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.背景：观察性研究提示线粒体DNA拷贝数（mitochondrial DNA copy number, mtDNA-CN）与肾功能存在相关性，但二者的因果关系尚不明确。本研究采用双样本双向孟德尔随机化（Mendelian randomization, MR）分析，探究线粒体DNA拷贝数与肾功能的遗传因果关联。 方法：线粒体DNA拷贝数的全基因组关联研究（Genome-wide association study, GWAS）数据来源于英国生物样本库（UK Biobank，n=395718）；肾功能数据主要取自CKDGen联盟与FinnGen研究。本研究共采用四种孟德尔随机化分析方法：以逆方差加权法作为主要分析手段，辅以加权中位数法、MR Egger法与MR-PRESSO法开展敏感性分析；多变量孟德尔随机化（multivariable MR, MVMR）用于评估研究结果的稳健性；反向孟德尔随机化则以肾功能作为暴露因素。本研究还使用来自CHARGE英国生物样本库的额外线粒体DNA拷贝数GWAS数据（n=465809）进行验证分析。 结果：正向孟德尔随机化分析显示，遗传预测的线粒体DNA拷贝数与估算肾小球滤过率（estimated glomerular filtration rate, eGFR）呈正相关[比值比（odds ratio, OR）=1.007，95%置信区间（confidence interval, CI）1.003~1.012，P=0.003]。多变量孟德尔随机化分析显示，在校正中性粒细胞计数后，该关联的证据强度有所减弱。反向孟德尔随机化分析显示，尿白蛋白肌酐比与微量白蛋白尿与线粒体DNA拷贝数存在因果关联[尿白蛋白肌酐比：OR=0.958，95%CI 0.923~0.994，P=0.023；微量白蛋白尿：OR=0.981，95%CI 0.965~0.997，P=0.021]，但经多重检验校正后，上述关联均无统计学显著性。敏感性分析与验证分析均证实研究结果稳健可靠，且验证分析所得结果与主分析保持一致。 结论：本研究提示线粒体DNA拷贝数与估算肾小球滤过率之间存在潜在的因果关联。然而，混杂因素的影响以及与其他肾功能标志物未呈现一致关联的结果，均凸显了开展进一步研究以明确线粒体DNA拷贝数在肾功能调控中作用的必要性。