Unveiling the enigma: Investigating the controversy surrounding mitochondrial DNA copy number and gastric cancer using Mendelian randomization analysis

Gastric cancer (GC), as one of the most prevalent malignant tumors, significantly impacts individuals' health. Many studies have examined the relationship between mitochondrial DNA (mtDNA) copy number and GC. However, conclusions remain inconclusive, with conflicting findings. The genome-wide association study summary statistics for mtDNA copy number were obtained from 2 sources: one from a robust cohort of 465,809 White individuals provided by the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the UK Biobank; and the other from a dataset comprising 395,718 UK Biobank participants. In addition, a total of 5 sets of genome-wide association study summary statistics for GC were obtained through datasets from Finland, the European Bioinformatics Institute, and the Integrative Epidemiology Unit at the University of Bristol, encompassing a total of 937,663 participants. Furthermore, we undertook a 2-sample bidirectional Mendelian randomization analysis to explore the association between mtDNA copy number and GC. The Inverse variance weighted (IVW) method was primarily utilized, complemented by 4 other validation methods. Based on our comprehensive investigation, no discernible causal relationship was found between mtDNA copy number and GC in both the training and validation cohorts (IVW, P >.05). Furthermore, in the reverse Mendelian randomization analysis, no association was observed between GC and mtDNA copy number either (IVW, P >.05). Additionally, all analyses showed no evidence of horizontal pleiotropy or heterogeneity. The findings of this study provide evidence that there is no causal relationship between mtDNA copy number and GC.