Mitochondrial DNA copy number as a genetic determinant of renal function: insights from bidirectional Mendelian randomization

Background: Observational studies suggest a correlation between mitochondrial DNA copy number (mtDNA-CN) and renal function; however, the causality remains uncertain. This study employed a two-sample bidirectional Mendelian randomization (MR) analysis to investigate the genetic causal relationship between mtDNA-CN and renal function. Methods: Genome-wide association study (GWAS) data for mtDNA-CN were obtained from the UK Biobank (n = 395,718), with renal function data primarily sourced from the CKDGen consortium and FinnGen studies. Four MR methods were employed, using inverse variance weighting as the primary approach, complemented by weighted median, MR Egger, and MR-PRESSO for sensitivity analyses. Multivariable MR (MVMR) assessed result robustness. Reverse MR treated renal function as the exposure. Validation was performed using additional mtDNA-CN GWAS data from the CHARGE UK Biobank (n = 465,809). Results: Forward MR analysis demonstrated a positive association between genetically predicted mtDNA-CN and estimated glomerular filtration rate (eGFR) odds ratio (OR) = 1.007, 95% CI 1.003-1.012, p = 0.003. MVMR suggested weaker evidence after adjusting for neutrophil count. Reverse MR revealed causal associations of urinary albumin-creatinine ratio (OR = 0.958, 0.923-0.994, p = 0.023) and microalbuminuria (OR = 0.981, 0.965-0.997, p = 0.021) with mtDNA-CN, though these effects were non-significant after multiple testing correction. Sensitivity and validation analyses confirmed robust. The findings from validation analyses were consistent. Conclusion: Our study suggests a potential causal association between mtDNA-CN and eGFR. However, the impact of confounding factors and the absence of consistent associations with other renal function markers underscore the necessity for further research to clarify the role of mtDNA-CN in renal function.