Background/Purpose: Most autoimmune diseases (ADs) are more prevalent in specific ethnic groups. We hypothesize that one reason for the ethnic disparity may be an effect of population-specific selection influencing the allele frequencies at some loci. Selection for specific alleles that improves fitness and survival in a specific environment can lead to increased disease risk in a different environment. Given the growing number of disease-associated loci in regions that show evidence of selection, identification of alleles under selection may provide insight into disease susceptibility.  Relative to other African-Americans (AA), the AA Gullah population has lower European admixture and higher ancestral homogeneity from the Sierra Leone area in Far-West Africa. The shorter genetic distance between the Gullahs and Sierra Leoneans suggests that population genetic signals, such as regions under recent selection, may be more easily detected in the Gullahs than in other African American (AA) populations. The goal of this study was to identify regions under recent positive selection in the Gullahs 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 one population relative to another. We compared 277 control Gullahs to 400 Sierra Leonean controls and to 203 HapMap Yorubans (YRI) from Nigeria. A total of 679,513 SNPs with MAF>5% met all statistical quality control criteria. Regions that met genome-wide significance ((|XP-EHH|>4, PResults: We identified multiple regions with evidence of recent selection. Over 20 regions showed evidence of selection between the Gullah and the Sierra Leoneans (|XP-EHH|>4, PDAB1 (Kawasaki disease), KCNH8 (Crohn’s disease, psoriasis), and LPP genes (vitiligo, celiac disease). Twenty four regions showed evidence of selection between the Gullah and the YRI, revealing an enrichment of genes involved in cytokine/chemokine mediated immunity (P-Bonferroni=0.0015), but only two regions were being selected for in the Gullahs, none of which has previously shown evidence of association with an AD. Regions associated with ADs showing evidence of selection in the YRI population include those of the the HLA region (all ADs), the CCR2 (celiac disease), and SMOC2 genes (vitiligo), with CCR2 also showing evidence of selection in the Sierra Leone population. This scan also identified the region around the APOL1 gene, which has been shown to be under selection and associated with multiple kidney diseases in AAs.

Conclusion: We have identified several risk alleles for ADs that are targets of recent positive selection in an AA population. Given the increased prevalence of several ADs in AAs and the homogeneity of the Gullahs, identification of these regions in the Gullahs has the potential to elucidate AD risks in AAs and help explain the ethnic disparity.

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