Mitochondrial DNA (mtDNA) variation has been implicated in many common complex diseases, but inconsistent and contradicting results are common. Here we introduce a novel mutational load hypothesis, which also considers the collective effect of mainly rare variants, utilising the MutPred Program. We apply this new methodology to investigate the possible role of mtDNA in two cardiovascular disease (CVD) phenotypes (hypertension and hyperglycaemia), within a two-population cohort (n = 363; mean age 45 ± 9 yrs). Very few studies have looked at African mtDNA variation in the context of complex disease, and none using complete sequence data in a well-phenotyped cohort. As such, our study will also extend our knowledge of African mtDNA variation, with complete sequences of Southern Africans being especially under-represented. The cohort showed prevalence rates for hypertension (58.6%) and prediabetes (44.8%). We could not identify a statistically significant role for mtDNA variation in association with hypertension or hyperglycaemia in our cohort. However, we are of the opinion that the method described will find wide application in the field, being especially useful for cohorts from multiple locations or with a variety of mtDNA lineages, where the traditional haplogroup association method has been particularly likely to generate spurious results in the context of association with common complex disease.

Soraya (2019) The unresolved role of mitochondrial DNA in Parkinson's disease: an overview of published studies, their limitations, and future prospects. Neurochemistry International.

Myalgic Encephalomyelitis (ME), also known as Chronic Fatigue Syndrome (CFS) is a debilitating condition. There is growing interest in a possible etiologic or pathogenic role of mitochondrial dysfunction and mitochondrial DNA (mtDNA) variation in ME/CFS. Supporting such a link, fatigue is common and often severe in patients with mitochondrial disease. We investigate the role of mtDNA variation in ME/CFS. No proven pathogenic mtDNA mutations were found. We then investigated population variation. Two cohorts were analysed, one from the UK (n = 89 moderately affected; 29 severely affected) and the other from South Africa (n = 143 moderately affected). For both cohorts, ME/CFS patients had an excess of individuals without a mildly deleterious population variant. The differences in population variation might reflect a mechanism important to the pathophysiology of ME/CFS.

SummaryCardiovascular disease (CVD) is a world-wide cause of mortality in humans and its incidence is on the rise in Africa. In this review, we discuss the putative role of mitochondrial dysfunction in the aetiology of CVD and consequently identify mitochondrial DNA (mtDNA) variation as a viable genetic risk factor to be considered. We then describe the contribution and pitfalls of several current approaches used when investigating mtDNA in relation to complex disease. We also propose an alternative approach, the adjusted mutational load hypothesis, which would have greater statistical power with cohorts of moderate size, and is less likely to be affected by population stratification. We therefore address some of the shortcomings of the current haplogroup association approach. Finally, we discuss the unique challenges faced by studies done on African populations, and recommend the most viable methods to use when investigating mtDNA variation in CVD and other common complex disease.

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