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)和严重抑郁症(MDD)是造成残疾、个人痛苦和经济成本的巨大负担。尽管在诊断和治疗这些疾病方面取得了进展，但关于它们的定义和病因的关键问题仍然存在。这些疾病最确定的危险因素是遗传脆弱性，而易感基因的识别为开发更有效的治疗和预防策略带来了巨大的希望。然而，这一领域的进展受到精神病学表型如何定义的根本不确定性的限制。基因似乎影响跨越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。这项建议是对RFA-MH-07-010“治疗反应：将基因与与患者、家庭和政策制定者相关的行为表型联系起来”的回应。这是第一个充分研究SCZ、BPD和MDD的基因影响，以及可能独立于诊断类别的致残症状和功能损害的研究。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实现--SCZ的CATIE研究(N=770)、BPD的STEP-BD研究(N=2090)和MOD的STAR*D研究(N=1953)--以及大样本筛选对照(N=2000)。本研究的目的是1)根据这些队列创建一个综合表型数据库，并得出用于遗传分析的关键表型变量；2)在15个被选为参与心境和精神障碍相关表型概率最大的基因中，对768个SNPs进行基因分型；3)进行分析，以确定这些基因的表型效应是否(A)支持精神病和心境障碍之间的病因学区别，(B)影响临床特征(精神病、自杀)和独立于诊断的功能结果。这项拟议的研究将解决有关重大精神疾病的病因学和遗传病因学及其功能后果的基本问题。因此，它将对提供对情绪和精神障碍的生物学和临床理解具有指导意义。最后，由这些分析得出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.