Comprehensive analysis of genetic pleiotropy in eleven neuropsychiatric disorders

11种神经精神疾病遗传多效性综合分析

• 批准号: 10523102
• 负责人: Phil H. Lee
• 金额: $ 48.85万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-18 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10523102
• 关键词: Affect; Alcohol dependence; Anorexia Nervosa; Anxiety Disorders; Attention deficit hyperactivity disorder; Biological; Biological Process; Bipolar Disorder; Brain; Cell Differentiation process; Cells; Characteristics; Clinical; Code; Collaborations; Communities; Computer software; Data; Data Analyses; Development; Diagnosis; Diagnostic; Disease; Etiology; Gene Expression; Gene set enrichment analysis; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genetic Risk; Genetic study; Genomics; Gilles de la Tourette syndrome; Goals; Health; Heterogeneity; Human; Individual; Knowledge; Longevity; Maps; Mental Depression; Mental disorders; Methods; Molecular; Pathogenicity; Pathway interactions; Persons; Pharmacologic Substance; Phenotype; Play; Post-Traumatic Stress Disorders; Prevalence; Prevention; Psychopathology; Public Health; Regulator Genes; Research; Research Personnel; Research Project Grants; Resolution; Resources; Risk; Role; Schizophrenia; Shapes; Structure; Symptoms; Testing; Time; Transcend; Transcriptional Regulation; Variant; Work; analytical method; autism spectrum disorder; base; bioinformatics resource; chromatin remodeling; clinical diagnostics; comorbidity; functional genomics; genetic analysis; genome resource; genome wide association study; genome-wide; genomic locus; histone modification; improved; insight; method development; nervous system development; neuropsychiatric disorder; novel; pleiotropism; psychiatric genomics; risk variant; secondary analysis; sex; simulation; success; transcriptomics

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.

摘要 这项建议的长期目标是了解精神障碍的共同遗传基础，以 提高对这些大病的预防、诊断和治疗水平。最近取得的大规模成功 基因组学研究证实，在主要精神障碍中，常见变异风险广泛共享 全基因组水平。然而，人们对哪些基因位点以及如何携带风险效应知之甚少。 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 11个菌株共有遗传效应的系统鉴定和功能鉴定 使用100多万个个体的全基因组SNP数据的神经精神障碍。我们的中心假设 在精神障碍的广泛领域中存在着共同的致病机制，其中之一 集中于神经系统的发育和控制大脑特定基因的染色质重塑 表情。为了支持这一假设，基于八种神经精神障碍的初步数据显示 一百多个遗传风险基因座具有显著和强大的多效性效应，富含在 对细胞识别、细胞分化和转录调控至关重要的脑活性基因。在这项研究中，我们将 使用无与伦比的大小和范围的全基因组遗传数据来实现以下三个目标 独立收益：(1)揭示全面的多效性风险影响，涉及11个方面 神经精神障碍；(2)系统评价多效性危险基因的特征；(3) 确定通常由精神病理学基础的多效性风险基因改变的生物学机制。 通过这项独特而强大的研究，我们希望对普遍存在的遗传多效性获得新的见解。 塑造了精神病理学的病因学和结构。这项研究还将产生新的分析方法和 适用于任何跨障碍遗传学研究的策略，提供即时和有意义的 对研究界的影响。