Cell-type-specific cis-eQTLs in eight human brain cell types identify novel risk genes for psychiatric and neurological disorders

To date, most expression quantitative trait loci (eQTL) studies, which investigate how genetic variants contribute to gene expression, have been performed in heterogeneous brain tissues rather than specific cell types. In this study, we performed an eQTL analysis using single-nuclei RNA sequencing from 192 individuals in eight brain cell types derived from the prefrontal cortex, temporal cortex and white matter. We identified 7,607 eGenes, a substantial fraction (46%, 3,537/7,607) of which show cell-type-specific effects, with strongest effects in microglia. Cell-type-level eQTLs affected more constrained genes and had larger effect sizes than tissue-level eQTLs. Integration of brain cell type eQTLs with genome-wide association studies (GWAS) revealed novel relationships between expression and disease risk for neuropsychiatric and neurodegenerative diseases. For most GWAS loci, a single gene co-localized in a single cell type, providing new clues into disease etiology. Our findings demonstrate substantial contrast in genetic regulation of gene expression among brain cell types and reveal potential mechanisms by which disease risk genes influence brain disorders. Bryois et al. mapped genetic variants regulating gene expression in eight major brain cell types. They found a large number of cell-type-specific genetic effects and leveraged their results to identify novel putative risk genes for brain disorders.

Automated summary

This study investigated the genetic regulation of gene expression in eight major brain cell types using single-nuclei RNA sequencing. The results showed cell-type-specific genetic effects, with the strongest effects observed in microglia. Cell-type-level genetic regulation affected more constrained genes and had larger effect sizes. Integration of these findings with genome-wide association studies revealed new relationships between gene expression and disease risk for brain disorders. Most disease-associated genetic loci co-localized to a single gene in a specific cell type, providing insights into disease etiology.