Background/Purpose The reasons for the ethnic disparities in rheumatologic and autoimmune diseases (ADs) are largely unknown. We posit that population-specific selection influencing the allele frequencies at some loci contribute to ethnic disparities. Relative to other African-Americans (AA), the Gullah population has lower European admixture and higher ancestral homogeneity from the Sierra Leone (SL) area in Far-West Africa. The shorter genetic distance between the Gullahs and SL suggests that population genetic signals, such as regions under recent selection, may be more easily detected in the Gullahs than in other AA populations. Since both protein-coding and regulatory variation have important roles in recent human adaptation, our goal was to integrate evidence for natural selection with functional annotation for the identification of biologically relevant signals that may harbor risk loci for ADs.

Methods We computed the cross population extended haplotype homozygosity test (XP-EHH) to identify alleles with higher than expected frequency relative to their haplotype length in Gullah population controls (n=277) relative to SL population controls (n=400), to HapMap Phase II  Africans (YRI, n=203), and Caucasians (CEU; n=165). In total 679,513 SNPs met standard GWAS quality control criteria. Variants that met suggestive significance (|XP-EHH|>4, PResults Nearly the same number of loci showed suggestive evidence for selection between the Gullah and YRI (0.15% of all SNPs), and Gullah and SL (0.14%), although only 106 SNPs in 12 regions showed evidence for selection in both comparisons. Fewer loci showed evidence for selection between Gullah and CEU (0.06%). This is reflected in the enrichment of different pathways in each comparison. Enhancer enrichment analysis of all suggestive SNPs revealed a significant enrichment of strongest enhancers in H1 human embryonic stem cells. Several regions showing evidence of selection between the Gullah and the YRI harbor missense SNPs in AD-relevant genes (CENPO, IKBKA, USP31). Other autoimmune-related genes harbor multiple SNPs with high regulatory scores based on the simultaneous presence of eQTLs, transcription factor binding and DNase sites, including those showing evidence of selection between Gullah and YRI (CCR2, ADCY2, HLA, CD36, CAV1, GLG1, FXR2), Gullah and SL (CCR2, ADCY2), and Gullah and CEU (TET3).

Conclusion These results reveal several autoimmune-related genes with evidence for selection and concomitant high functional potential in the Gullah AA population. Given the increased prevalence of several ADs in AAs and the homogeneity of the Gullah, identification of functional regions under selection in the Gullah has the potential to elucidate AD risks in AA and help explain the ethnic disparity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-autoimmune-functional-variants-under-positive-selection-in-the-gullah-african-american-population-of-south-carolina/