Nuclear genetic modulation of tissue-specific mitochondrial RNA processing contributes to common disease risk

Mitochondrial dysfunction is widely implicated in human disease, yet whether it plays a causal role and why effects are tissue-specific remain unclear. Here, we analyse over 15,000 RNA-sequencing datasets from 49 tissue types integrated with germline genetic data to investigate the impact of mitochondrial DNA (mtDNA) transcription on disease risk. We identify 25 nuclear genetic variants associated with mtDNA transcript abundance, revealing gene- and tissue-specific regulatory architectures. We then develop tissue-specific genetic scores to predict mtDNA transcript levels and validate them in independent datasets. Applying these scores to 377,439 UK Biobank participants reveals significant associations between predicted mtDNA transcript abundance and multiple common diseases and quantitative traits, many showing marked tissue specificity, including associations with hypertension and Parkinson's disease in biologically relevant tissues. These findings provide genetic evidence that variation in mtDNA transcriptional processes contributes to complex disease biology and highlight mitochondrial RNA processing as a compelling therapeutic target.