Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, and Department of Psychiatry, Massachusetts General Hospital, Boston; and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, and Department of Psychiatry, Massachusetts General Hospital, Boston; and Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
Biol Psychiatry. 2021 Jan 1;89(1):20-31. doi: 10.1016/j.biopsych.2020.09.026. Epub 2020 Oct 10.
Genome-wide analyses of common and rare genetic variations have documented the heritability of major psychiatric disorders, established their highly polygenic genetic architecture, and identified hundreds of contributing variants. In recent years, these studies have illuminated another key feature of the genetic basis of psychiatric disorders: the important role and pervasive nature of pleiotropy. It is now clear that a substantial fraction of genetic influences on psychopathology transcend clinical diagnostic boundaries. In this review, we summarize evidence in psychiatry for pleiotropy at multiple levels of analysis: from overall genome-wide correlation to biological pathways and down to the level of individual loci. We examine underlying mechanisms of observed pleiotropy, including genetic effects on neurodevelopment, diverse actions of regulatory elements, mediated effects, and spurious associations of genomic variation with multiple phenotypes. We conclude with an exploration of the implications of pleiotropy for understanding the genetic basis of psychiatric disorders, informing nosology, and advancing the aims of precision psychiatry and genomic medicine.
全基因组常见和罕见遗传变异分析记录了主要精神疾病的遗传性,确定了其高度多基因遗传结构,并鉴定了数百个致病变异。近年来,这些研究揭示了精神疾病遗传基础的另一个关键特征:多效性的重要作用和普遍性质。现在很清楚,精神病理学的遗传影响很大一部分跨越了临床诊断界限。在这篇综述中,我们总结了精神病学中在多个分析层面上的多效性证据:从全基因组的整体相关性到生物途径,再到单个基因座的水平。我们研究了观察到的多效性的潜在机制,包括遗传对神经发育的影响、调控元件的多种作用、介导效应以及基因组变异与多种表型的虚假关联。最后,我们探讨了多效性对理解精神疾病遗传基础、为分类学提供信息以及推进精准精神病学和基因组医学目标的意义。
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