Exploring dynamics and convergence of gene expression regulation in brain disorders

Abstract

Understanding how genetic variants contribute to disease remains a major challenge in human genetics. In neuropsychiatric disorders, numerous risk variants have been identified, yet their functional roles and impact on brain biology are still not completely understood. Gene expression serves as a key endophenotype that links genetic variation to complex traits and disorders. This study aimed to enhance the functional interpretation of disease-associated variants by integrating gene expression data from various brain tissues and cell types across six prevalent neuropsychiatric disorders. The work first developed context-aware transcriptome-wide association study (TWAS) models, by incorporating dynamic, cell type, and cell state-specific expression quantitative trait loci (eQTLs). Application of these models to schizophrenia genome-wide association studies (GWAS) revealed novel, cell type specific risk associations not detected in bulk tissue analyses. Next, GWAS, whole exome sequencing, and tissue-level transcriptomic data were integrated to evaluate convergence between common and rare genetic risk across disorders. By mapping genetic variants to their downstream regulatory effects, convergent transcriptional programs between common and rare risk genes were uncovered. Genes convergently coexpressed with both variant types showed stronger evolutionary constraint and enrichment for essential genesets and known drug targets. Finally, by extending the framework to single-cell transcriptomic data from the human prefrontal cortex, this work further delineated convergent biological pathways across neuronal and non-neuronal populations. Together, this study illustrated how high-resolution mapping of gene regulation can reveal the dynamic and context-specific architecture of genetic risk. It also provides a scalable framework to identify convergent, network-level disruptions across diverse genetic risk factors advancing our understanding of disease biology.