小柯机器人

英国惠康基金会Nicole Soranzo课题组取得一项新突破。他们的研究利用调节表型相关遗传确定了12种免疫介导疾病因果变异的精细定位。相关论文于2022年3月14日发表在《自然-遗传学》杂志上。

研究人员使用来自BLUEPRINT、GTEx和eQTLGen项目所揭示的调控数量性状基因座(QTL)，精细绘制12种免疫介导疾病的可能因果变异。研究人员确定了340个独特的基因座，它们以高后验概率(≥98%)与调节性QTL共定位，并将贝叶斯统计应用于每个基因座的精细映射关联。研究表明，与疾病汇总统计相比，源自监管QTL的精细映射可信集更小。此外，它们丰富了功能上可解释的候选因果变体和可能的因果插入/缺失(INDEL)多态性。

最后，研究利用大规模平行报告基因分析来评估与炎症性肠病相关ITGA4基因座的候选因果变异。总体而言，该研究结果表明，与疾病相关调控QTL的精细定位可以增强对潜在致病变异的发掘，并增强对潜在致病基因和分子机制的理解。

据了解，揭示遗传变异的因果关系有助于理解疾病生物学。

附：英文原文

Title: Genetic associations at regulatory phenotypes improve fine-mapping of causal variants for 12 immune-mediated diseases

Author: Kundu, Kousik, Tardaguila, Manuel, Mann, Alice L., Watt, Stephen, Ponstingl, Hannes, Vasquez, Louella, Von Schiller, Dominique, Morrell, Nicholas W., Stegle, Oliver, Pastinen, Tomi, Sawcer, Stephen J., Anderson, Carl A., Walter, Klaudia, Soranzo, Nicole

Issue&Volume: 2022-03-14

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.

DOI: 10.1038/s41588-022-01025-y

Source: https://www.nature.com/articles/s41588-022-01025-y

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