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

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共同遗传变异的实质性贡献。然而，最近对结构遗传变异的分析已经确定并迅速证实了一些导致这种疾病的罕见变异。令人惊讶的是，同样罕见的遗传因素经常被发现是多种神经精神疾病的危险因素，包括精神分裂症、智力迟钝、自闭症和癫痫。这表明，这些罕见的变异可能赋予了“神经精神脆弱性”，最终的表现取决于其他遗传或环境影响。这表明，患有多种并发疾病的患者可能是那些最有可能携带罕见、高渗透风险因素的患者。此外，具有与相同罕见遗传变异相关的多种神经精神疾病的家庭可能在解剖遗传和环境对精神障碍的影响方面最有价值。在这项研究中，我们建议收集100名患有精神分裂症或分裂情感性障碍的慢性精神疾病患者，以及尽可能多的他们的一、二、三度亲属，并进行全基因组测序，以确定具有相对高外显率的易患疾病的罕见基因变异。利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，根据健康对照人群中预测的功能和频率，选择潜在的疾病相关基因变异。然后，我们将检查相关变异在家庭中的分布，确定它们与哪些疾病、症状或特征相关，以及受影响和未受影响的携带者之间存在的环境和遗传背景差异。通过关注具有强烈遗传负担和精神疾病家族史的患者，并将整个基因组纳入我们对遗传易感性的研究，我们希望能够找到其他方法无法检测到的罕见的高渗透性变异。

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.