Neolithic introgression of IL23R-related protection against chronic inflammatory bowel diseases in modern Europeans

BackgroundThe hypomorphic variant rs11209026-A in the IL23R gene provides significant protection against immune-related diseases in Europeans, notably inflammatory bowel disease (IBD). Today, the A-allele occurs with an average frequency of 5% in Europe. MethodsThis study comprised 251 ancient genomes from Europe spanning over 14,000 years. In these samples, the investigation focused on admixture informed analyses and selection scans of rs11209026-A and its haplotypes. Findingsrs11209026-A was found at high frequencies in Anatolian Farmers (AF, 18%) where it was likely under weak positive selection. AF later introduced the allele into the ancient European gene-pool. Subsequent admixture caused its frequency to decrease and formed the current southwest-to-northeast allele frequency cline in Europe. The geographic distribution of rs11209026-A may influence the gradient in IBD incidence rates that are highest in northern and eastern Europe. InterpretationGiven the dramatic changes from hunting and gathering to agriculture during the Neolithic, AF might have been exposed to selective pressures from a pro-inflammatory lifestyle and diet. Therefore, the protective A-allele may have increased survival by reducing intestinal inflammation and microbiome dysbiosis. The adaptively evolved function of the variant likely contributes to the high efficacy and low side-effects of modern IL-23 neutralization therapies for chronic inflammatory diseases. This study highlights how evolutionary informed research can provide promising targets for new therapeutic strategies. FundingDeutsche Forschungsgemeinschaft (DFG German Research Foundation) under Germanys Excellence Strategy - EXC 2167 390884018 and EXC 2150 390870439.