Deep Sequencing in Schizophrenia

描述(由申请人提供)： 精神分裂症是一种终生疾病，其特征是幻觉、妄想、说话混乱、严重的混乱行为和阴性症状。虽然家庭、双胞胎和收养研究一直证明精神分裂症的遗传病因，但尚未发现致病基因。因此，我们对精神分裂症的潜在病因学有更深入的了解是至关重要的。精神分裂症遗传易感因素的识别是发现高风险患精神分裂症的症状前个体的关键一步，设计新的治疗靶点以降低相关的发病率和死亡率，并最终预防这种疾病。随着技术的新进步，出现了更强大的方法。其中一种新方法，称为“下一代测序”，是一种可以检测基因组中所有遗传序列变异的方法。虽然对人类基因组中存在的30亿个核苷酸中的每一个进行测序是可能的，但对大量个体的基因组进行测序在经济上是不可行的，特别是因为全基因组测序所需的计算和生物信息学数据处理方法仍在开发中。或者，人类外显子组包含基因组中的所有外显子或编码区(~5Mb)，人们认为外显子组包含人类的大部分功能变异。这些最近的进展为确定潜在的稀有遗传变异所必需的各种全面分析奠定了基础，特别是在基于家庭的样本方面，这是本提案的重点。整个外显子组和靶向序列数据，包括与非编码区相关的数据，现在提供了进行全面分析的机会，将在基于家庭的样本中识别精神分裂症易感基因。我们假设，家系中罕见的遗传变异的鉴定和分析 与精神分裂症的关系将有助于我们理解精神分裂症背后的生物学途径。具体地说，我们假设具有相对高外显率的稀有变体将 在从退伍军人事务合作研究计划#366和国家精神卫生研究所精神分裂症遗传倡议中选择的家族性精神分裂症家系中具有重要地位。我们的跨学科研究小组预计，我们可以使用新的分析方法、下一代测序和公开可用的生物信息学信息来识别这些罕见的变异。虽然个别罕见，但这些更高外显性的精神分裂症形式将有助于更好地理解精神分裂症的遗传和分子基础。了解这些危险基因将有助于在分子水平上探索精神分裂症的发病机制，并开发这种疾病的动物和细胞模型。这样的研究努力将极大地推动精神分裂症治疗的寻找。

DESCRIPTION (provided by applicant): Schizophrenia is a lifelong illness that is characterized by hallucinations, delusions, disorganized speech, grossly disorganized behavior, and negative symptoms. Although family, twin, and adoption studies have consistently demonstrated a genetic etiology for schizophrenia, no causative genes have yet been identified. Therefore, it is crucial that we pursue an increased understanding of the underlying etiology of schizophrenia. The identification of genetic susceptibility factors in schizophrenia represents a critical step toward detecting presymptomatic individuals who are at high risk for developing the disease, designing novel therapeutic targets to decrease associated morbidity and mortality, and ultimately, preventing the disorder. With new advances in technology, more powerful approaches have emerged. One of these new approaches, called "next-generation sequencing," is a method that can detect all of the genetic sequence variants in a genome. Although sequencing every one of the three billion nucleotides that is present in the human genome is possible, it is not financially feasible to sequence the genomes of a large number of individuals, particularly because the necessary computational and bioinformatics data processing methods for whole-genome sequencing are still under development. Alternatively, the human exome contains all of the exons or coding regions in a genome (~5 Mb), and it is believed that the exome harbors much of the functional variation in humans. These recent advances set the stage for the kinds of comprehensive analysis that are necessary to identify underlying rare genetic variants, particularly in regard to family-based samples, which are the focus of this proposal. Whole exome and targeted sequence data, including data related to noncoding regions, now provide the opportunity to perform comprehensive analyses that will identify schizophrenia susceptibility genes in family-based samples. We hypothesize that the identification and analysis of rare inherited variants in families with schizophrenia will contribute to our understanding of the biological pathways that underlie schizophrenia. Specifically, we hypothesize that rare variants with relatively high penetrance will be important in familial schizophrenia pedigrees selected from the Veterans Affairs Cooperative Study Program #366 and National Institute of Mental Health Genetic Initiative on Schizophrenia. Our interdisciplinary group of investigators anticipates that we can identify these rare variants using novel analytic approaches, next- generation sequencing, and publicly available bioinformatics information. Although individually rare, these higher-penetrance forms of schizophrenia will lead to an improved understanding of the genetic and molecular basis of schizophrenia. Knowledge of these risk genes will facilitate exploration of the pathogenesis of schizophrenia at a molecular level and the development of animal and cellular models for the disease. Such research endeavors will significantly advance the search for treatments for schizophrenia.