Genetic architecture of transdiagnostic psychosis symptom dimensions

项目摘要 这个K奖将提供正式的培训，指导和精神病学研究经验， 疾病分类学，先进的心理测量学和多祖先统计遗传学方法， 候选人实现其成为独立调查员的长期职业目标 有能力领导高影响力的研究，获得外部资金，并与 现代精神病基因组学研究的快速发展。成功完成本 该项目将完善我们对精神病遗传结构的理解，并使Dr. Lapato将维度表型方法与分子遗传学相结合， 领导大规模分析，以在遗传多样性群体中获得稳健结果。的 这项建议的首要研究目标是调查精神病的遗传结构 与精神分裂症、情感障碍和双相I型精神障碍一样。数据来源 基因组精神病学研究小组的精神病体征和症状由训练有素的 临床工作人员使用半结构化的临床访谈。在K01导师的指导下， 由Kenneth Kendler博士领导的团队，Lapato博士将使用探索性和验证性因素分析 得出精神病症状维度的经验测量。她将在全基因组范围内 关联（GWA）测试并导出后GWA度量（例如，SNP遗传力，多基因风险 分数）使用单一和多祖先方法。关键的人口统计学、临床、行为和 环境变量（包括健康的社会决定因素）将用于验证 精神病症状因子及其多基因风险评分。成功完成该项目 将完善我们对精神病遗传结构的理解， 在精神病学遗传学研究中取得成功的必要技能。

Project Summary This K Award will provide formalized training, mentorship, and research experience in psychiatric nosology, advanced psychometrics, and multi-ancestry statistical genetics methods requisite for the candidate to achieve her long-term career goal of becoming an independent investigator capable of leading high-impact studies, securing external funding, and staying apace with the rapidly evolving nature of modern psychiatric genomics research. Successful completion of this project will refine our understanding of the genetic architecture of psychosis and enable Dr. Lapato to integrate dimensional phenotypic approaches with molecular genetics so that she can lead large-scale analyses required for robust results in genetically diverse cohorts. The overarching research goal of this proposal is to investigate the genetic architecture of psychosis as it presents in schizophrenia, schizoaffective disorder, and bipolar I disorder. The data come from the Genomic Psychiatry Cohort. Psychosis signs and symptoms were assessed by trained clinical staff using a semi-structured clinical interview. Under the guidance of her K01 mentorship team led by Dr. Kenneth Kendler, Dr. Lapato will use exploratory and confirmatory factor analysis to derive empirical measures of psychosis symptom dimensions. She will conduct genome-wide association (GWA) testing and derive post-GWA metrics (e.g., SNP heritability, polygenic risk scores) using both single and multi-ancestry methods. Key demographic, clinical, behavioral, and environmental variables (including social determinants of health) will be used to validate the psychosis symptom factors and their polygenic risk scores. Successful completion of this project will refine our understanding of the genetic architecture of psychosis and equip Dr. Lapato with the requisite skills to progress on to a successful career in psychiatric genetics research.