小柯机器人

美国博德研究所Alkes L. Price、Steven Gazal等研究人员合作发现，新方法可识别疾病基因和评估疾病的全基因遗传性。相关论文于2022年6月6日在线发表在《自然—遗传学》杂志上。

据研究人员介绍，疾病相关的单核苷酸多态性（SNP）通常不会牵涉到目标基因，因为大多数疾病的SNP是调节性的。许多SNP到基因（S2G）的连接策略已经被开发出来，可以将调节性SNP与它们所调节的基因顺式连接起来。

研究人员开发了一个基于遗传率的框架，用于评估和组合不同的S2策略，从而优化其对常见疾病风险的信息量。最佳组合S2G策略（cS2G）包括七个组成的S2G策略，实现了0.75的精确度和0.33的召回率，是任何单独策略召回率的两倍以上。研究人员将cS2G应用于49种英国生物库疾病/性状的精细图谱结果，并以高置信度预测了5,095个因果SNP-基因-疾病三联体（有S2G衍生的功能解释）。

研究人员进一步应用cS2G对疾病的全基因遗传性进行了经验评估；研究人员确定前1%的基因解释了与所有基因相关的SNP遗传性的大约一半，并且基因水平的结构随变异等位基因频率的变化而变化。

附：英文原文

Title: Combining SNP-to-gene linking strategies to identify disease genes and assess disease omnigenicity

Author: Gazal, Steven, Weissbrod, Omer, Hormozdiari, Farhad, Dey, Kushal K., Nasser, Joseph, Jagadeesh, Karthik A., Weiner, Daniel J., Shi, Huwenbo, Fulco, Charles P., OConnor, Luke J., Pasaniuc, Bogdan, Engreitz, Jesse M., Price, Alkes L.

Issue&Volume: 2022-06-06

Abstract: Disease-associated single-nucleotide polymorphisms (SNPs) generally do not implicate target genes, as most disease SNPs are regulatory. Many SNP-to-gene (S2G) linking strategies have been developed to link regulatory SNPs to the genes that they regulate in cis. Here, we developed a heritability-based framework for evaluating and combining different S2G strategies to optimize their informativeness for common disease risk. Our optimal combined S2G strategy (cS2G) included seven constituent S2G strategies and achieved a precision of 0.75 and a recall of 0.33, more than doubling the recall of any individual strategy. We applied cS2G to fine-mapping results for 49 UK Biobank diseases/traits to predict 5,095 causal SNP–gene-disease triplets (with S2G-derived functional interpretation) with high confidence. We further applied cS2G to provide an empirical assessment of disease omnigenicity; we determined that the top 1% of genes explained roughly half of the SNP heritability linked to all genes and that gene-level architectures vary with variant allele frequency.

DOI: 10.1038/s41588-022-01087-y

Source: https://www.nature.com/articles/s41588-022-01087-y

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex