Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
Departments of Neurology, Psychiatry, and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Institute for Precision Health, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Cell. 2019 Mar 21;177(1):162-183. doi: 10.1016/j.cell.2019.01.015.
Studies of the genetics of psychiatric disorders have become one of the most exciting and fast-moving areas in human genetics. A decade ago, there were few reproducible findings, and now there are hundreds. In this review, we focus on the findings that have illuminated the genetic architecture of psychiatric disorders and the challenges of using these findings to inform our understanding of pathophysiology. The evidence is now overwhelming that psychiatric disorders are "polygenic"-that many genetic loci contribute to risk. With the exception of a subset of those with ASD, few individuals with a psychiatric disorder have a single, deterministic genetic cause; rather, developing a psychiatric disorder is influenced by hundreds of different genetic variants, consistent with a polygenic model. As progressively larger studies have uncovered more about their genetic architecture, the need to elucidate additional architectures has become clear. Even if we were to have complete knowledge of the genetic architecture of a psychiatric disorder, full understanding requires deep knowledge of the functional genomic architecture-the implicated loci impact regulatory processes that influence gene expression and the functional coordination of genes that control biological processes. Following from this is cellular architecture: of all brain regions, cell types, and developmental stages, where and when are the functional architectures operative? Given that the genetic architectures of different psychiatric disorders often strongly overlap, we are challenged to re-evaluate and refine the diagnostic architectures of psychiatric disorders using fundamental genetic and neurobiological data.
精神疾病遗传学研究已成为人类遗传学中最令人兴奋和快速发展的领域之一。十年前，几乎没有可重复的发现，而现在已经有数百个了。在这篇综述中，我们重点介绍了阐明精神疾病遗传结构的发现，以及利用这些发现来增进我们对病理生理学理解的挑战。现在压倒性的证据表明，精神疾病是“多基因的”——许多遗传位点都与风险有关。除了 ASD 的一部分患者之外，很少有精神疾病患者有单一的、确定性的遗传原因；相反，精神疾病的发生受到数百种不同遗传变异的影响，符合多基因模型。随着越来越大的研究揭示了更多关于其遗传结构的信息，阐明其他结构的需求变得显而易见。即使我们完全了解精神疾病的遗传结构，全面理解也需要深入了解功能基因组结构——涉及的基因座影响调节过程，从而影响基因表达和控制生物过程的基因的功能协调。由此产生的是细胞结构：在所有脑区、细胞类型和发育阶段，功能结构在何时何地起作用？鉴于不同精神疾病的遗传结构经常强烈重叠，我们面临着使用基本遗传和神经生物学数据重新评估和细化精神疾病的诊断结构的挑战。
