Background and scientific rational
Mitochondria play a critical role in energy production through ATP synthesis, which is vital for fundamental cellular functions and key physiological processes. Mitochondrial dysfunction has been implicated in both rare inherited diseases and common diseases such as type 2 diabetes, cancer, and neurodegenerative disorders. Notably, certain mtDNA haplotypes (e.g., Haplogroup UK) have been associated with disease risk modification, such as reduced risk of ischemic stroke linked to altered metabolite levels like N-formylmethionine. All of these complex traits have been associated with genetic variants of nuclear DNA, but the combination of nuclear and mtDNA risk has not been studied in depth at scale.
Research questions
We aim to investigate whether a mismatch between nuclear and mitochondrial DNA (mtDNA) to the risk of common diseases. By examining the prevalence of nuclear-mtDNA genetic mismatch across diverse populations, we seek to understand how this phenomenon influences disease risk and key physiological traits. Additionally, we will identify the specific nuclear loci and mtDNA variants driving any observed associations, providing deeper insights into the genetic and molecular mechanisms underlying mitochondrial dysfunction in human health.
Aim and objectives
We aim to identify and characterize individuals with nuclear-mtDNA mismatch using whole genome sequencing (WGS) data. This will allow us to assess the association between nuclear-mtDNA mismatch and common diseases, encompassing both qualitative phenotypes, such as ICD-10 codes, and quantitative traits like blood pressure and HbA1c levels. Furthermore, we seek to define the nuclear loci and mtDNA variants driving these associations, providing insights for mechanistic and functional studies. Finally, we will explore the potential role of nuclear-mtDNA mismatch in accounting for missing heritability in quantitative traits.
