Genome-wide admixture and association analysis identifies African ancestry–specific risk loci of eosinophilic esophagitis in African Americans - 04/05/23
for the
Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) investigators∗
Abstract |
Background |
Eosinophilic esophagitis (EoE), a chronic allergic inflammatory disease, is linked to multiple genetic risk factors, but studies have focused on populations of European ancestry. Few studies have assessed Black or African American (AA) populations for loci involved in EoE susceptibility.
Objective |
We performed admixture mapping (AM) and genome-wide association study (GWAS) of EoE using participants from AA populations.
Methods |
We conducted AM and GWAS of EoE using 137 EoE cases and 1465 healthy controls from the AA population. Samples were genotyped using molecular evolutionary genetics analysis (MEGA). Genotype imputation was carried out with the Consortium on Asthma Among African-Ancestry Populations in the Americas (CAAPA) reference panel using the Michigan Imputation Server. Global and local ancestry inference was carried out, followed by fine mapping and RNA sequencing. After quality control filtering, over 6,000,000 variants were tested by logistic regression adjusted for sex, age, and global ancestry.
Results |
The global African ancestry proportion was found to be significantly lower among cases than controls (0.751 vs 0.786, P = .012). Case-only AM identified 3 significant loci (9p13.3, 12q24.22-23, and 15q11.2) associated with EoE, of which 12q24.22-23 and 9p13.3 were further replicated in the case–control analysis, with associations observed with African ancestry. Fine mapping and multiomic functional annotations prioritized the variants rs11068264 (FBXW8) and rs7307331 (VSIG10) at 12q24.23 and rs2297879 (ARHGEF39) at 9p13.3. GWAS identified 1 genome-wide significant locus at chromosome 1p22.3 (rs17131726, DDAH1) and 10 other suggestive loci. Most GWAS variants were low-frequency African ancestry–specific variants. RNA sequencing revealed that esophageal DDAH1 and VSIG10 were downregulated and ARHGEF39 upregulated among EoE cases.
Conclusions |
GWAS and AM for EoE in AA revealed that African ancestry–specific genetic susceptibility loci exist at 1p22.3, 9p13.3, and 12q24.23, providing evidence of ancestry-specific inheritance of EoE. More independent genetic studies of different ancestries for EoE are needed.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Eosinophilic esophagitis, admixture mapping, African American, genome-wide association, annotation, gene score
Abbreviations used : AA, AM, CAAPA, CADD, CCHMC, CEGIR, CoFAR, EA, EoE, eQTL, FDR, GWAS, IPA, LD, MAF, MEGA, PC, RNA-Seq, SNP, UTR, VEP
Plan
| Supported by the National Institutes of Health (NIH) R01 HL132344 and R01 HG011411 grants support (T.B.M.) and by NIH R01 AI24355; the Campaign Urging Research for Eosinophilic Disease (CURED); and the Sunshine Charitable Foundation and its supporters, Denise and David Bunning, by CEGIR (U54 AI117804), which is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), and is cofunded by National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and NCATS, and in part by the Division of Intramural Research, NIAID. CEGIR is also supported by patient advocacy groups including the American Partnership for Eosinophilic Disorders (APFED), Campaign Urging Research for Eosinophilic Disease (CURED), and Eosinophilic Family Coalition (EFC) (M.E.R.). |
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| Disclosure of potential conflict of interest: M. E. Rothenberg is a consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celldex, Nextstone One, Bristol Myers Squibb, Astra Zeneca, Ellodi Pharma, GlaxoSmithKline, Regeneron/Sanofi, Revolo Biotherapeutics, and Guidepoint; has an equity interest in Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celldex, and Nextstone One; receives royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust), and UpToDate; and is an inventor of patents owned by Cincinnati Children’s Hospital. M. Chehade received consultant fees from Regeneron, Allakos, Adare/Ellodi, Shire/Takeda, AstraZeneca, Sanofi, Bristol Myers Squibb, and Phathom; and research funding from Regeneron, Allakos, Shire/Takeda, AstraZeneca, Adare/Ellodi, and Danone, all outside the scope of this work. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 151 - N° 5
P. 1337-1350 - mai 2023 Retour au numéro
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