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Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features.
- Source :
-
Nature communications [Nat Commun] 2020 Mar 06; Vol. 11 (1), pp. 1237. Date of Electronic Publication: 2020 Mar 06. - Publication Year :
- 2020
-
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.
- Subjects :
- Cell Line, Tumor
Genetic Predisposition to Disease
Genetic Variation immunology
Haplotypes genetics
Haplotypes immunology
Humans
Linkage Disequilibrium
Multifactorial Inheritance immunology
Proof of Concept Study
Autoimmune Diseases genetics
Genetic Loci genetics
Genome-Wide Association Study methods
Multifactorial Inheritance genetics
Tumor Necrosis Factor alpha-Induced Protein 3 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 32144282
- Full Text :
- https://doi.org/10.1038/s41467-020-15022-4