Many lines of evidence implicate mitochondria in phenotypic variation: (a) rare mutations in
mitochondrial proteins cause metabolic, neurological, and muscular disorders; (b) alterations in oxidative phosphorylation are characteristic of
type 2 diabetes,
Parkinson disease,
Huntington disease, and other diseases; and (c) common missense variants in the mitochondrial genome (
mtDNA) have been implicated as having been subject to natural selection for adaptation to cold climates and contributing to "energy
deficiency" diseases today. To test the hypothesis that common
mtDNA variation influences human physiology and disease, we identified all 144 variants with frequency >1% in Europeans from >900 publicly available European
mtDNA sequences and selected 64 tagging single-nucleotide polymorphisms that efficiently capture all common variation (except the hypervariable D-loop). Next, we evaluated the complete set of common
mtDNA variants for association with
type 2 diabetes in a sample of 3,304 diabetics and 3,304 matched nondiabetic individuals. Association of
mtDNA variants with other metabolic traits (body mass index, measures of insulin secretion and action, blood pressure, and
cholesterol) was also tested in subsets of this sample. We did not find a significant association of common
mtDNA variants with these metabolic phenotypes. Moreover, we failed to identify any physiological effect of alleles that were previously proposed to have been adaptive for energy metabolism in human evolution. More generally, this comprehensive association-testing framework can readily be applied to other diseases for which
mitochondrial dysfunction has been implicated.