Article ; Online: Genetic associations at regulatory phenotypes improve fine-mapping of causal variants for 12 immune-mediated diseases.
2022 Volume 54, Issue 3, Page(s) 251–262
Abstract: The resolution of causal genetic variants informs understanding of disease biology. We used regulatory quantitative trait loci (QTLs) from the BLUEPRINT, GTEx and eQTLGen projects to fine-map putative causal variants for 12 immune-mediated diseases. We ... ...
| Abstract | The resolution of causal genetic variants informs understanding of disease biology. We used regulatory quantitative trait loci (QTLs) from the BLUEPRINT, GTEx and eQTLGen projects to fine-map putative causal variants for 12 immune-mediated diseases. We identify 340 unique loci that colocalize with high posterior probability (≥98%) with regulatory QTLs and apply Bayesian frameworks to fine-map associations at each locus. We show that fine-mapping credible sets derived from regulatory QTLs are smaller compared to disease summary statistics. Further, they are enriched for more functionally interpretable candidate causal variants and for putatively causal insertion/deletion (INDEL) polymorphisms. Finally, we use massively parallel reporter assays to evaluate candidate causal variants at the ITGA4 locus associated with inflammatory bowel disease. Overall, our findings suggest that fine-mapping applied to disease-colocalizing regulatory QTLs can enhance the discovery of putative causal disease variants and enhance insights into the underlying causal genes and molecular mechanisms. |
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| MeSH term(s) | Bayes Theorem ; Causality ; Genome-Wide Association Study ; Phenotype ; Polymorphism, Single Nucleotide/genetics ; Quantitative Trait Loci/genetics |
| Language | English |
| Publishing date | 2022-03-14 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 1108734-1 |
| ISSN | 1546-1718 ; 1061-4036 |
| ISSN (online) | 1546-1718 |
| ISSN | 1061-4036 |
| DOI | 10.1038/s41588-022-01025-y |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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