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Birth Cohort, Age, and Sex Strongly Modulate Effects of Lipid Risk Alleles Identified in Genome-Wide Association Studies.

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Date
2015
Authors
Kulminski, Alexander M
Culminskaya, Irina
Arbeev, Konstantin G
Arbeeva, Liubov
Ukraintseva, Svetlana V
Stallard, Eric
Wu, Deqing
Yashin, Anatoliy I
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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 article
Subject
Adult
Age Factors
Alleles
Cholesterol
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Male
Polymorphism, Single Nucleotide
Quantitative Trait, Heritable
Sex Factors
Permalink
https://hdl.handle.net/10161/14863
Published Version (Please cite this version)
10.1371/journal.pone.0136319
Publication 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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Scholars@Duke

Arbeev

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
Kulminskaya

Irina Kulminskaya

Research Scientist, Senior
Kulminski

Alexander Kulminski

Research Professor in the Social Science Research Institute
Ukraintseva

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
Wu

Dequing Wu

Research Scientist, Senior
Yashin

Anatoli I. Yashin

Research Professor in the Social Science Research Institute
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