Revealing brain cell-stratified causality through dissecting causal variants according to their cell-type-specific effects on gene expression

Ruo-Han Hao, Tian-Pei Zhang, Feng Jiang, Jun-Hui Liu, Shan-Shan Dong, Meng Li, Yan Guo () and Tie-Lin Yang ()
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Ruo-Han Hao: Xi’an Jiaotong University
Tian-Pei Zhang: Xi’an Jiaotong University
Feng Jiang: Xi’an Jiaotong University
Jun-Hui Liu: Xi’an Jiaotong University
Shan-Shan Dong: Xi’an Jiaotong University
Meng Li: The First Affiliated Hospital of Xi’an Jiaotong University
Yan Guo: Xi’an Jiaotong University
Tie-Lin Yang: Xi’an Jiaotong University

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49263-4

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