Genetic architecture of transdiagnostic psychosis symptom dimensions

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.