Using Genetics to Dissect Schizhoprenia, Bipolar Disorder, and Depression

描述（由申请人提供）：精神分裂症（SCZ）、双相情感障碍（BPD）和重度抑郁症（MDD）造成了巨大的残疾负担、个人痛苦和经济成本。尽管这些疾病的诊断和治疗取得了进展，但关于其定义和病因的关键问题仍然存在。这些疾病最确定的风险因素是遗传易感性，易感基因的鉴定为开发更有效的治疗和预防策略提供了巨大的希望。然而，这一领域的进展受到精神病学表型如何最好定义的基本不确定性的限制。基因似乎会影响跨DSM-IV诊断界限的成分表型，并可能对疾病发病率甚至死亡率（例如自杀）产生重大影响。本提案是对RFA-MH-07-010“治疗反应：将与患者、家庭和决策者相关的行为表型相关的基因联系起来”的回应。它代表了第一个充分有力的研究来剖析遗传对SCZ的影响；BPD， MDD以及致残症状和功能损伤可能独立于诊断类别。这将通过结合来自三个大型多中心nimh资助的治疗研究的表型和遗传数据来完成：SCZ的CATIE研究（N = 770）， BPD的STEP-BD研究（N = 2090）， MOD的STAR*D研究（N = 1953），以及筛选的大样本对照（N = 2000）。该研究的目的是1)从这些队列中创建一个复合表型数据库，并获得用于遗传分析的关键表型变量；2) 15个基因的768个snp基因型在情绪和精神病相关表型中具有最强的先验概率；3)进行分析，以确定这些基因的表型效应是否(a)支持精神病和情绪障碍之间的病理性区别，(b)影响独立于诊断的临床特征（精神病、自杀倾向）和功能结果。拟议的研究将解决有关主要精神疾病的分类学和遗传病因及其功能后果的基本问题。因此，它将对情绪和精神障碍的生物学和临床理解产生影响。最后，从这些分析中得到的表型和遗传数据库将为科学界未来的遗传研究提供宝贵的资源。

DESCRIPTION (provided by applicant): Schizophrenia (SCZ), bipolar disorder (BPD), and major depression (MDD) are responsible for an enormous burden of disability, personal suffering, and economic cost. Despite progress in the diagnosis and treatment of these disorders, crucial questions about their definition and etiology remain. The best-established risk factor for these disorders is genetic vulnerability, and the identification of susceptibility genes offers tremendous hope for the development of more effective treatment and prevention strategies. However, progress in this area has been limited by fundamental uncertainties in how psychiatric phenotypes are best defined. Genes appear to influence component phenotypes that cross DSM-IV diagnostic boundaries and that may have substantial impact on illness morbidity and even mortality (e.g., suicidality). This proposal is a response to RFA-MH-07-010 "Treatment Response: Linking Genes with Behavioral Phenotypes of Relevance to Patients, Families and Policymakers". It represents the first, adequately powered study to dissect genetic influences on SCZ; BPD, and MDD as well as disabling symptoms and functional impairment that may be independent of diagnostic categories. This will be accomplished by combining phenotypic and genetic data from three large multicenter NIMH-funded treatment studies-the CATIE study of SCZ (N = 770), the STEP-BD study of BPD (N = 2090), and the STAR*D study of MOD (N = 1953)-as well as a large sample of screened controls (N = 2000). The aims of the study are to 1) create a composite phenotypic database from these cohorts and derive key phenotypic variables for genetic analyses; 2) genotype 768 SNPs in 15 genes selected for having the strongest prior probability of involvement in the mood- and psychosis-related phenotypes; 3) perform analyses to determine whether phenotypic effects of these genes (a) support nosologic distinctions among psychotic and mood disorders and (b) influence clinical features (psychosis, suicidality) and functional outcomes independent of diagnosis. The proposed research will address fundamental questions about the nosology and genetic etiology of major mental illness and its functional consequences. As such, it will have implications for informing both the biological and clinical understanding of mood and psychotic disorders. Finally, the phenotypic and genetic database derived from these analyses will provide a valuable resource for future genetic studies by the scientific community.