Genetic association between mitochondrial DNA copy number and glioma risk: insights from causality.

Background: The genetic causal association between the mitochondrial DNA copy number (mtDNA-CN) and the development of glioma and glioblastoma (GBM) remains unclear.

Methods: The summary-level datasets for mtDNA-CN were obtained from participants in the UK Biobank and the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. Additionally, summary statistics datasets related to glioma were collected from a comprehensive meta-analysis genome-wide association study, which included 12,488 cases and 18,169 controls. The main method employed was inverse variance weighting, supplemented by Bonferroni correction to account for multiple tests. Additionally, sensitivity analyses were performed to address potential pleiotropy and strengthen the reliability of the results.

Results: In the primary analysis, no genetic causal association was found between mtDNA-CN and glioma (OR = 1.20, 95%CI = 0.94-1.52, P = 0.1394), nor with low-grade glioma (OR = 1.09, 95%CI = 0.79-1.51, P = 0.5588). However, a suggestive genetic relationship between mtDNA-CN and glioblastoma was observed (OR = 1.42, 95%CI = 1.02-1.96, P = 0.0347). These findings were replicated in the MR analysis. Comprehensive analyses, including heterogeneity and pleiotropy analyses, as well as reverse analysis, confirmed the robustness of these results.

Conclusion: Our MR study did not find a genetic causal association between mtDNA-CN and the risk of glioma. A suggestive causal association between GBM and mtDNA-CN was detected.