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

Kulminski, Alexander M

Culminskaya, Irina

Arbeev, Konstantin G

Arbeeva, Liubov

Ukraintseva, Svetlana V

Stallard, Eric

Wu, Deqing

Yashin, Anatoliy I

Zeller, Tanja

United States

2017-06-06T18:12:39Z

2017-06-06T18:12:39Z

2015

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.

https://www.ncbi.nlm.nih.gov/pubmed/26295473

PONE-D-15-07409

1932-6203

https://hdl.handle.net/10161/14863

eng

Public Library of Science (PLoS)

PLoS One

10.1371/journal.pone.0136319

Adult

Age Factors

Alleles

Cholesterol

Female

Genetic Predisposition to Disease

Genome-Wide Association Study

Humans

Male

Polymorphism, Single Nucleotide

Quantitative Trait, Heritable

Sex Factors

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

Journal article

Arbeev, Konstantin G|0000-0002-4195-7832

https://www.ncbi.nlm.nih.gov/pubmed/26295473

e0136319

8

Center for Population Health & Aging

Duke

Duke Cancer Institute

Duke Population Research Center

Duke Population Research Institute

Institutes and Centers

Institutes and Provost's Academic Units

Sanford School of Public Policy

School of Medicine

Social Science Research Institute

Staff

University Institutes and Centers

Published online

10