PROFILING THE MOLECULAR STATE OF THE LIVING BRAIN IN SCHIZOPHRENIA AND ALZHEIMER'S DISEASE USING BRAINGENIE: THE BRAIN GENE EXPRESSION AND NETWORK IMPUTATION ENGINE

Abstract

In 2005, Professor Ming T. Tsuang and his team published the first blood-based transcriptomic study of a psychiatric disorder in the journal he founded, Neuropsychiatric Genetics. In that pioneering work, Tsuang et al. established the validity of blood-based gene-expression profiles for the classification of schizophrenia and bipolar disorder. This exciting discovery and novel methodological approach initiated a movement in the field, spawning numerous similar research projects across the globe and dozens of published papers in the literature. To date, blood-based transcriptomic studies have been conducted on a wide range of phenotypes, including neurodevelopmental disorders such as autism spectrum disorders and attention-deficit/hyperactivity disorder, neuropsychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder, and post-traumatic stress disorder, and neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease. As the pursuit of blood-based biomarkers for brain disorders matured, Tsuang recognized the need for more than just strong metrics and good classification performance. Rather, he came to understand that blood-based transcriptomes could be leveraged to make inferences about the molecular state of the living brain. So, in 2023, Tsuang and his team leveraged the within-subject multi-tissue transcriptome data from the Genotype Tissue Expression (GTEx) project to identify mapping functions relating principal components of peripheral blood transcriptome data to expression levels of individual transcripts in ten distinct brain regions. The discovered transcript-specific imputation algorithms were then compiled in a software package called BrainGENIE: The Brain Gene Expression and Network Imputation Engine. BrainGENIE enabled the reliable prediction of thousands of brain-regional gene-expression levels from peripheral blood samples, opening the door to new applications (e.g., repeated longitudinal sampling in living individuals) and novel insights that could not be gleaned from studying the postmortem brain or blood gene expression alone. In this presentation, I will describe the evolution of our pursuit of blood-based biomarkers for neuropsychiatric disorders, from its earliest days when accuracy was our only benchmark to the current day where we want more than just a set of reliable biomarkers but also a window into the molecular mechanisms, pathophysiology, and etiology of brain disorders. In addition to this historical perspective, I will present the latest results from our application of BrainGENIE to various brain-disorder datasets, including cross-sectional studies of schizophrenia and Alzheimer’s disease, and a longitudinal study of risk for and resilience to post-traumatic stress disorder. Lastly, I will compare and integrate findings across disorders, and connect these ideas to Tsuang’s long-held and oft-enunciated core beliefs in the dimensional nature of psychopathology, the existence of biological (endo)phenotypes for psychiatric disorders, the possibility of identifying new treatment targets by studying resilience, and our potential to realize the ultimate promise of prevention.