Improving the Precision of Genetic Markers for Psychotic Disorders

项目总结 在美国，精神障碍占心理健康相关疾病负担的10%以上 但仍然很难预测谁会患上精神障碍，他们的病情会如何发展， 以及他们将如何应对可用的治疗方法。最近的发现表明遗传标记很有希望用于 精神疾病，但这些工具是不精确的，限制了它们在基础研究和临床应用中的效用。 这份K08申请书概述了一项支持申请者发展的研究和培训计划 走向由美国国立卫生研究院资助的独立研究事业，调查严重精神疾病的遗传责任 生病了。本申请中概述的活动以应聘者的临床和数量背景为基础， 并通过在资源丰富的环境中进行的培训活动，促进在1) 科学交流和负责任的研究；2)统计遗传学，3)精神病遗传学 4)用于评估临床应用的遗传标记的翻译研究。该计划的目的是 这项提案中概述的研究是验证一种识别精神病患者多基因风险的新方法 考虑到重叠症状和共同的遗传脆弱性的疾病。这种方法的目的是 提高多基因风险评分的精确度。这一方法将应用于不同种族的 30,000名精神障碍患者，确定一般和特定的多基因风险得分 精神病症状学的各个方面。由此产生的风险分数将在九个风险分数的汇集分析中进行验证 纵向队列研究，共1,785例。风险分数将被测试为精神病的预测因子。 发病、诊断、症状轨迹、心理社会结果和治疗反应。如果建议的 研究成功地确定了精神障碍特定维度的遗传相关性，这些维度预测 这些重要的健康结果，将对病因学研究具有重要意义，因为它可能有助于 确定干预目标。这一发现也将对临床翻译研究具有重要意义，因为 遗传标记在辅助诊断和预后方面有潜在的应用前景。

PROJECT SUMMARY Psychotic disorders account for more than 10% of mental-health-related disease burden in the United States, but it remains difficult to predict who will develop a psychotic disorder, how their illness will progress, and how they will respond to available treatments. Recent findings suggest promise for genetic markers for psychotic illnesses, but these tools are imprecise, limiting their utility for basic research and clinical application. This K08 application outlines a research and training program that will support the applicant's development towards an NIH-funded, independent research career investigating the genetic liabilities for serious mental illness. The activities outlined in this application build on the candidate's clinical and quantitative background, and through training exercises set in a resource-rich environment, facilitate the development of expertise in 1) scientific communication and responsible conduct of research; 2) statistical genetics, 3) genetics of psychotic disorders, and 4) translational research for evaluating genetic markers for clinical applications. The aim of the research outlined in this proposal is to validate a novel method of identifying polygenic risk for psychotic disorders that takes account of overlapping symptoms and common genetic vulnerabilities. This approach aims to improve the precision of polygenic risk scores. This method will be applied in an ethnically diverse sample of 30,000 individuals with psychotic disorders, identifying polygenic risk scores for both general and specific facets of psychotic symptomatology. The resulting risk scores will be validated in pooled analysis of nine longitudinal cohort studies, comprising 1,785 cases. Risk scores will be tested as predictors of psychosis onset, diagnosis, symptom trajectory, psychosocial outcomes, and treatment response. If the proposed research succeeds in identifying genetic correlates of specific dimensions of psychotic disorders that predict these important health outcomes, it will have important implications for etiological research, as it may help to identify targets for intervention. The findings would also have significance for clinical translational research, as genetic markers have potential application as aids in diagnosis and prognosis.