Birth Cohort, Age, and Sex Strongly Modulate Effects of Lipid Risk Alleles Identified in Genome-Wide Association Studies.
Abstract
Insights into genetic origin of diseases and related traits could substantially impact
strategies for improving human health. The results of genome-wide association studies
(GWAS) are often positioned as discoveries of unconditional risk alleles of complex
health traits. We re-analyzed the associations of single nucleotide polymorphisms
(SNPs) associated with total cholesterol (TC) in a large-scale GWAS meta-analysis.
We focused on three generations of genotyped participants of the Framingham Heart
Study (FHS). We show that the effects of all ten directly-genotyped SNPs were clustered
in different FHS generations and/or birth cohorts in a sex-specific or sex-unspecific
manner. The sample size and procedure-therapeutic issues play, at most, a minor role
in this clustering. An important result was clustering of significant associations
with the strongest effects in the youngest, or 3rd Generation, cohort. These results
imply that an assumption of unconditional connections of these SNPs with TC is generally
implausible and that a demographic perspective can substantially improve GWAS efficiency.
The analyses of genetic effects in age-matched samples suggest a role of environmental
and age-related mechanisms in the associations of different SNPs with TC. Analysis
of the literature supports systemic roles for genes for these SNPs beyond those related
to lipid metabolism. Our analyses reveal strong antagonistic effects of rs2479409
(the PCSK9 gene) that cautions strategies aimed at targeting this gene in the next
generation of lipid drugs. Our results suggest that standard GWAS strategies need
to be advanced in order to appropriately address the problem of genetic susceptibility
to complex traits that is imperative for translation to health care.
Type
Journal articleSubject
AdultAge Factors
Alleles
Cholesterol
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Male
Polymorphism, Single Nucleotide
Quantitative Trait, Heritable
Sex Factors
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https://hdl.handle.net/10161/14863Published Version (Please cite this version)
10.1371/journal.pone.0136319Publication Info
Kulminski, Alexander M; Culminskaya, Irina; Arbeev, Konstantin G; Arbeeva, Liubov;
Ukraintseva, Svetlana V; Stallard, Eric; ... Yashin, Anatoliy I (2015). Birth Cohort, Age, and Sex Strongly Modulate Effects of Lipid Risk Alleles Identified
in Genome-Wide Association Studies. PLoS One, 10(8). pp. e0136319. 10.1371/journal.pone.0136319. Retrieved from https://hdl.handle.net/10161/14863.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Konstantin Arbeev
Associate Research Professor in the Social Science Research Institute
Konstantin G. Arbeev received the M.S. degree in Applied Mathematics from Moscow State
University (branch in Ulyanovsk, Russia) in 1995 and the Ph.D. degree in Mathematics
and Physics (specialization in Theoretical Foundations of Mathematical Modeling, Numerical
Methods and Programming) from Ulyanovsk State University (Russia) in 1999. He was
a post-doctoral fellow in Max Planck Institute for Demographic Research in Rostock
(Germany) before moving to Duke University in 2004 to work as a Resea
Irina Kulminskaya
Research Scientist, Senior
Alexander Kulminski
Research Professor in the Social Science Research Institute
Svetlana Ukraintseva
Associate Research Professor in the Social Science Research Institute
Dr. Ukraintseva studies causes of human aging and related decline in resilience, to
identify genetic and other factors responsible for the increase in mortality risk
with age eventually limiting longevity. She explores complex relationships, including
trade-offs, between physiological aging-changes and risks of major diseases (with
emphasis on Alzheimer’s and cancer), as well as survival, to find new genetic and
other targets for anti-aging interventions and disease prevention. S
Dequing Wu
Research Scientist, Senior
Anatoli I. Yashin
Research Professor in the Social Science Research Institute
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