Genome-wide admixture and association analysis identifies African ancestry specific risk loci of eosinophilic esophagitis in African American

Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease. Multiple genetic risk factors linked to EoE have been identified; however, these studies have been primarily focused on populations of European ancestry. There is a lack of studies leveraging the genetic architecture of Black or African American (AA) populations for the identification of loci involved in EoE susceptibility. Herein, we present admixture mapping (AM) and genome-wide association analysis (GWAS) of EoE using the participants of AA populations.We conducted AM and GWAS of EoE using 137 EoE cases and 1465 healthy controls from AA population. Samples were genotyped using the Multi-Ethnic Genotyping Array (MEGA). Genotype imputation was carried out with the CAAPA reference panel using the Michigan Imputation Server. Global and local ancestry inference was carried out using RFMix v2, followed by fine-mapping analysis based on imputed genotypes, and RNAseq analysis. After standard quality control filtering, over 6,000,000 variants were tested by logistic regression adjusted for sex, age, and global ancestry.Global African ancestry proportion was found to be significantly lower among cases than controls (0.751 vs. 0.786, p-value = 0.012). Case-only AM identified four significant loci (9p13.3, 12q24.22-23, and 15q11.2) associated with EoE, two of which (12q24.22-23 and 9p13.3) were further replicated in the case-control analysis. At the two loci (12q24.23 and 9p13.3), the associations were observed for excess African ancestry. Fine mapping and multi-omic functional annotations prioritized the variants rs11068264 (FBXW8) and rs7307331 (VSIG10) at 12q24.23 and rs2297879 (ARHGEF39) at 9p13.3. GWAS identified one genome-wide significant locus at chromosome 1p22.3 (rs17131726, p-value = 2.39e-27, DDAH1) and 10 other suggestive loci including FAM179A (rs145050353), SCAND3 (rs56100858), TBC1D13 (rs114834583), MT2 (rs34800257) and PCSK2 (rs75293413) associated with EoE at p-value1×10We have identified an African ancestry specific genetic susceptibility locus DDAH1 at 1p22.3, 1p22.3, 9p13.3, and 12q24.23, through GWAS and admixture mapping for EoE in AA, providing evidence of ancestral specific inheritance of EoE. These findings highlight the need of independent genetic studies of different ancestries for EoE.