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

Abstract

Background: The hypomorphic variant rs11209026-A in the IL23R gene provides significant protection against immune-related diseases in Europeans, notably inflammatory bowel diseases (IBD). Today, the A-allele occurs with an average frequency of 5% in Europe.

Methods: This 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.

Findings: rs11209026-A was found at high frequencies in Anatolian Farmers (AF, 18%). 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.

Interpretation: Given 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 neutralisation therapies for chronic inflammatory diseases.

Funding: German Research Foundation (EXC 2167 390884018 and EXC 2150 390870439).

Keywords: Ancient genomics; Crohn's disease; IL-23-signalling; IL23R; Inflammatory bowel diseases; Ulcerative colitis.

Fig. 1

Map of rs11209026-A frequencies based on data from modern west-Eurasians (Supplementary Table S1). Colour corresponds to allele frequency according to the key bar on the right. The black dots represent the countries from which frequencies were used for the interpolation. The map shows an increasing north-south and east-west cline.

Fig. 2

a Frequency of the rs11209026-A allele in seven ancient populations and a modern European reference (CEU). An expected frequency is shown next to each population resulting from one of two past major demographic events, I: admixture of WHG with EF (purple diamond); II: admixture of LF with Steppe herders (red diamond). The expected frequency of an offspring population was calculated using the observed frequency of its parental populations and the respective admixture component of these parental populations in the offspring population. A Fisher's exact test was used to assess whether there were significant differences between the observed frequencies of ancient populations. For clarity, only the p-values for three population pairs (WHG vs. AF, EF, LF) are shown. Errors bars indicate the 95% CI in observed frequencies. Errors bars on the expected frequencies indicate the expected frequency range. b Distribution of the distances between expected allele frequencies based on admixture (F_exp) and observed frequencies (F_obs) of variants located in neutral regions of the genome.

Fig. 3

EHH plot for rs11209026 in AF, EF, LF, and CEU populations. The x-axis represents the coordinates around the SNV while the y-axis shows the homozygosity scale ranging from 0 (no haplotype homozygosity) to 1 (complete haplotype homozygosity). In EF, LF, and CEU the extended homozygosity is seen for the haplotype with the derived A-allele.