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

Nature communications (2020-03-08)
John P Ray, Carl G de 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, Nir Hacohen
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
PMA, for use in molecular biology applications, ≥99% (HPLC)
Sigma-Aldrich
Bovine Serum Albumin solution, 35% in DPBS, sterile-filtered, BioXtra, suitable for cell culture
Sigma-Aldrich
Mineral oil, BioReagent, for molecular biology, light oil
Sigma-Aldrich
HEPES solution, 1 M, pH 7.0-7.6, sterile-filtered, BioReagent, suitable for cell culture