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Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features

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Item Type:Article
Title:Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features
Creators Name:Ray, J.P. and de Boer, C.G. and Fulco, C.P. and Lareau, C.A. and Kanai, M. and Ulirsch, J.C. and Tewhey, R. and Ludwig, L.S. and Reilly, S.K. and Bergman, D.T. and Engreitz, J.M. and Issner, R. and Finucane, H.K. and Lander, E.S. and Regev, A. and Hacohen, N.
Abstract:Genome-wide association studies have associated thousands of genetic variants with complex traits and diseases, but pinpointing the causal variant(s) among those in tight linkage disequilibrium with each associated variant remains a major challenge. Here, we use seven experimental assays to characterize all common variants at the multiple disease-associated TNFAIP3 locus in five disease-relevant immune cell lines, based on a set of features related to regulatory potential. Trait/disease-associated variants are enriched among SNPs prioritized based on either: (1) residing within CRISPRi-sensitive regulatory regions, or (2) localizing in a chromatin accessible region while displaying allele-specific reporter activity. Of the 15 trait/disease-associated haplotypes at TNFAIP3, 9 have at least one variant meeting one or both of these criteria, 5 of which are further supported by genetic fine-mapping. Our work provides a comprehensive strategy to characterize genetic variation at important disease-associated loci, and aids in the effort to identify trait causal genetic variants.
Keywords:Autoimmune Diseases, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Haplotypes, Linkage Disequilibrium, Multifactorial Inheritance, Proof of Concept Study, Tumor Cell Line, Tumor Necrosis Factor alpha-Induced Protein 3
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:1237
Date:6 March 2020
Official Publication:https://doi.org/10.1038/s41467-020-15022-4
PubMed:View item in PubMed

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