Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features
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 characte...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Springer Science and Business Media LLC
2021
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| Online Access: | https://hdl.handle.net/1721.1/136246 |
| _version_ | 1826196065211121664 |
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| author | 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 Engreitz, Jesse M Issner, Robbyn Finucane, Hilary K Lander, Eric S Regev, Aviv Hacohen, Nir |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology 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 Engreitz, Jesse M Issner, Robbyn Finucane, Hilary K Lander, Eric S Regev, Aviv Hacohen, Nir |
| author_sort | Ray, John P |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T10:19:58Z |
| format | Article |
| id | mit-1721.1/136246 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T10:19:58Z |
| publishDate | 2021 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1362462023-12-14T15:26:29Z Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features 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 Engreitz, Jesse M Issner, Robbyn Finucane, Hilary K Lander, Eric S Regev, Aviv Hacohen, Nir Massachusetts Institute of Technology. Department of Biology 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. 2021-10-27T20:34:29Z 2021-10-27T20:34:29Z 2020 2021-07-20T17:34:56Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/136246 en 10.1038/S41467-020-15022-4 Nature Communications Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Springer Science and Business Media LLC Nature |
| spellingShingle | 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 Engreitz, Jesse M Issner, Robbyn Finucane, Hilary K Lander, Eric S Regev, Aviv Hacohen, Nir Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features |
| title | Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features |
| title_full | Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features |
| title_fullStr | Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features |
| title_full_unstemmed | Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features |
| title_short | Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features |
| title_sort | prioritizing disease and trait causal variants at the tnfaip3 locus using functional and genomic features |
| url | https://hdl.handle.net/1721.1/136246 |
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