A cross-tissue transcriptome-wide association study identifies new key genes in ischemic stroke

Zhiwei Song; Yupeng Han; Wangyu Li; Yiya Xu; Yingchao He; Yinzhou Wang

doi:10.1016/j.gene.2024.149207

A cross-tissue transcriptome-wide association study identifies new key genes in ischemic stroke

Gene. 2025 Jan 2:149207. doi: 10.1016/j.gene.2024.149207. Online ahead of print.

Authors

Zhiwei Song¹, Yupeng Han², Wangyu Li³, Yiya Xu¹, Yingchao He¹, Yinzhou Wang⁴

Affiliations

¹ Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China; Department of Neurology, Fujian Provincial Hospital, Fuzhou, Fujian, China.
² Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China; Department of Anesthesiology, Fujian Provincial Hospital, Shengli Clinical Medical College.
³ Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China; Department of Pain Management, Fujian Provincial Hospital, Fuzhou, Fujian, China.
⁴ Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China; Department of Neurology, Fujian Provincial Hospital, Fuzhou, Fujian, China; Fujian Key Laboratory of Medical Analysis, Fujian Academy of Medical Sciences, Fuzhou, Fujian, China. Electronic address: yinzhouw@163.com.

PMID: 39755263
DOI: 10.1016/j.gene.2024.149207

Abstract

Background: Ischemic stroke (IS) is an important disease causing death and disability worldwide, and further investigation of IS-related genes through genome-wide association study (GWAS) data is valuable.

Methods: The study included GWAS data from 62,100 IS patients of European origin and 1,234,808 controls in a cross-tissue transcriptome association study (TWAS). A joint analysis was first performed by the Unified Test for Molecular Markers (UTMOST) and FUSION methods. The results of the joint analysis were also validated by fine-mapping through FOCUS. Mendelian randomisation analysis was performed to determine whether the obtained genes were causally related to IS. Genome Annotated Multiple Marker Analysis (MAGMA) explored which biological functions the genes associated with IS. We used Coloc to co-localise GWAS and eQTL of the genes. We also biologically validated the results by Western blotting and immunofluorescence staining in the middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model.

Results: Four TWAS methods identified only one new susceptibility gene (USP38) associated with IS risk. Mendelian randomization and colocalization analysis found that USP38 may be protective against IS development. Functional enrichment analysis indicated IS-related genes were mainly associated with the intrinsic fibrinogen activation, acute myocardial infarction, exogenous fibrinogen activation, coagulation cascade response, TNF signalling pathway and GRB2 signalling pathway. Western blotting and immunofluorescence staining demonstrated a reduction in USP38 expression in MCAO/R mice.

Conclusion: Our research indicates that USP38 is an essential gene related to IS, with its expression strongly connected with IS risk, thus providing new perspectives on the genetic framework of IS.

Keywords: FOCUS; FUSION; Fine-mapping; Ischemic Stroke; TWAS.