Cell-type-specific cis-eQTLs in eight human brain cell types identify novel risk genes for psychiatric and neurological disorders
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Abstract
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.
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The directional effect of the AD risk allele of rs10792832 on PICALM expression was consistent with other hMG eQTL findings.
“The directional effect of the AD risk allele of rs10792832 on PICALM expression was consistent with other hMG eQTL findings8,9,25.”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [9]
The 'Brain cell type eQTLs mediate brain disease associations' section reports a microglial PICALM co-localization signal and associates increased PICALM expression with decreased AD risk. The 'Mapping of risk variants to cell type regulatory elements' section identifies rs10792832 at a microglia-specific enhancer connected to PICALM, but our copy does not establish the expression effect of that particular risk allele or compare its direction with other human microglia eQTL findings. The indexed passages provide section labels but no specific page for these statements. (LLM, conf=0.82)
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- Authors
- Bryois, J., Calini, D., Macnair, W., Foo, L., Urich, E., Ortmann, W., Iglesias, V. A., Selvaraj, S., Nutma, E., Marzin, M., Amor, S., Williams, A., Castelo-Branco, G., Menon, V., De Jager, P., & Malhotra, D.
- Affiliations
- F. Hoffmann-La Roche AG (CH)
- Genentech (US)
- Amsterdam University Medical Centers (NL)
- Queen Mary University of London (GB)
- MRC Centre for Regenerative Medicine (GB)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Bryois, Julien
- Malhotra, Dheeraj
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2022-08
- Volume
- 25
- Issue
- 8
- Pages
- 1104-1112
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W4289261763
- Cited by
- 311
- References
- 20
- Citations by year
- 2026: 84 · 2025: 88 · 2024: 81 · 2023: 41 · 2022: 17
- FWCI
- 36.05
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- medRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (acceptedVersion, other-oa)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Illinois Department of Public Health (P30AG10161, R01AG15819, R01AG17917, R01AG30146)
- Rush University
- Translational Genomics Research Institute
- National Institute on Aging (R01AG36042, U01AG46161, P30-AG 10161, U01 AG32984, R01 AG30146, R01‐AG17917, R01 AG15819, R01-AG36836, U01‐AG61356, R01AG48015, RC2AG036547, RF1AG57473, U01‐AG46152)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- cis-eQTL, cell type-specific gene expression, brain cell types, single-nucleus RNA sequencing, microglia, prefrontal cortex, temporal cortex, white matter, neuropsychiatric disorders, neurodegenerative diseases, risk genes, genetic colocalization, expression quantitative trait loci
- MeSH terms
- Brain, Humans, Nervous System Diseases, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study
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