TY - JOUR
T1 - Cell-type-specific cis-eQTLs in eight human brain cell types identify novel risk genes for psychiatric and neurological disorders
AU - Bryois, Julien
AU - Calini, Daniela
AU - Macnair, Will
AU - Foo, Lynette
AU - Urich, Eduard
AU - Ortmann, Ward
AU - Iglesias, Victor Alejandro
AU - Selvaraj, Suresh
AU - Nutma, Erik
AU - Marzin, Manuel
AU - Amor, Sandra
AU - Williams, Anna
AU - Castelo-Branco, Gonçalo
AU - Menon, Vilas
AU - De Jager, Philip
AU - Malhotra, Dheeraj
N1 - Funding Information:
The results presented here are, in whole or in part, based on data obtained from the AD Knowledge Portal (https://adknowledgeportal.org). Study data were provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center. Data collection was supported through funding by National Institute on Aging grants P30AG10161 (ROS), R01AG15819 (ROSMAP; genomics and RNA-seq), R01AG17917 (MAP), R01AG30146, R01AG36042 (5hC methylation, ATAC-seq), RC2AG036547 (H3K9Ac), R01AG36836 (RNA-seq), R01AG48015 (monocyte RNA-seq) RF1AG57473 (single-nuclei RNA-seq), U01AG32984 (genomic and whole-exome sequencing), U01AG46152 (ROSMAP AMP-AD, targeted proteomics), U01AG46161 (TMT proteomics), U01AG61356 (whole-genome sequencing, targeted proteomics, ROSMAP AMP-AD), the Illinois Department of Public Health (ROSMAP) and the Translational Genomics Research Institute (genomic). Additional phenotypic data can be requested at www.radc.rush.edu.
Funding Information:
The results presented here are, in whole or in part, based on data obtained from the AD Knowledge Portal ( https://adknowledgeportal.org ). Study data were provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center. Data collection was supported through funding by National Institute on Aging grants P30AG10161 (ROS), R01AG15819 (ROSMAP; genomics and RNA-seq), R01AG17917 (MAP), R01AG30146, R01AG36042 (5hC methylation, ATAC-seq), RC2AG036547 (H3K9Ac), R01AG36836 (RNA-seq), R01AG48015 (monocyte RNA-seq) RF1AG57473 (single-nuclei RNA-seq), U01AG32984 (genomic and whole-exome sequencing), U01AG46152 (ROSMAP AMP-AD, targeted proteomics), U01AG46161 (TMT proteomics), U01AG61356 (whole-genome sequencing, targeted proteomics, ROSMAP AMP-AD), the Illinois Department of Public Health (ROSMAP) and the Translational Genomics Research Institute (genomic). Additional phenotypic data can be requested at www.radc.rush.edu .
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
KW - Brain
KW - Genetic Predisposition to Disease/genetics
KW - Genome-Wide Association Study
KW - Humans
KW - Nervous System Diseases
KW - Polymorphism, Single Nucleotide/genetics
KW - Quantitative Trait Loci/genetics
UR - https://www.scopus.com/pages/publications/85135229265
U2 - 10.1038/s41593-022-01128-z
DO - 10.1038/s41593-022-01128-z
M3 - Article
SN - 1097-6256
VL - 25
SP - 1104
EP - 1112
JO - Nature neuroscience
JF - Nature neuroscience
IS - 8
ER -