美国纽约西奈山伊坎医学院 Panos Roussos和Gabriel E. Hoffman共同合作取得一项新突破。他们通过使用人类大脑的多祖先等位基因元分析确定了脑相关性状的候选因果变异。该研究于2022年1月20日在线发表于《自然—遗传学》杂志上。

在这里，研究人员开发了多变量多QTL方法，并进行了大规模、多祖先的QTL元分析，以提高功效和精细映射的分辨率。对来自2119名捐赠者的3983份RNA测序样本进行分析，包括474名非欧洲人，得出的有效样本量为3154份。eQTL和GWAS的联合统计精细映射确定了24个大脑相关性状的329个变体-性状对，由189个独特基因的204个候选因果变异驱动。这一综合分析确定了候选的因果变异，并阐明了精神分裂症、双相情感障碍和阿尔茨海默病基因的潜在调节机制。

据了解，虽然大规模的全基因组关联研究(GWAS)已经确定了数百个与大脑相关性状有关的基因位点，但识别这些性状背后的变异、基因和分子机制仍然具有挑战性。GWAS与表达数量性状基因座(eQTL)的整合和共享遗传结构的识别已被广泛应用于基因提名和候选因果变异。然而，这种方法受到样本大小、统计能力和连锁不平衡的限制。

附：英文原文

Title: Multi-ancestry eQTL meta-analysis of human brain identifies candidate causal variants for brain-related traits

Author: Zeng, Biao, Bendl, Jaroslav, Kosoy, Roman, Fullard, John F., Hoffman, Gabriel E., Roussos, Panos

Issue&Volume: 2022-01-20

Abstract: While large-scale, genome-wide association studies (GWAS) have identified hundreds of loci associated with brain-related traits, identification of the variants, genes and molecular mechanisms underlying these traits remains challenging. Integration of GWAS with expression quantitative trait loci (eQTLs) and identification of shared genetic architecture have been widely adopted to nominate genes and candidate causal variants. However, this approach is limited by sample size, statistical power and linkage disequilibrium. We developed the multivariate multiple QTL approach and performed a large-scale, multi-ancestry eQTL meta-analysis to increase power and fine-mapping resolution. Analysis of 3,983RNA-sequenced samples from 2,119donors, including 474non-European individuals, yielded an effective sample size of 3,154. Joint statistical fine-mapping of eQTL and GWAS identified 329variant–trait pairs for 24brain-related traits driven by 204unique candidate causal variants for 189unique genes. This integrative analysis identifies candidate causal variants and elucidates potential regulatory mechanisms for genes underlying schizophrenia, bipolar disorder and Alzheimer’s disease.

DOI: 10.1038/s41588-021-00987-9

Source: https://www.nature.com/articles/s41588-021-00987-9