Show simple item record

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

dc.contributor.author Arbeev, Konstantin
dc.contributor.author Arbeeva, L
dc.contributor.author Culminskaya, IV
dc.contributor.author Kulminski, Alexander
dc.contributor.author Stallard, Eric
dc.contributor.author Ukraintseva, Svetlana
dc.contributor.author Wu, Dequing
dc.contributor.author Yashin, Anatoli I
dc.coverage.spatial United States
dc.date.accessioned 2017-06-06T18:12:39Z
dc.date.available 2017-06-06T18:12:39Z
dc.date.issued 2015
dc.identifier https://www.ncbi.nlm.nih.gov/pubmed/26295473
dc.identifier PONE-D-15-07409
dc.identifier.uri https://hdl.handle.net/10161/14863
dc.description.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.
dc.language eng
dc.relation.ispartof PLoS One
dc.relation.isversionof 10.1371/journal.pone.0136319
dc.subject Adult
dc.subject Age Factors
dc.subject Alleles
dc.subject Cholesterol
dc.subject Female
dc.subject Genetic Predisposition to Disease
dc.subject Genome-Wide Association Study
dc.subject Humans
dc.subject Male
dc.subject Polymorphism, Single Nucleotide
dc.subject Quantitative Trait, Heritable
dc.subject Sex Factors
dc.title Birth Cohort, Age, and Sex Strongly Modulate Effects of Lipid Risk Alleles Identified in Genome-Wide Association Studies.
dc.type Journal article
pubs.author-url https://www.ncbi.nlm.nih.gov/pubmed/26295473
pubs.begin-page e0136319
pubs.issue 8
pubs.organisational-group Center for Population Health & Aging
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Duke Population Research Center
pubs.organisational-group Duke Population Research Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Institutes and Provost's Academic Units
pubs.organisational-group Sanford School of Public Policy
pubs.organisational-group School of Medicine
pubs.organisational-group Social Science Research Institute
pubs.organisational-group Staff
pubs.organisational-group University Institutes and Centers
pubs.publication-status Published online
pubs.volume 10
dc.identifier.eissn 1932-6203


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record