Genetic correlation, pleiotropy, and causal associations between substance use and psychiatric disorder.
Genetic correlation, pleiotropy, and causal associations between substance use and psychiatric disorder.
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DOI：
10.1017/s003329172000272x
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发表时间：
2022-04
影响因子：
6.9
通讯作者：
Vrieze S
中科院分区：
文献类型：
--
作者：
Jang SK;Saunders G;Liu M;23andMe Research Team;Jiang Y;Liu DJ;Vrieze S
精神疾病患者中物质使用的发生率很高。遗传信息研究有可能阐明这些现象的病因。全基因组关联研究（GWAS）的最新进展为研究提供了新的途径。利用GWAS荟萃分析的结果，我们对遗传相关结构进行了因子分析，对共享基因座进行了全基因组搜索，并对六种物质使用表型（四种吸烟、一种酒精和一种大麻使用）和五种精神疾病（ADHD、厌食症、抑郁症、双相情感障碍和精神分裂症）进行了因果信息测试。虽然模型拟合低于常规标准，但发现两个相关的外化和内化/精神病因素。在先前物质使用和精神疾病的单变量GWAS中报告的458个基因座中，约50%（230个基因座）是多效性的，另外111个多效性基因座未在过去的GWAS中报告。在341个多效性基因座中，152个与物质使用和精神障碍有关，涉及神经发育、细胞形态发生、生物粘附途径以及13种不同脑组织的富集。75个和114个多效位点分别与精神疾病或物质使用表型相关，分别涉及神经元信号通路和网格蛋白结合功能/结构。在不同的孟德尔随机化方法中没有发现表型因果关系的一致证据。物质使用和精神障碍的遗传病因是高度多效性的，涉及共同的神经发育途径、神经传递和细胞内运输。总的来说，这种模式与垂直多效性不一致，更可能反映水平多效性或更复杂的表型因果关系。
Substance use occurs at a high rate in persons with a psychiatric disorder. Genetically informative studies have the potential to elucidate the etiology of these phenomena. Recent developments in genome-wide association studies (GWAS) allow new avenues of investigation. Using results of GWAS meta-analyses, we performed a factor analysis of the genetic correlation structure, a genome-wide search of shared loci, and causally informative tests for six substance use phenotypes (four smoking, one alcohol, and one cannabis use) and five psychiatric disorders (ADHD, anorexia, depression, bipolar disorder, and schizophrenia). Two correlated externalizing and internalizing/psychosis factor were found, although model fit was beneath conventional standards. Of 458 loci reported in previous univariate GWAS of substance use and psychiatric disorders, about 50% (230 loci) were pleiotropic with additional 111 pleiotropic loci not reported from past GWAS. Of the 341 pleiotropic loci, 152 were associated with both substance use and psychiatric disorders, implicating neurodevelopment, cell morphogenesis, biological adhesion pathways, and enrichment in 13 different brain tissues. Seventy-five and 114 pleiotropic loci were specific to either psychiatric disorders or substance use phenotypes, implicating neuronal signaling pathway and clathrin-binding functions/structures, respectively. No consistent evidence for phenotypic causation was found across different Mendelian randomization methods. Genetic etiology of substance use and psychiatric disorders is highly pleiotropic and involves shared neurodevelopmental path, neurotransmission, and intracellular trafficking. In aggregate, the patterns are not consistent with vertical pleiotropy, more likely reflecting horizontal pleiotropy or more complex forms of phenotypic causation.