Comprehensive analysis of genetic pleiotropy in eleven neuropsychiatric disorders

摘要 这项提案的长期目标是了解精神疾病的共同遗传基础， 加强对这些严重疾病的预防、诊断和治疗。最近大规模的成功 基因组学研究证实，在主要精神疾病中， a genome-wide基因组level水平.尽管如此，对于哪些基因位点以及某些基因位点如何产生风险影响， 超越了传统的诊断界限。为了填补这一关键空白，我们首次提出 系统鉴定和功能特性的遗传效应之间共享的11个 使用超过100万个体的全基因组SNP数据来评估神经精神疾病。我们的核心假设 在精神疾病的广泛领域中，有一些共同的致病机制，其中之一， 神经系统的发育和染色质的重塑，控制脑特异性基因 表情为了支持这一假设，基于八种神经精神疾病的初步数据显示， 超过100个携带显著和强大多效性效应的遗传风险位点富集在 脑活性基因对细胞身份、细胞分化和转录调控至关重要。在这项研究中，我们将 利用规模和范围无与伦比的全基因组遗传数据，实现以下三个目标， 独立的好处：（1）揭示了一个全面的多效性风险效应，跨越11个 神经精神疾病;（2）系统评估多效性风险基因的特征;（3） 确定通常由潜在精神病理学的多效性风险基因改变的生物学机制。 通过这项独特而有力的研究，我们希望获得新的见解，了解遗传多效性是如何普遍存在的。 形成了精神病理学的病因和结构。这项研究还将产生新的分析方法， 适用于任何交叉疾病遗传学研究的策略，提供直接和重要的 对研究界的影响。

ABSTRACT The long-term goal of this proposal is to understand the shared genetic bases of psychiatric disorders to improve prevention, diagnosis, and treatment of these serious illnesses. Recent successes of large-scale genomics studies have verified extensive sharing of common variant risk across major psychiatric disorders at a genome-wide level. Nevertheless, little is known of which and how certain genetic loci carry risk effects transcending traditional diagnostic boundaries. To fill in this critical gap, we propose for the first time the systematic identification and functional characterization of genetic effects shared among eleven neuropsychiatric disorders using genome-wide SNP data on over 1 million individuals. Our central hypothesis is that there are pathogenic mechanisms shared amongst broad domains of psychiatric disorders, one of which centers on the development of the nervous system and chromatin remodeling that governs brain-specific gene expression. In support of this hypothesis, preliminary data based on eight neuropsychiatric disorders show that more than a hundred of genetic risk loci carrying significant and robust pleiotropic effects are enriched among brain-active genes critical to cell identity, cell differentiation, and transcriptional regulation. In this study, we will use genome-wide genetic data of unparalleled size and scope to achieve the following three aims with independent benefits: (1) to uncover a comprehensive spectrum of pleiotropic risk effects spanning eleven neuropsychiatric disorders; (2) to systematically evaluate the characteristics of pleiotropic risk genes; and (3) to identify biological mechanisms commonly altered by pleiotropic risk genes underlying psychopathology. Through this unique and powerful study, we expect to gain new insight into how pervasive genetic pleiotropy shapes the etiology and structure of psychopathology. This study will also produce novel analytic methods and strategies that are applicable in any cross-disorder genetics studies, providing immediate and significant impact to the research community.