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

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.

Biological Processes Modulating Longevity across Primates: A Phylogenetic Genome-Phenome Analysis

“…Similarly, wound healing and blood coagulation categories, proposed by our evolutionary analysis in primates were also enriched in pleiotropic effects, highlighting that these genes are involved in multiple pathways and exhibiting the importance that these categories could have in the evolution of senescence, as predicted by the AP theory of aging. In agreement with our results, a recent study found that coronary artery disease loci are enriched in antagonistic-pleiotropic signals and suggests that natural selection may have maintained genetic variation contributing to cardiovascular disorders because of its beneficial effects in early life ( Byars et al. 2017 ).…”

Reproduction and longevity A Mendelian randomization study of gonadotropin-releasing hormone and ischemic heart disease

“…Consistent with theoretical predictions from evolutionary biology and empirical evidence, 6 this study showed GnRH1, but not GnRH2, positively associated with IHD.…”

“…5 Genetic selection in favour of both fertility and ischemic heart disease (IHD) has been demonstrated. 6 Reproduction is driven centrally by gonadotropin-releasing hormone 1 (GnRH1) 7 likely driven by environmental factors to ensure optimal timing of reproduction. We used Mendelian randomization to estimate the causal effect of GnRH1 on IHD.…”

Genetic predictors of testosterone and their associations with cardiovascular disease and risk factors: A Mendelian randomization investigation

“…Applying theories from evolutionary biology, growth and reproduction would be expected to trade-off against longevity [ 49 ]. Consistent with this theory, evidence of genetic selection in favour of both fertility and CAD has recently been reported [ 50 ]. A recent Mendelian randomization study also found some indications that genetically-predicted higher follicle stimulating hormone, usually associated with higher androgen levels, was positively associated with CAD risk, but genetically-predicted higher anti-Müllerian hormone and higher risk of testicular dysgenesis syndrome, usually associated with lower androgen levels, were negatively associated with CAD risk [ 51 ].…”