What it is
The authors used single-nucleus gene expression profiles from the dorsolateral prefrontal cortex of the multi-ancestry PsychAD cohort to build models that impute genetically regulated gene expression in each major brain cell type. Applied to neuropsychiatric and neurodegenerative disorders, the models reveal thousands of gene-trait associations that bulk tissue analyses cannot detect and resolve many signals to specific neuronal, glial and immune cell populations. Cross-ancestry analyses in the Million Veteran Program confirmed these associations.
Why it matters
Genome-wide association studies have found many risk loci for brain disorders, but many lie in non-coding regions that act on gene expression in particular cell types, and bulk brain analyses, often focused on European-ancestry cohorts, average that cellular detail away. A cell-type-resolved, ancestry-aware map of genetically regulated expression helps pin genetic risk to causal genes, pathways and cell types, and the authors report that trait-related dysregulation is conserved across ancestries.
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Filed underGenetic Associations and Epidemiology, Single-cell and spatial transcriptomics, Functional Brain Connectivity Studies