Genetic loci associated with coronary artery disease harbor evidence of selection and antagonistic pleiotropy

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Byars , S G , Huang , Q Q , Gray , L-A , Bakshi , A , Ripatti , S , Abraham , G , Stearns , S C & Inouye , M 2017 , ' Genetic loci associated with coronary artery disease harbor evidence of selection and antagonistic pleiotropy ' , PLoS Genetics , vol. 13 , no. 6 , 1006328 . https://doi.org/10.1371/journal.pgen.1006328

Title: Genetic loci associated with coronary artery disease harbor evidence of selection and antagonistic pleiotropy
Author: Byars, Sean G.; Huang, Qin Qin; Gray, Lesley-Ann; Bakshi, Andrew; Ripatti, Samuli; Abraham, Gad; Stearns, Stephen C.; Inouye, Michael
Contributor: University of Helsinki, Clinicum
Date: 2017-06
Language: eng
Number of pages: 27
Belongs to series: PLoS Genetics
ISSN: 1553-7404
URI: http://hdl.handle.net/10138/203759
Abstract: Traditional genome-wide scans for positive selection have mainly uncovered selective sweeps associated with monogenic traits. While selection on quantitative traits is much more common, very few signals have been detected because of their polygenic nature. We searched for positive selection signals underlying coronary artery disease (CAD) in worldwide populations, using novel approaches to quantify relationships between polygenic selection signals and CAD genetic risk. We identified new candidate adaptive loci that appear to have been directly modified by disease pressures given their significant associations with CAD genetic risk. These candidates were all uniquely and consistently associated with many different male and female reproductive traits suggesting selection may have also targeted these because of their direct effects on fitness. We found that CAD loci are significantly enriched for lifetime reproductive success relative to the rest of the human genome, with evidence that the relationship between CAD and lifetime reproductive success is antagonistic. This supports the presence of antagonistic-pleiotropic tradeoffs on CAD loci and provides a novel explanation for the maintenance and high prevalence of CAD in modern humans. Lastly, we found that positive selection more often targeted CAD gene regulatory variants using HapMap3 lymphoblastoid cell lines, which further highlights the unique biological significance of candidate adaptive loci underlying CAD. Our study provides a novel approach for detecting selection on polygenic traits and evidence that modern human genomes have evolved in response to CAD-induced selection pressures and other early-life traits sharing pleiotropic links with CAD.
Subject: GENOME-WIDE ASSOCIATION
POLYCYSTIC-OVARY-SYNDROME
RECENT POSITIVE SELECTION
NATURAL-SELECTION
HEART-DISEASE
HAPLOTYPE STRUCTURE
HUMAN ADAPTATION
CANDIDATE GENES
ADIPOSE-TISSUE
DEFICIENT MICE
3111 Biomedicine
3142 Public health care science, environmental and occupational health
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