The genetic and phenotypic correlates of mtDNA copy number in a multi-ancestry cohort

Abstract

Mitochondrial DNA copy number (mtCN) is often treated as a proxy for mitochondrial (dys)function and disease risk. Pathological changes in mtCN are common symptoms of rare mitochondrial disorders but reported associations between mtCN and common diseases vary considerably across studies. We sought to understand the biology of mtCN by carrying out genome and phenome-wide association studies of mtCN in 30,666 individuals from the Penn Medicine BioBank--a large, diverse cohort of largely African and European ancestry. We estimated mtCN in peripheral blood using exome sequence data, taking into account the effects of blood cell composition, particularly neutrophil and platelet counts. We replicated known genetic associations of mtCN in the PMBB and found that their effect sizes are highly correlated between individuals of European and African ancestry. However, the heritability of mtCN was much higher among individuals of largely African ancestry (h2 = 0.3) compared to European ancestry individuals (h2 = 0.1). Admixture mapping suggests that there are undiscovered variants underlying mtCN that are differentiated in frequency between individuals with African and European ancestry. We further show that mtCN is associated with many health-related phenotypes. We discovered robust associations between mtDNA copy number and diseases of metabolically active tissues, such as cardiovascular disease and liver damage that were consistent across African and European ancestry individuals. Other associations, such as epilepsy, prostate cancer, and disorders of iron metabolism were only discovered in either individuals with European or African ancestry, but not both. Even though we replicate known genetic and phenotypic associations of mtCN, we demonstrate that they are sensitive to blood cell composition and environmental modifiers, explaining why such associations are inconsistent across studies. Peripheral blood mtCN might therefore be used as a biomarker of mitochondrial dysfunction and disease risk, but such associations must be interpreted with care.