Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features
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s41467-020-15022-4.pdf
Description
Published version
Size
1.13 MB
Format
Adobe PDF
Checksum (MD5)
4ac66bac8137f10fcf695b921ae133f7
Author(s)
Ray, John P
de Boer, Carl G
Fulco, Charles P
Lareau, Caleb A
Kanai, Masahiro
Ulirsch, Jacob C
Tewhey, Ryan
Ludwig, Leif S
Reilly, Steven K
Bergman, Drew T
Date Issued
2020
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/S41467-020-15022-4
