Whole-genome sequencing for rare highly penetrant gene variants in schizophrenia

精神分裂症罕见高渗透基因变异的全基因组测序

• 批准号: 7856844
• 负责人: David B. Goldstein
• 金额: $ 167.12万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7856844
• 关键词: Affect; Autistic Disorder; Bioinformatics; Brain; Collection; Comorbidity; DNA; Diagnosis; Disease; Employee Strikes; Environment; Environmental Risk Factor; Epilepsy; Family; Family history of; Family member; Frequencies; General Population; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Variation; Genome; Genotype; Individual; Investigation; Mental Retardation; Mental disorders; Mentally Ill Persons; Molecular; Morbidity - disease rate; Other Genetics; Patients; Penetrance; Pervasive Development Disorder; Pharmaceutical Preparations; Population Control; Recruitment Activity; Relative (related person); Research; Risk; Risk Factors; Role; Schizoaffective Disorders; Schizophrenia; Second Degree Relative; Selection Criteria; Specificity; Symptoms; Technology; Time; Variant; Work; base; case control; disorder risk; genetic risk factor; genetic variant; genome sequencing; genome wide association study; genome-wide; meetings; neuropsychiatry; next generation; novel; proband; public health relevance; tool; trait

DESCRIPTION (provided by applicant): Large-scale genetics studies on schizophrenia to date have failed to discover a substantial contribution of common genetic variation. However, recent analyses of structural genetic variation have identified and rapidly confirmed a number of rare variants contributing to this disorder. Surprisingly, the same rare genetic contributors have often been found to be risk factors for multiple neuropsychiatric conditions, including schizophrenia, mental retardation, autism and epilepsy. This suggests that these rare variants may confer a "neuropsychiatric vulnerability" and that the ultimate manifestation depends on other genetic or environmental influences. This suggests that patients with multiple co-occurring conditions may be those most likely to carry an elevated burden of rare, high-penetrant risk factors. Additionally, families that have multiple neuropsychiatric conditions associated with the same rare genetic variant could be the most valuable in dissecting the genetic and environmental influences on mental disorders. With this research, we propose to collect 100 chronically mentally ill patients with schizophrenia or schizoaffective disorder and as many of their first, second and third degree relatives as possible, and to perform whole-genome sequencing to identify rare gene variants that predispose to disease with relatively high-penetrance. Using DNA collected from these subjects, we will use next-generation whole genome sequencing technology and a variety of novel bioinformatic tools to select potentially disease-associated gene variants on the basis of predicted function and frequency in healthy control populations. We will then examine the distribution of associated variants in the families, determining which disorders, symptoms or traits they are associated with, and what differences in environment and genetic background are present between affected and unaffected carriers. By focusing on patients with a strong genetic burden and a family history of mental illness, and including the entire genome in our search for genetic susceptibility, we expect to be able to find rare highly penetrant variants that would be undetectable with other approaches. PUBLIC HEALTH RELEVANCE: Schizophrenia is a highly heritable neuropsychiatric condition that affects millions of individuals in the U.S. alone. The proposed study seeks to increase our understanding of the genetic basis of this disease by performing whole-genome sequencing in 100 schizophrenia patients to search for rare, highly penetrant associated genetic variants. Potentially associated genetic markers will be genotyped in affected and unaffected family members to determine their specificity for schizophrenia, and to investigate genetic and environmental modifiers of their effects. This work could elucidate the molecular basis of schizophrenia and potentially indicate novel targets for psychiatric drugs.

描述（由申请人提供）：迄今为止对精神分裂症的大规模遗传学研究未能发现常见遗传变异的实质性贡献。但是，最近对结构遗传变异的分析已经确定并迅速证实了许多导致这种疾病的罕见变异。令人惊讶的是，经常发现同样的罕见遗传贡献者是多种神经精神病疾病的危险因素，包括精神分裂症，智力低下，自闭症和癫痫。这表明这些罕见的变体可能会赋予“神经精神上的脆弱性”，并且最终的表现取决于其他遗传或环境影响。这表明患有多个同时发生疾病的患者可能是最有可能承担罕见，高渗透危险因素的负担。此外，与同样的罕见遗传变异相关的多种神经精神病疾病的家庭可能是剖析遗传和环境对精神疾病的影响最有价值的家庭。通过这项研究，我们提议收集100例患有精神分裂症或精神分裂症的慢性病患者，以及尽可能多的第一，二级和三级亲戚，并进行全基因组测序，以识别稀有基因变异，这些变体易受疾病的疾病相对较高的渗透率。使用从这些受试者中收集的DNA，我们将使用下一代全基因组测序技术和各种新型生物信息学工具来选择与健康对照群体中预测的功能和频率的潜在相关基因变异。然后，我们将检查家庭中相关变体的分布，确定与之相关的疾病，症状或特征，以及受影响和未影响的载体之间存在环境和遗传背景的差异。通过专注于具有巨大遗传负担和精神疾病家族史的患者，并在我们寻求遗传易感性的过程中包括整个基因组，我们希望能够找到罕见的高度渗透变体，而其他方法则无法检测到。 公共卫生相关性：精神分裂症是一种高度可遗传的神经精神疾病，仅在美国就会影响数百万人。 拟议的研究旨在通过在100名精神分裂症患者中进行全基因组测序来寻找罕见的，高度渗透性相关的遗传变异，以提高我们对该疾病遗传基础的理解。潜在相关的遗传标记将在受影响和未受影响的家庭成员中基因分型，以确定其对精神分裂症的特异性，并研究其作用的遗传和环境修饰符。 这项工作可以阐明精神分裂症的分子基础，并可能表明精神病药物的新靶标。