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Brain expression quantitative trait locus mapping informs genetic studies of psychiatric diseases

脑组织的表达数量性状遗传位点定位方法解析精神疾病遗传基础

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Abstract

Genome-wide association study (GWAS) can be used to identify genes that increase the risk of psychiatric diseases. However, much of the disease heritability is still unexplained, suggesting that there are genes to be discovered. Functional annotation of the genetic variants may increase the power of GWAS to identify disease genes, by providing prior information that can be used in Bayesian analysis or in reducing the number of tests. Expression quantitative trait loci (eQTLs) are genomic loci that regulate gene expression. Genetic mapping of eQTLs can help reveal novel functional effects of thousands of single nucleotide polymorphisms (SNPs). The present review mainly focused on the current knowledge on brain eQTL mapping, and discussed some major methodological issues and their possible solutions. The frequently ignored problems of batch effects, covariates, and multiple testing were emphasized, since they can lead to false positives and false negatives. The future application of eQTL data in GWAS analysis was also discussed.

摘要

全基因组关联分析(genome-wide association study, GWAS)是一种在人类全基因组范围内寻找与疾病相关的序列变异的方法, 它也是寻找精神疾病易感基因的一个有力工具。 然而, 疾病遗传力的来源在很大程度上仍未知, 期待将来的研究能发现更多的疾病易感基因。 对遗传变异生物学功能的了解能提高GWAS发现新易感基因的效能。 表达数量性状遗传位点(expression quantitative trait loci, eQTLs)是指一些能调节基因表达水平的位点。 eQTL作图法可揭示众多单核苷酸多态(single nucleotide polymorphisms, SNPs)的未知生物学功能。 本综述主要回顾了脑组织中eQTL的研究现状, 并对eQTL定位方法的局限性及相应的对策进行了讨论。 此外, 对在实际研究中经常被忽略的一些能导致假阳性和假阴性关联结果的问题(例如批次效应、 协变量和多重测试)进行了探讨。 最后, 对eQTL研究在GWAS 分析中的应用进行了展望。

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  1. Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, 60637, USA

    Chunyu Liu  (刘春宇)

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Liu, C. Brain expression quantitative trait locus mapping informs genetic studies of psychiatric diseases. Neurosci. Bull. 27, 123–133 (2011). https://doi.org/10.1007/s12264-011-1203-5

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