生物
数量性状位点
遗传学
索引
计算生物学
表达数量性状基因座
基因座(遗传学)
全基因组关联研究
基因
单核苷酸多态性
基因型
作者
Kousik Kundu,Manuel Tardáguila,Alice Mann,Stephen M. Watt,Hannes Ponstingl,Louella Vasquez,Dominique Von Schiller,Nicholas W. Morrell,Oliver Stegle,Tomi Pastinen,Stephen Sawcer,Carl A. Anderson,Klaudia Walter,Nicole Soranzo
出处
期刊:Nature Genetics
[Springer Nature]
日期:2022-03-01
卷期号:54 (3): 251-262
被引量:35
标识
DOI:10.1038/s41588-022-01025-y
摘要
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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