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

John P. Ray, Carl G. Boer, Charles P. Fulco, Caleb A. Lareau, Masahiro Kanai, Jacob C. Ulirsch, Ryan Tewhey, Leif S. Ludwig, Steven K. Reilly, Drew T. Bergman, Jesse M. Engreitz, Robbyn Issner, Hilary K. Finucane, Eric S. Lander, Aviv Regev () and Nir Hacohen ()
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John P. Ray: Broad Institute of MIT and Harvard
Carl G. Boer: Broad Institute of MIT and Harvard
Charles P. Fulco: Broad Institute of MIT and Harvard
Caleb A. Lareau: Broad Institute of MIT and Harvard
Masahiro Kanai: Broad Institute of MIT and Harvard
Jacob C. Ulirsch: Broad Institute of MIT and Harvard
Ryan Tewhey: Broad Institute of MIT and Harvard
Leif S. Ludwig: Broad Institute of MIT and Harvard
Steven K. Reilly: Broad Institute of MIT and Harvard
Drew T. Bergman: Broad Institute of MIT and Harvard
Jesse M. Engreitz: Broad Institute of MIT and Harvard
Robbyn Issner: Broad Institute of MIT and Harvard
Hilary K. Finucane: Broad Institute of MIT and Harvard
Eric S. Lander: Broad Institute of MIT and Harvard
Aviv Regev: Broad Institute of MIT and Harvard
Nir Hacohen: Broad Institute of MIT and Harvard

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15022-4

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