Mitochondrial-Related Pathogenic Genes in Systemic Lupus Erythematosus: A Multi-Omics Mendelian Randomization Study

Abstract

Background: Recent studies have emphasized a significant connection between mitochondrial function and systemic lupus erythematosus (SLE). However, the specific genes involved and their underlying mechanisms remain unknown. Herein, we used Summary data-based Mendelian randomization (SMR) to identify putative causal effects and underlying mechanisms of mitochondrial genes in SLE.

Methods: SMR analyses were employed to explore the causal associations between 1,136 mitochondrial-related genes, sourced from the MitoCarta3.0 database, and SLE. This was achieved through the integration of blood-based methylation quantitative trait loci (mQTL), expression quantitative trait loci (eQTL), and protein quantitative trait loci (pQTL) data with SLE genome-wide association studies (GWAS) data. Colocalization analyses were conducted to identify genetic variants that are shared between traits. The initial discovery phase utilized data from the GCST003156 dataset, followed by validation using the ieu-a-815 and FinGen data sets.

Findings: Through SMR and colocalization screening, we identified 140 methylation sites (79 genes), 40 genes expression, and 7 proteins abundance were associated with SLE. Two methylation sites corresponding toACOT7 were verified in the ieu-a-815 cohort, and high expression of this gene was positively associated with the risk of SLE. 12 methylation sites and 10 gene expressions played key roles through the integration of mQTLs and eQTLs. Among these genes, 3 genes (COMTD1, OXNAD1 and RPUSD4) had strong evidence for colocalization. Notably, MSRA was a intersection gene in the results of mQTL, eQTL and pQTL, and this gene is inversely associated with SLE risk.

Interpretation: We employed a multi-omics Mendelian randomization approach and identified ACOT7, MSRA, COMTD1, OXNAD1, and RPUSD4 as key mitochondrial genes likely involved in the pathogenesis of SLE. These findings may provide a novel foundation for the early prevention and treatment of SLE.

Funding: This study was supported by the Basic Scientific Research Project of The Educational Department of Liaoning province in 2022 (Grant No.LJKMZ20221183).

Declaration of Interest: The authors declare that they have no competing interests.

Keywords: mitochondrial, systemic lupus erythematosus, multi-omics, Mendelian randomization analysis, colocalization