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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    ABSTRACT: Genome-wide scans for selection have identified multiple regions of the human genome as being targeted by positive selection. However, only a small proportion has been replicated across studies, and the prevalence of positive selection as a mechanism of adaptive change in humans remains controversial. Here we explore the power of two haplotype-based statistics - the integrated haplotype score (iHS) and the Derived Intra-allelic Nucleotide Diversity (DIND) test - in the context of next-generation sequencing data, and evaluate their robustness to demography and other selection modes. We show that these statistics are both powerful for the detection of recent positive selection, regardless of population history, and robust to variation in coverage, with DIND being insensitive to very low coverage. We apply these statistics to whole-genome sequence datasets from the 1000 Genomes Project and Complete Genomics. We found that putative targets of selection were highly significantly enriched in genic and non-synonymous SNPs, and that DIND was more powerful than iHS in the context of small sample sizes, low-quality genotype calling or poor coverage. As we excluded genomic confounders and alternative selection models, such as background selection, the observed enrichment attests to the action of recent, strong positive selection. Further support to the adaptive significance of these genomic regions came from their enrichment in functional variants detected by genome-wide association studies, informing the relationship between past selection and current benign and disease-related phenotypic variation. Our results indicate that hard sweeps targeting low-frequency standing variation have played a moderate, albeit significant, role in recent human evolution.
    Molecular Biology and Evolution 04/2014; DOI:10.1093/molbev/msu118 · 14.31 Impact Factor
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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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    ABSTRACT: It has recently been hypothesized that polygenic adaptation, resulting in modest allele frequency changes at many loci, could be a major mechanism behind the adaptation of complex phenotypes in human populations. Here we leverage the large number of variants that have been identified through genome-wide association (GWA) studies to comprehensively study signatures of natural selection on genetic variants associated with complex traits. Using population differentiation based methods, such as FST and phylogenetic branch length analyses, we systematically examined nearly 1300 SNPs associated with 38 complex phenotypes. Instead of detecting selection signatures at individual variants, we aimed to identify combined evidence of natural selection by aggregating signals across many trait associated SNPs. Our results have revealed some general features of polygenic selection on complex traits associated variants. First, natural selection acting on standing variants associated with complex traits is a common phenomenon. Second, characteristics of selection for different polygenic traits vary both temporarily and geographically. Third, some studied traits (e.g. height and urate level) could have been the primary targets of selection, as indicated by the significant correlation between the effect sizes and the estimated strength of selection in the trait associated variants; however, for most traits, the allele frequency changes in trait associated variants might have been driven by the selection on other correlated phenotypes. Fourth, the changes in allele frequencies as a result of selection can be highly stochastic, such that, polygenic adaptation may accelerate differentiation in allele frequencies among populations, but generally does not produce predictable directional changes. Fifth, multiple mechanisms (pleiotropy, hitchhiking, etc) may act together to govern the changes in allele frequencies of genetic variants associated with complex traits.
    12/2013; 2. DOI:10.1016/j.atg.2013.10.002
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    ABSTRACT: Infectious diseases, both in their endemic and epidemic forms, have shaped the human genome. Ecology has also contributed to geographically constrained pressures on human populations. There are now multiple examples of population-specific genetic variants that modulate susceptibility to infection - several of which have been observed solely in Europeans. The pathogen genome also mutates and adapts to individuals and common alleles in populations. The current understanding has benefited from genome-wide association studies as well as from rapid progress in the genetic characterization of Mendelian immunodeficiencies that are defined by susceptibility to specific pathogens. It is expected that current efforts to characterize rare human genetic variants will contribute to the understanding of severe manifestations of common infections in European and other human groups. © 2014 S. Karger AG, Basel.
    Human Heredity 01/2013; 76(3-4):187-93. DOI:10.1159/000357758 · 1.64 Impact Factor
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