DEVELOPMENTAL ORIGINS OF PSYCHIATRIC RISK: DISSECTING GENE REGULATION THROUGH SINGLE-CELL MULTIOMIC ANALYSIS

Abstract

Psychiatric disorders such as schizophrenia, bipolar disorder, major depression, and autism spectrum disorder frequently originate from disruptions in neurodevelopmental processes, many of which unfold long before clinical symptoms emerge. However, dissecting the molecular and regulatory mechanisms that underlie these early developmental perturbations has remained a major challenge, particularly due to limited access to human brain tissue across the lifespan and the complexity of brain cellular diversity.

To address this, we applied state-of-the-art single-nucleus multi-omic technologies—simultaneously profiling gene expression and chromatin accessibility—to construct high-resolution atlases spanning key stages of human brain development and adulthood. Our datasets encompass over one million nuclei from multiple brain regions, including the dorsolateral prefrontal cortex (DLPFC), a region central to cognition and psychiatric vulnerability, and the olfactory epithelium (OE), a regenerative sensory tissue with neurogenic potential. These integrative datasets enable unprecedented insights into dynamic transcriptional programs and epigenetic regulation during neurodevelopment and aging.

Through trajectory inference and enhancer-gene regulatory network reconstruction, we identified stage-specific transcription factors and cell-type-specific cis-regulatory modules that guide neuronal and glial lineage commitment. We discovered striking convergence in gene regulatory dynamics between olfactory sensory neuron development and early-stage cortical excitatory neurons, suggesting that the OE may serve as a surrogate system to model human neurodevelopment. Furthermore, integrating our regulatory maps with genome-wide association study (GWAS) loci for major psychiatric disorders allowed us to prioritize putative causal genes and regulatory elements operating at specific developmental windows.

Collectively, our findings highlight the power of multiomic single-cell analysis in unraveling the developmental origins of psychiatric disease. By linking genetic risk to temporally defined regulatory programs and accessible cell types, this work lays a foundation for future efforts to pinpoint disease mechanisms and therapeutic targets. Moreover, our demonstration that accessible neurogenic tissues can recapitulate key features of brain development opens new avenues for modeling psychiatric risk in vivo.