Genome-wide Admixture and Association Analysis Identifies African Ancestry-specific Risk Loci of Eosinophilic Esophagitis in African Americans

Overview

Journal J Allergy Clin Immunol

Specialty Allergy & Immunology

Date 2022 Nov 18

PMID 36400179

Authors

Yadu Gautam

Julie Caldwell

Leah Kottyan

Mirna Chehade

Evan S Dellon

Marc E Rothenberg

Tesfaye B Mersha

Affiliations

Soon will be listed here.

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.

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References

Sleiman P, Wang M, Cianferoni A, Aceves S, Gonsalves N, Nadeau K . GWAS identifies four novel eosinophilic esophagitis loci. Nat Commun. 2014; 5:5593. PMC: 4238044. DOI: 10.1038/ncomms6593. View

Chang X, March M, Mentch F, Nguyen K, Glessner J, Qu H . A genome-wide association meta-analysis identifies new eosinophilic esophagitis loci. J Allergy Clin Immunol. 2021; 149(3):988-998. PMC: 9579995. DOI: 10.1016/j.jaci.2021.08.018. View

Browning B, Tian X, Zhou Y, Browning S . Fast two-stage phasing of large-scale sequence data. Am J Hum Genet. 2021; 108(10):1880-1890. PMC: 8551421. DOI: 10.1016/j.ajhg.2021.08.005. View

Krzystek-Korpacka M, Fleszar M, Bednarz-Misa I, Lewandowski L, Szczuka I, Kempinski R . Transcriptional and Metabolomic Analysis of L-Arginine/Nitric Oxide Pathway in Inflammatory Bowel Disease and Its Association with Local Inflammatory and Angiogenic Response: Preliminary Findings. Int J Mol Sci. 2020; 21(5). PMC: 7084352. DOI: 10.3390/ijms21051641. View

Potaczek D, Alashkar Alhamwe B, Miethe S, Garn H . Epigenetic Mechanisms in Allergy Development and Prevention. Handb Exp Pharmacol. 2021; 268:331-357. DOI: 10.1007/164_2021_475. View

Mathias R, Taub M, Gignoux C, Fu W, Musharoff S, OConnor T . A continuum of admixture in the Western Hemisphere revealed by the African Diaspora genome. Nat Commun. 2016; 7:12522. PMC: 5062574. DOI: 10.1038/ncomms12522. View

Assaad A, Putnam P, Collins M, Akers R, Jameson S, Kirby C . Pediatric patients with eosinophilic esophagitis: an 8-year follow-up. J Allergy Clin Immunol. 2007; 119(3):731-8. DOI: 10.1016/j.jaci.2006.10.044. View

Maples B, Gravel S, Kenny E, Bustamante C . RFMix: a discriminative modeling approach for rapid and robust local-ancestry inference. Am J Hum Genet. 2013; 93(2):278-88. PMC: 3738819. DOI: 10.1016/j.ajhg.2013.06.020. View

Reeves S, Kolstad T, Lien T, Elliott M, Ziegler S, Wight T . Asthmatic airway epithelial cells differentially regulate fibroblast expression of extracellular matrix components. J Allergy Clin Immunol. 2014; 134(3):663-670.e1. PMC: 4149938. DOI: 10.1016/j.jaci.2014.04.007. View

10.

Fishilevich S, Nudel R, Rappaport N, Hadar R, Plaschkes I, Iny Stein T . GeneHancer: genome-wide integration of enhancers and target genes in GeneCards. Database (Oxford). 2017; 2017. PMC: 5467550. DOI: 10.1093/database/bax028. View

11.

de Leeuw C, Mooij J, Heskes T, Posthuma D . MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput Biol. 2015; 11(4):e1004219. PMC: 4401657. DOI: 10.1371/journal.pcbi.1004219. View

12.

Kinker K, Gibson A, Bass S, Day B, Deng J, Medvedovic M . Overexpression of dimethylarginine dimethylaminohydrolase 1 attenuates airway inflammation in a mouse model of asthma. PLoS One. 2014; 9(1):e85148. PMC: 3894860. DOI: 10.1371/journal.pone.0085148. View

13.

Kottyan L, Davis B, Sherrill J, Liu K, Rochman M, Kaufman K . Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease. Nat Genet. 2014; 46(8):895-900. PMC: 4121957. DOI: 10.1038/ng.3033. View

14.

Franciosi J, Tam V, Liacouras C, Spergel J . A case-control study of sociodemographic and geographic characteristics of 335 children with eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2009; 7(4):415-9. DOI: 10.1016/j.cgh.2008.10.006. View

15.

Shriner D, Adeyemo A, Rotimi C . Joint ancestry and association testing in admixed individuals. PLoS Comput Biol. 2012; 7(12):e1002325. PMC: 3245293. DOI: 10.1371/journal.pcbi.1002325. View

16.

Lin M, Park D, Zaitlen N, Henn B, Gignoux C . Admixed Populations Improve Power for Variant Discovery and Portability in Genome-Wide Association Studies. Front Genet. 2021; 12:673167. PMC: 8181458. DOI: 10.3389/fgene.2021.673167. View

17.

Wu C, Kraft P, Zhai K, Chang J, Wang Z, Li Y . Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions. Nat Genet. 2012; 44(10):1090-7. DOI: 10.1038/ng.2411. View

18.

Jin W, Li R, Zhou Y, Xu S . Distribution of ancestral chromosomal segments in admixed genomes and its implications for inferring population history and admixture mapping. Eur J Hum Genet. 2013; 22(7):930-7. PMC: 4060116. DOI: 10.1038/ejhg.2013.265. View

19.

Cheng K, Gupta S, Kantor S, Kuhl J, Aceves S, Bonis P . Creating a multi-center rare disease consortium - the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). Transl Sci Rare Dis. 2018; 2(3-4):141-155. PMC: 5757645. DOI: 10.3233/TRD-170016. View

20.

Zhao B, Luo T, Li T, Li Y, Zhang J, Shan Y . Genome-wide association analysis of 19,629 individuals identifies variants influencing regional brain volumes and refines their genetic co-architecture with cognitive and mental health traits. Nat Genet. 2019; 51(11):1637-1644. PMC: 6858580. DOI: 10.1038/s41588-019-0516-6. View