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Am J Hum Genet DOI:10.1016/j.ajhg.2013.03.001

Common risk alleles for inflammatory diseases are targets of recent positive selection.

Publication TypeJournal Article
Year of Publication2013
AuthorsRaj, T, Kuchroo, M, Replogle, JM, Raychaudhuri, S, Stranger, BE, De Jager, PL
JournalAm J Hum Genet
Date Published2013 Apr 04
KeywordsAlleles, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Haplotypes, Humans, Inflammation, Protein Interaction Maps, Quantitative Trait Loci, Risk Factors, Selection, Genetic

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.


Alternate JournalAm. J. Hum. Genet.
PubMed ID23522783
PubMed Central IDPMC3617371
Grant ListF32 AG043267 / AG / NIA NIH HHS / United States
R01 NS067305 / NS / NINDS NIH HHS / United States
RC2 GM093080 / GM / NIGMS NIH HHS / United States
U01 HG007033 / HG / NHGRI NIH HHS / United States