Genome-wide association study and meta-analysis in multiple populations identifies new loci for peanut allergy and establishes c11orf30/EMSY as a genetic risk factor for food allergy

Publication date: Available online 10 October 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Yuka Asai, Aida Eslami, C. Dorien van Ginkel, Loubna Akhabir, Ming Wan, George Ellis, Moshe Ben-Shoshan, David Martino, Manuel A. Ferreira, Katrina Allen, Bruce Mazer, Hans de Groot, Nicolette W. de Jong, Roy N. Gerth van Wijk, Anthony E.J. Dubois, Rick Chin, Steven Cheuk, Joshua Hoffman, Eric Jorgensen, John S. Witte, Ronald B. Melles, Xiumei Hong, Xiaobin Wang, Jennie Hui, Arthur W. (Bill) Musk, Michael Hunter, Alan L. James, Gerard H. Koppelman, Andrew J. Sandford, Ann E. Clarke, Denise Daley
BackgroundPeanut allergy (PA) is a complex disease with both environmental and genetic risk factors. Previously PA loci were identified in FLG and HLA in candidate gene studies, and loci in HLA in a genome-wide association study and meta-analysis.ObjectiveTo investigate genetic susceptibility to PA.MethodsEight hundred and fifty cases and 926 hyper-controls and >7.8 million genotyped and imputed single nucleotide polymorphisms (SNPs) were analyzed in a genome-wide association study to identify susceptibility variants for PA in the Canadian population. Meta-analysis of two phenotypes (PA and food allergy) was conducted using 7 studies from the Canadian, American (2), Australian, German and Dutch (2) populations.ResultsA SNP near ITGA6 reached genome-wide significance with PA (p=1.80×10^-8), while SNPs associated with SKAP1, MMP12/MMP13, CTNNA3, ARHGAP24, ANGPT4, c11orf30 (EMSY), and EXOC4 reached a threshold suggestive of association (p≤1.49×10^-6). In the meta-analysis of PA, loci in or near ITGA6, ANGPT4, MMP12/MMP13, c11orf30 and EXOC4 were significant (p≤1.49×10^-6). When a phenotype of any food allergy was used for meta-analysis, the c11orf30 locus reached genome-wide significance (p=7.50×10^-11), while SNPs associated with ITGA6, ANGPT4, MMP12/MMP13, EXOC4 and additional c11orf30 SNPs were suggestive (p≤1.49×10^-6). Functional annotation indicated SKAP1 regulates expression of CBX1, which co-localizes with the EMSY protein coded by c11orf30.ConclusionThis study identifies multiple novel loci as risk factors for PA and food allergy and establishes c11orf30 as a risk locus for both peanut and food allergy. Multiple genes (c11orf30/EMSY, SKAP1 and CTNNA3) identified by this study are involved in epigenetic regulation of gene expression.

Teaser

C11orf30 (EMSY) is a risk locus for food allergy, reaching genome-wide significance in meta-analysis (p=7.50×10^-11). Meta-analyses showed five loci suggestive of significance with peanut allergy. These 6 novel loci suggest epigenetic mechanisms.


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