keep in mind that this study examined just 3
genes. Thus, if one were to fully sequence the coding regions
of many more genes relevant to known BP control pathways,
it would not be surprising to find more individually rare
variants of potential functional significance in many more
people.
To investigate whether many individually rare gene variants play a major role in genetic susceptibility to essential
hypertension, it will be necessary to find the variants and then
somehow determine their effects on BP. Finding such rare
gene variants will require sequencing large numbers of genes
in many thousands of people. Thanks to radical advances
occurring in DNA sequencing technology, it appears that
comprehensive searches for rare gene variants are becoming
more feasible.5 The task of finding rare gene variants will be
easy compared with the task of determining which ones are
actually influencing BP and risk for hypertension. Although it
will be a challenge to clearly establish the impact of rare gene
variants on BP and risk for hypertension, the work of Lifton
and colleagues suggests some potential usefully ways to
approach this problem in the future.13
Future Perspectives
Although GWA studies have failed to unlock the genetics of
hypertension, there is reason to hope that some of the
next-generation research technologies and strategies being
developed will prove to be more effective in this regard.
Nevertheless, the ultimate clinical value of identifying many
if not most of the DNA sequence variants, both rare and
common, that mediate genetic risk for essential hypertension
remains open to question. It has been argued that, because the
individual phenotypic effects of rare gene variants are stronger than those of common gene variants, identification of rare
gene variants could be of more practical clinical use than
identification of common gene variants.14 However, for
medical disorders like essential hypertension that are characterized by very high prevalence and where much of the risk is
influenced by nongenetic factors, genetic profiles that incorporate rare variants with relatively large effects on BP may
still not provide sufficient discriminative accuracy to make
them very useful in clinical practice.15 It also remains to be
determined whether identification of rare variants associated
with increased risk for essential hypertension will lead to new
insights into better methods for prevention or treatment of
hypertension. Thus, even if the next-generation sequencing
tools and analytic strategies prove to be more successful than
GWA studies in unlocking the genetics of hypertension, it
would seem prudent to avoid promoting these new research
opportunities in the hyped up manner in which GWA studies
were promoted in the past.
Acknowledgments
We thank Dr Allyn Mark for organizing the debate on GWASs at the
2010 meeting of the American Society of Hypertension and for
proposing this topic as a subject for the Controversies in Hypertension series.
Disclosures
None.
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Response to Genome-Wide Association Studies Will Unlock the Genetic Basis of
Hypertension: Con Side of the Argument
Anna F. Dominiczak, and Patricia B. Munroe
Prof Kurtz eloquently tries to persuade us that new concepts and methods in genetics and genomics of hypertension are a
waste of time and money. I and many of my colleagues respectfully disagree.
The GWASs demonstrated, for the first time, that it is possible to study a million or more SNPs across the entire genome.
Novel findings of mechanistic significance for many complex polygenic traits, such as coronary artery disease, diabetes
mellitus, obesity, and many others have been established. Human essential hypertension is the most common treatable
polygenic trait. It would have been neglectful of us not to apply the new tools of genomics to improve our understanding
of this disease.
What have we gained? I think we gained the understanding that both the common variant/common disease and rare
variant/common disease hypotheses are needed to explain the genetic determinants of hypertension. The common variants
identified as being associated with essential hypertension are currently a subject of further functional studies, which are
likely to reveal new pathways and new drug targets. The rare variants similar to those studied by Lifton’s group are about
to be revealed by the ongoing exome sequencing efforts, particularly where careful phenotyping and patient selection allow
us to study the extremes of BP and cardiovascular risk distribution.
The future of genomics is bright, and the GWASs have been an important building block for a future success.
Genome-Wide Association Studies Will Unlock the Genetic Basis of Hypertension: Con
Side of the Argument
Theodore W. Kurtz
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Hypertension. 2010;56:1021-1025; originally published online November 8, 2010;
doi: 10.1161/HYPERTENSIONAHA.110.156190
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