Single-nucleus transcriptome-wide association study of human brain disorders

Neuropsychiatric and neurodegenerative disorders exhibit cell-type-specific characteristics1-8, yet most transcriptome-wide association studies have been constrained by the use of homogenate brain tissue9-11, limiting their resolution and power. Here, we present a single-nucleus transcriptome-wide association study (snTWAS) leveraging single-nucleus RNA sequencing of over 6 million nuclei from the dorsolateral prefrontal cortex of 1,494 donors across three ancestries--European, African, and Admixed American. We constructed ancestry-specific single-nucleus-derived transcriptomic imputation models (snTIMs) including up to 27 non-overlapping cellular populations, enhancing the resolution of genetically regulated gene expression (GReX) in the brain and uncovering novel gene-trait associations across 12 neuropsychiatric and neurodegenerative traits. Our snTWAS framework revealed cell-type-specific dysregulation of GReX, identifying over 4,000 novel gene-trait associations not detected by bulk tissue approaches. By applying these snTIMs to the Million Veteran Program, we validated major findings and explored the pleiotropy of cell-type-specific GReX, revealing cross-ancestry concordance and fine-mapping causal genes. This approach enhances the discovery of biologically relevant pathways and gene targets, highlighting the importance of cell-type resolution and ancestry-specific models in understanding the genetic architecture of complex brain disorders.