Given that the whole mitochondrial genome is involved in the synthesis of OXPHOS proteins, it is plausible that several rare variants could add together to compromise ATP production and thus contribute to human disease. We aim to test this hypothesis in several disease cohorts and to compare these data to the ALSPAC control cohorts. We will use NGS to determine the frequency of mtDNA variants present at MAFgreater than 1% in at least four diseases (Parkinson's disease, ischaemic stroke, sepsis and osteoarthritis) for which we have the strongest preliminary data, and then five additional human diseases where mtDNA variants have been implicated (hypertension, Type 2 diabetes, coronary artery disease, Alzheimer's disease, primary biliary cirrhosis), depending on the degree of pooling that can be reliably achieved. For each disease we will study 2000 cases, and compare the data to both control cohorts to identify 200 variants most strongly associated with each specific disease. We will use iPLEX Sequenom MassArray to individually genotype both the discovery and an equal-sized replication cohort for each disease. Individual genotyping of both the discovery and replication cohort will enable the analysis of haplotypes and/or clusters of potentially related SNPs, which is not possible for the pooled data. Our power calculation indicate that this experimental design will have greater than 80% power to detect an association at Pless than 0.0001 for a single allele at MAFgreater than 6% with a relative risk (RR) of greater than 1.6; at a MAFgreater than 1% for a RRgreater than 3