RT Journal Article
SR Electronic
T1 Genetic loci associated with coronary artery disease harbor evidence of selection and antagonistic pleiotropy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 064758
DO 10.1101/064758
A1 Sean G. Byars
A1 Qinqin Huang
A1 Lesley-Ann Gray
A1 Samuli Ripatti
A1 Gad Abraham
A1 Stephen C. Stearns
A1 Michael Inouye
YR 2016
UL http://biorxiv.org/content/early/2016/07/19/064758.abstract
AB 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 candidate adaptive loci that may have been directly modified by disease pressures given their significant associations with CAD genetic risk. Top candidates were consistently associated with reproductive-traits suggesting antagonistic-pleiotropic tradeoffs with early-life phenotypes and also showed more evidence of gene regulatory effects in HapMap3 lymphoblastoid cell lines than non-adaptive candidates. 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.HighlightsWidespread genomic signals of positive selection are present underlying coronary artery disease (CAD) lociSelection peaks that significantly associated with genetic risk suggest loci modified (in)directly by CADSelection was more often associated with variants important for regulating gene expressionCAD loci share many pleiotropic links with early-life traits suggesting antagonistic effects