Investigating the genetic modulation of phenotypic and transcriptomic convergence in bipolar disorder and schizophrenia - ABSTRACT Schizophrenia (SCZ) and bipolar disorder (BD) are severe psychiatric conditions that affect over 2% of the global population, leading to significant disability, reduced life expectancy, and a heavy socioeconomic burden. Genetic studies have advanced our understanding of the factors contributing to these disorders, but most research has been conducted on populations of few ancestries, leaving major gaps in how SCZ and BD manifest in comprehensive populations. Understanding the genetic architecture of these disorders across minimally characterized groups is crucial for developing more broadly applicable precision medicine approaches. In this research proposal, I aim to investigate the genetic and biological convergence of SCZ and BD by leveraging large-scale datasets that include multi-omics data—genomics, transcriptomics, and clinical data from comprehensive and unique populations. Specifically, I will (1) evaluate the transcriptional convergence of SCZ and BD genes using single-cell RNA sequencing (scRNA-seq) data from neurons; (2) explore how rare genetic variants in SCZ and BD impact phenotypic comorbidities and convergence by examining clinical trajectories and comorbidities in individuals using longitudinal electronic health records (EHRs); and (3) extend my prior work developing the GISMO evolutionary constraint metric to noncoding regions through GISMO-Reg, enabling systematic prioritization of regulatory elements intolerant to disruption, and performing rare variant burden analyses within these elements to identify convergent noncoding risk factors. Together, these aims will reveal key molecular, regulatory, and clinical pathways shared between SCZ and BD while clarifying disorder-specific differences, providing a foundation for more precise psychiatric diagnosis and treatment. This project will be led by Dr. Calwing (Cal) Liao, a statistical geneticist with expertise in psychiatric genetics, multi-omic data integration, and the analysis of rare variants. Dr. Liao has developed a comprehensive research plan to complete these aims while advancing his career development through training in electronic health record analysis, single-cell transcriptomics, and psychiatric genomics in comprehensive populations. This will support his long-term goal of becoming an independent investigator who integrates multi-omic and genetic data to uncover the molecular underpinnings of complex psychiatric disorders such as SCZ and BD. Dr. Liao’s exceptional advisory team will directly support his career development. His primary mentor, Dr. Ben Neale, is a leader in psychiatric genetics and large-scale genetic analysis. Additional advisory team members include experts in biostatistics, functional genomics, and psychiatric phenotyping, providing critical guidance across the research and career development objectives. Dr. Liao’s advisory team, combined with the collaborative and resource-rich environment at the Broad Institute of MIT and Harvard, will ensure his successful transition to an independent research career in psychiatric genetics.
