Functional characterization of schizophrenia related risk genes and variants in neurogenesis using cerebral organoids

Schizophrenia (SCZ) is a severe psychiatric disorder with a complex genetic component. Genetic studies have identified a strong link between genetic risk and the neurodevelopmental processes of the brain, contributing to SCZ etiology. Notably, neurogenesis is especially vulnerable to disruption by SCZ genetic factors. However, which SCZ-associated risk genes and variants affect neurogenesis and how non-coding risk variants influence risk gene expression remains largely unknown. The overarching goal of this K99/R00 project is to systematically delineate the direct connection among SCZ-associated variants, risk genes, and neurogenesis by developing and applying advanced functional genomic screening platforms in cerebral organoids. During the K99 phase, I will elucidate the roles of SCZ risk genes in neurogenesis by conducting pooled high throughput CRISPR interference screens in key neurogenic cell types derived from cerebral organoids. During the K99/R00 phase, I will employ prime editing screens in cerebral organoids to assess the effects of individual SCZ-associated variants on neurogenesis. Finally, during the R00 phase, I will investigate the regulatory impact of non-coding SCZ variants on gene expression using single-cell prime editing screens in cerebral organoids. The successful completion of these aims will provide novel insights into which and how SCZ-associated genes and variants disrupt neurogenesis, advancing our understanding of the neurodevelopmental basis of SCZ and aiding in identifying novel therapeutic targets. Additionally, this research will enhance our ability to interpret the broader role of genetic factors in neurogenesis and will generate essential training data for machine learning models focused on neurogenesis, with potential implications for other neurodevelopmental disorders. During the K99 phase, I will further improve my expertise in functional genomics, organoid models, statistical analysis, machine learning, and neurobiology of SCZ, as well as other essential professional skills, including leadership, mentoring, writing, and presentation. To achieve my training and research objectives, I have assembled an exceptional and interdisciplinary team of mentors and collaborators including Dr. Yin Shen (primary mentor, functional genomics and gene regulation), Dr. Arnold Kriegstein (co-mentor, brain organoid), Dr. Katherine Pollard (co-mentor, statistics and machine learning), Dr. Hongjun Song (co-mentor, SCZ neurobiology), and Dr. Xin Jin (collaborator, complex in vivo screening methodologies). This comprehensive mentorship and collaborative research environment will foster my transition to an independent research career, with a long-term goal of elucidating the genomic mechanisms underpinning neurological disorders, ultimately enabling the identification of novel therapeutic targets for prevention and treatment. Project Number: 1K99MH141253-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Han Yang | Institution: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, SAN FRANCISCO, CA | Award Amount: $117,747 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZRG1 BN-H (95)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11371839