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A cross-tissue transcriptome-wide association study identifies new key genes in ischemic stroke
Zhiwei Song1, Yupeng Han2, Wangyu Li3
1Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China; Department of Neurology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian, China.
Gene
|January 4, 2025
Summary
This study identified USP38 as a novel gene associated with ischemic stroke (IS) risk. Lower USP38 expression may protect against IS, offering new genetic insights into this disabling disease.
Area of Science:
- Genetics
- Neuroscience
- Cardiovascular Research
Background:
- Ischemic stroke (IS) is a leading cause of global mortality and disability.
- Investigating IS-associated genes using genome-wide association study (GWAS) data is crucial for understanding disease mechanisms.
Purpose of the Study:
- To identify novel genes associated with ischemic stroke risk using cross-tissue transcriptome-wide association study (TWAS).
- To determine the causal relationship and biological functions of identified genes in IS development.
Main Methods:
- Utilized GWAS data from 62,100 IS patients and 1,234,808 controls for TWAS analysis.
- Employed Mendelian randomization, fine-mapping (FOCUS), and functional enrichment analysis (MAGMA).
- Validated findings using Western blotting and immunofluorescence in a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model.
Main Results:
- Identified USP38 as a novel gene associated with IS risk across four TWAS methods.
- Mendelian randomization and colocalization suggested USP38 has a protective role in IS.
- Functional analysis linked IS genes to coagulation and inflammatory pathways; USP38 expression was reduced in MCAO/R mice.
Conclusions:
- USP38 is a significant gene linked to IS risk, with its expression levels correlating with IS susceptibility.
- This finding provides novel perspectives on the genetic architecture of ischemic stroke.
