| Title: | Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features |
| Journal: | Nature Communications |
| Published: | 6 Mar 2020 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/32144282/ |
| DOI: | https://doi.org/10.1038/s41467-020-15022-4 |
| URL: | https://www.nature.com/articles/s41467-020-15022-4.pdf |
Publication 7505
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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.16 Authors
- 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
Enabling scientific discoveries that improve human health