Article

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

Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham & Women's Hospital, Boston, MA 02115, USA
The American Journal of Human Genetics (Impact Factor: 10.99). 03/2013; 92(4). DOI: 10.1016/j.ajhg.2013.03.001
Source: PubMed

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.

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    • "Importantly, we also observed a strong skew in selection, targeting alleles associated with a higher risk of immune-related diseases. Our results further support the hypothesis that the incidence of immune-related disorders in modern societies may at least partly reflect the consequences of past selection for stronger immune responses to combat infection (Barreiro and Quintana-Murci 2010; Raj et al. 2013). "
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    • "The results from GWA studies not only confirmed the highly polygenic nature of most complex human traits (McCarthy et al., 2008; Stranger et al., 2011) but also enabled aggregating signals of selection across multiple trait associated variants, each of which might not stand out above the neutral background (Pritchard et al., 2010). For examples, Amato et al. (2011) found the mean F ST of the 180 variants associated with human height to be significantly higher than the genomic background; Turchin et al. (2012) identified systematic allele frequency differences of height SNPs between Northern and Southern Europeans; Casto and Feldman (2011) demonstrated widespread selection on complex human traits through examination over 1300 GWAS SNPs; and Raj et al. (2013) observed significant enrichment of recent positive selection signatures among more than 500 inflammatory-disease susceptibility SNPs. However, there were also contradictory reports (Adeyemo and Rotimi, 2010; Ding and Kullo, 2011; Lohmueller et al., 2006; Myles et al., 2008) that did not detect unusually more differentiation of diseases associated variants between populations, which might suggest that positive selection does not have a strong effect on risk alleles in general. "
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