2025 Theses Doctoral

Brain circuits and cell types targeted by mutations explain the pleiotropy and specificity of psychiatric disorders

Wang, Jiayao

Neuropsychiatric disorders such as autism spectrum disorder (ASD) and schizophrenia (SCZ) exhibit significant phenotypic and genetic diversity, presenting a fundamental challenge in understanding how genetic perturbations lead to brain circuit dysfunction and clinical symptoms. This dissertation addresses this challenge by developing computational frameworks that integrate genome-wide genetic data with brain-wide transcriptomics, anatomical connectomics, and single-cell analyses to identify affected neural circuits and cell types across psychiatric disorders.

Through three interrelated studies, I demonstrate that rare and common genetic variants associated with psychiatric disorders converge on a set of specific brain circuits and cell types. Using GENCIC, a novel computational approach that integrates genetics with spatial transcriptomics and with anatomical connectome data, I show that ASD mutations target spatially distributed brain circuits involved in sensory integration and decision-making. Analysis of human brain single-nucleus data reveals caudal ganglionic eminence (CGE) interneurons as a vulnerable axis for cognitive deficits across such disorders as ASD and SCZ, the effect experimentally validated using cell-type resolved calcium imaging in a 22q11.2 deletion mouse model.

Finally, analysis of GWAS data across multiple psychiatric disorders identifies shared cell-type biases that explain a substantial fraction of comorbidity patterns across different mental disorders. Overall, by revealing both shared and disorder-specific vulnerabilities, this research illuminates the neurobiological basis of psychiatric conditions and their complex phenotypic manifestations.