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Genetic Architecture of 11 Major Psychiatric Disorders at Biobehavioral, Functional Genomic, and Molecular Genetic Levels of Analysis
medRxiv - Genetic and Genomic Medicine Pub Date : 2020-09-23 , DOI: 10.1101/2020.09.22.20196089
Andrew D. Grotzinger , Travis T. Mallard , Wonuola A. Akingbuwa , Hill F. Ip , Mark J. Adams , Cathryn M. Lewis , Andrew M. McIntosh , Jakob Grove , Søren Dalsgaard , Klaus Peter-Lesch , Nora Strom , Sandra M. Meier , Manuel Mattheisen , Anders D. Børglum , Ole Mors , Gerome Breen , Phil H. Lee , Kenneth S. Kendler , Jordan W. Smoller , Elliot M. Tucker-Drob , Michel G. Nivard , , , , ,

We systematically interrogate the joint genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic, and molecular genetic levels of analysis. We identify four broad factors (Neurodevelopmental, Compulsive, Psychotic, and Internalizing) that underlie genetic correlations among the disorders, and test whether these factors adequately explain their genetic correlations with biobehavioral traits. We introduce Stratified Genomic Structural Equation Modelling, which we use to identify gene sets and genomic regions that disproportionately contribute to pleiotropy, including protein-truncating variant intolerant genes expressed in excitatory and GABAergic brain cells that are enriched for pleiotropy between disorders with psychotic features. Multivariate association analyses detect a total of 152 (20 novel) independent loci which act on the four factors, and identify nine loci that act heterogeneously across disorders within a factor. Despite moderate to high genetic correlations across all 11 disorders, we find very little utility of, or evidence for, a single dimension of genetic risk across psychiatric disorders.

中文翻译:

生物行为学,功能基因组学和分子遗传学分析水平下11种主要精神疾病的遗传结构

我们在生物行为学,功能基因组学和分子遗传学分析水平上系统地询问了11种主要精神疾病的联合遗传结构。我们确定了障碍之间遗传相关性的四个广泛因素(神经发育,强迫,精神病和内在化),并测试这些因素是否充分说明了它们与生物行为特征的遗传相关性。我们介绍了分层基因组结构方程模型,该模型用于确定对多效性不成比例地起作用的基因集和基因组区域,包括在兴奋性和GABA能脑细胞中表达的截短蛋白的不耐受基因,这些丰富了具有精神病特征的疾病之间的多效性。多变量关联分析检测到总共152个(20个新的)独立位点,它们作用于这四个因素,并确定了九个位点在一个因素中跨疾病的异质作用。尽管在所有11种疾病中都有中度到高度的遗传相关性,但我们发现跨精神疾病的遗传风险的单一维度实用性或证据很少。
更新日期:2020-09-23
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