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 C. Foo,Eduard Urich,Ward A. Ortmann,Victor A. Iglesias,Suresh Selvaraj,Erik Nutma,Manuel C. Marzin,Sandra Amor,Anna Williams,Gonçalo Castelo-Branco,Vilas Menon,Philip L. De Jager,Dheeraj Malhotra +15 more
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TLDR
This article 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, and identified 7,607 eGenes, a substantial fraction (46%, 3,537/7,607) of which show cell-type-specific effects with strongest effects in microglia.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. 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. read more
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The missing link between genetic association and regulatory function
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TL;DR: The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations, and has reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-generation sequencing, deep exome sequencing, and dense microarray genotyping.
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