Genetically prioritized mitochondrial regulators of advanced renal failure: multi-omic Mendelian randomization and biological plausibility assessment in allograft fibrosis.

BACKGROUND

Advanced renal failure remains a major global health burden. Mitochondrial dysfunction is frequently observed during progressive kidney injury and chronic allograft dysfunction (CAD), but observational data cannot distinguish causal involvement from secondary consequences. We applied a multi-omic genetic prioritization framework to evaluate whether inherited variation affecting mitochondrial gene regulation is associated with a proxy phenotype for advanced renal failure and fibrotic allograft remodeling.

METHODS

We integrated cis-mQTL (DNA methylation), cis-eQTL (gene expression), and cis-pQTL (plasma protein) data for MitoCarta3.0 genes with a UK Biobank GWAS of kidney transplant recipient status (369 cases, 397,602 controls) as a proxy endpoint for advanced renal failure. Summary-data-based Mendelian randomization (SMR; Wald ratio) was performed using a single lead cis-QTL instrument per gene per layer, with HEIDI heterogeneity testing and Bayesian colocalization to assess whether molecular QTL and outcome signals were consistent with a shared causal variant (PPH4 ≥ 0.70). Because no association survived false discovery rate (FDR) correction across the mitochondrial gene set, we used a tiered, exploratory prioritization scheme based on nominal MR evidence and colocalization. Instrument strength metrics (F-statistics and R²) are reported.

RESULTS

At a nominal threshold (p < 0.05; none surviving FDR < 0.05), we observed suggestive SMR associations in the methylation and expression layers, with generally weaker signals in the protein layer. Integrating MR evidence with colocalization support prioritized eight mitochondrial candidate genes (C20orf72/MGME1, NDUFA13, MRPS18C, MTIF3, ECHDC1, MTHFD1L, QDPR, and TST). Translational evaluation showed dysregulation of several prioritized candidates in human CAD allograft tissues and in a murine allogeneic kidney transplantation model of chronic allograft fibrosis. In TGF-β-stimulated HK-2 cells, mitochondrial dysfunction accompanied profibrotic responses, and functional perturbation supported NDUFA13 as a plausible node linking mitochondrial bioenergetics to fibrotic remodeling.

CONCLUSIONS

Given the limited number of outcome cases, the proxy nature of transplant recipient status, and no FDR-significant associations, the genetic results should be interpreted as exploratory and hypothesis-generating rather than causal proof. Nonetheless, multi-omic genetic prioritization with kidney-relevant experimental data highlights mitochondrial pathways as plausible contributors to advanced renal failure and fibrotic allograft remodeling, motivating replication in larger outcome GWAS and kidney-relevant QTL resources.