Revealing brain cell-stratified causality through dissecting causal variants according to their cell-type-specific effects on gene expression.
Nat Commun
; 15(1): 4890, 2024 Jun 07.
Article
em En
| MEDLINE
| ID: mdl-38849352
ABSTRACT
The human brain has been implicated in the pathogenesis of several complex diseases. Taking advantage of single-cell techniques, genome-wide association studies (GWAS) have taken it a step further and revealed brain cell-type-specific functions for disease loci. However, genetic causal associations inferred by Mendelian randomization (MR) studies usually include all instrumental variables from GWAS, which hampers the understanding of cell-specific causality. Here, we developed an analytical framework, Cell-Stratified MR (csMR), to investigate cell-stratified causality through colocalizing GWAS signals with single-cell eQTL from different brain cells. By applying to obesity-related traits, our results demonstrate the cell-type-specific effects of GWAS variants on gene expression, and indicate the benefits of csMR to identify cell-type-specific causal effect that is often hidden from bulk analyses. We also found csMR valuable to reveal distinct causal pathways between different obesity indicators. These findings suggest the value of our approach to prioritize target cells for extending genetic causation studies.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Encéfalo
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Polimorfismo de Nucleotídeo Único
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Locos de Características Quantitativas
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Estudo de Associação Genômica Ampla
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Análise da Randomização Mendeliana
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Obesidade
Limite:
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article