title: Comprehensive association testing of common mitochondrial DNA variation in metabolic disease.
abstract: 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.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, USA.
authors.forename: Richa
authors.initials: R
authors.lastname: Saxena
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.forename: Karyn
authors.initials: K
authors.lastname: Singer
authors.forename: Vamsi
authors.initials: V
authors.lastname: Mootha
authors.forename: Noel
authors.initials: N
authors.lastname: Burtt
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Daniel
authors.initials: D
authors.lastname: Gaudet
authors.forename: Bo
authors.initials: B
authors.lastname: Isomaa
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Ardlie
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
mesh_terms: D015992:Body Mass Index; D016022:Case-Control Studies; D004272:DNA, Mitochondrial / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D006801:Humans; D008659:Metabolic Diseases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D004272:DNA, Mitochondrial