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

Julien Bryois, Daniela Calini, Will Macnair, Lynette Foo, Eduard Urich, Ward Ortmann, Victor Alejandro Iglesias, Suresh Selvaraj, Erik Nutma, Manuel Marzin, Sandra Amor, Anna Williams, Gonçalo Castelo-Branco, Vilas Menon, Philip De Jager, Dheeraj Malhotra

Research output: Contribution to journalArticleAcademicpeer-review

40 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1104-1112
Number of pages9
JournalNature neuroscience
Issue number8
Publication statusPublished - Aug 2022


  • Brain
  • Genetic Predisposition to Disease/genetics
  • Genome-Wide Association Study
  • Humans
  • Nervous System Diseases
  • Polymorphism, Single Nucleotide/genetics
  • Quantitative Trait Loci/genetics

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