Improving the Precision of Genetic Markers for Psychotic Disorders

项目摘要 精神障碍占美国精神健康相关疾病负担的10%以上 但是仍然很难预测谁会患上精神病，他们的病情会如何发展， 以及他们对现有治疗的反应。最近的研究结果表明，遗传标记的承诺， 精神疾病，但这些工具是不精确的，限制了他们的基础研究和临床应用的效用。 此K 08申请概述了一个研究和培训计划，将支持申请人的发展 走向NIH资助的独立研究事业，调查严重精神疾病的遗传责任。 病本申请中概述的活动基于候选人的临床和定量背景， 并通过在资源丰富的环境中开展培训活动，促进以下方面的专门知识的发展： 科学交流和负责任的研究行为; 2）统计遗传学，3）精神病遗传学 疾病，和4）用于评估临床应用的遗传标记的转化研究。的目的 这项建议中概述的研究是为了验证一种识别精神病多基因风险的新方法， 考虑到重叠症状和共同遗传脆弱性的疾病。这一方法的目的是 以提高多基因风险评分的精确度。这种方法将应用于一个种族多样的样本， 30，000名精神病患者，确定一般和特定的多基因风险评分 精神病学的方方面面由此产生的风险评分将在9项合并分析中进行验证。 纵向队列研究，包括1，785例病例。将测试风险评分作为精神病的预测因素 发病、诊断、症状轨迹、心理社会结果和治疗反应。如果拟议的 一项研究成功地确定了精神障碍特定维度的遗传相关性， 这些重要的健康结果，它将对病因学研究产生重要影响，因为它可能有助于 确定干预目标。这些发现对临床转化研究也具有重要意义， 遗传标记在诊断和预后方面具有潜在的应用。

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.