Multi-tissue transcriptome analyses identify genetic mechanisms underlying neuropsychiatric traits

多组织转录组分析确定神经精神特征的遗传机制

The genetic architecture of psychiatric disorders is characterized by a large number of small-effect variants1 located primarily in non-coding regions, suggesting that the underlying causal effects may influence disease risk by modulating gene expression2-4. We provide comprehensive analyses using transcriptome data from an unprecedented collection of tissues to gain pathophysiological insights into the role of the brain, neuroendocrine factors (adrenal gland) and gastrointestinal systems (colon) in psychiatric disorders. In each tissue, we perform PrediXcan analysis and identify trait-associated genes for schizophrenia (n associations = 499; n unique genes = 275), bipolar disorder (n associations = 17; n unique genes = 13), attention deficit hyperactivity disorder (n associations = 19; n unique genes = 12) and broad depression (n associations = 41; n unique genes = 31). Importantly, both PrediXcan and summary-data-based Mendelian randomization/heterogeneity in dependent instruments analyses suggest potentially causal genes in non-brain tissues, showing the utility of these tissues for mapping psychiatric disease genetic predisposition. Our analyses further highlight the importance of joint tissue approaches as 76% of the genes were detected only in difficult-to-acquire tissues.

精神疾病的遗传结构以大量主要位于非编码区的小效应变体1为特征，表明潜在的因果效应可能通过调节基因表达2-4来影响疾病风险。我们使用来自前所未有的组织收集的转录组数据进行全面的分析，以获得关于大脑、神经内分泌因子(肾上腺)和胃肠系统(结肠)在精神疾病中的作用的病理生理学见解。在每个组织中，我们进行PrediXcan分析并鉴定精神分裂症（n associations = 499; n unique genes = 275），双相情感障碍（n associations = 17; n unique genes = 13），注意力缺陷多动障碍（n associations = 19; n unique genes = 12），显著抑郁（n associations = 41; n unique genes = 31）的特征相关基因。重要的是，依赖性仪器分析中的PrediXcan和基于汇总数据的孟德尔随机化/异质性都表明非脑组织中存在潜在的因果基因，显示这些组织在绘制精神疾病遗传易感性的效用。我们的分析进一步强调了联合组织方法的重要性，因为76%的基因仅在难以获得的组织中被检测到。

2019 Jun 发表于Nat Genet