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.

中文翻译：

---

精神疾病中的多效性和跨疾病遗传学

对常见和罕见遗传变异的全基因组分析记录了主要精神疾病的遗传性，建立了其高度多基因的遗传结构，并鉴定了数百种致病变异。近年来，这些研究阐明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。现在很清楚，遗传对精神病理学的影响很大一部分超越了临床诊断的界限。在这篇综述中，我们总结了精神病学中多效性证据的多个分析水平：从整体基因组相关性到生物途径，再到个体基因座水平。我们研究了观察到的多效性的潜在机制，包括对神经发育的遗传效应、调节元件的不同作用、介导效应以及基因组变异与多种表型的虚假关联。最后，我们探索了多效性对于理解精神疾病的遗传基础、为疾病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影响。