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Comprehensive association testing of common mitochondrial DNA variation in metabolic disease

Saxena, R ; de Bakker, PIW ; Singer, K ; Mootha, V ; Burtt, N ; Hirschhorn, JN ; Gaudet, D ; Isomaa, B ; Daly, MJ and Groop, Leif LU , et al. (2006) In American Journal of Human Genetics 79(1). p.54-61
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
American Journal of Human Genetics
volume
79
issue
1
pages
54 - 61
publisher
Cell Press
external identifiers
  • pmid:16773565
  • wos:000238341200006
  • scopus:33745273048
ISSN
0002-9297
language
English
LU publication?
yes
id
1c812e98-5a9e-4258-a53d-01ec23bd447f (old id 406349)
alternative location
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1474138&rendertype=abstract
date added to LUP
2016-04-01 11:42:28
date last changed
2020-07-29 02:09:17
@article{1c812e98-5a9e-4258-a53d-01ec23bd447f,
  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.},
  author       = {Saxena, R and de Bakker, PIW and Singer, K and Mootha, V and Burtt, N and Hirschhorn, JN and Gaudet, D and Isomaa, B and Daly, MJ and Groop, Leif and Ardlie, KG and Altshuler, D},
  issn         = {0002-9297},
  language     = {eng},
  number       = {1},
  pages        = {54--61},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {Comprehensive association testing of common mitochondrial DNA variation in metabolic disease},
  url          = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1474138&rendertype=abstract},
  volume       = {79},
  year         = {2006},
}