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

Nat Commun
Authors
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.

Year of Publication
2020
Journal
Nat Commun
Volume
11
Issue
1
Pages
1237
Date Published
2020 Mar 06
ISSN
2041-1723
DOI
10.1038/s41467-020-15022-4
PubMed ID
32144282
PubMed Central ID
PMC7060350
Links
Grant list
K99 HG009920 / HG / NHGRI NIH HHS / United States
P50 HG006193 / HG / NHGRI NIH HHS / United States
Additional Materials