Common Risk Alleles for Inflammatory Diseases Are Targets of Recent Positive Selection

Abstract

Genome-wide association studies (GWASs) have identified hundreds of loci harboring genetic variation influencing inflammatory-disease susceptibility in humans. It has been hypothesized that present day inflammatory diseases may have arisen, in part, due to pleiotropic effects of host resistance to pathogens over the course of human history, with significant selective pressures acting to increase host resistance to pathogens. The extent to which genetic factors underlying inflammatory-disease susceptibility has been influenced by selective processes can now be quantified more comprehensively than previously possible. To understand the evolutionary forces that have shaped inflammatory-disease susceptibility and to elucidate functional pathways affected by selection, we performed a systems-based analysis to integrate (1) published GWASs for inflammatory diseases, (2) a genome-wide scan for signatures of positive selection in a population of European ancestry, (3) functional genomics data comprised of protein-protein interaction networks, and (4) a genome-wide expression quantitative trait locus (eQTL) mapping study in peripheral blood mononuclear cells (PBMCs). We demonstrate that loci for inflammatory-disease susceptibility are enriched for genomic signatures of recent positive natural selection, with selected loci forming a highly interconnected protein-protein interaction network. Further, we identify 21 loci for inflammatory-disease susceptibility that display signatures of recent positive selection, of which 13 also show evidence of cis-regulatory effects on genes within the associated locus. Thus, our integrated analyses highlight a set of susceptibility loci that might subserve a shared molecular function and has experienced selective pressure over the course of human history; today, these loci play a key role in influencing susceptibility to multiple different inflammatory diseases, in part through alterations of gene expression in immune cells.

Early farmers from across Europe directly descended from Neolithic Aegeans

“…Interestingly, we observe derived states for six of eight loci in a protein-protein interaction network inferred to have undergone concerted positive selection 2.6-1.2 kya in Europeans (17), suggesting that any recent selection on these loci acted on standing variation present at already appreciable frequency (SI Appendix, SI12. Functional Markers).…”

Interindividual variation in human T regulatory cells

“…Indeed, under the strong selective pressure elicited by pathogens, immune system genes are those that show the strongest marks of adaptation and positive selection for variant alleles in different populations (42). Inflammatory disease-associated variants such as those underlying T1D are enriched in signatures of positive selection (43). Some of these variants are eQTL (expression quantitative trait loci) that affect transcriptional rate or mRNA stability (44) and may mediate the effect of inflammatory-disease susceptibility loci (45).…”

Accurate and Fast Multiple-Testing Correction in eQTL Studies

“…4,12,14,[16][17][18] This is a nonparametric test, and its power and type I error are robust to the deviance of expressions from the normal distribution. The Spearman's rank correlation is defined as the Pearson correlation of the ranks where ties are given mean values.…”