Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease

Joelle M. Van Der Walt, Kristin K. Nicodemus, Eden R. Martin, William K. Scott, Martha A. Nance, Ray L. Watts, Jean P. Hubble, Jonathan L. Haines, William C. Koller, Kelly Lyons, Rajesh Pahwa, Matthew B. Stern, Amy Colcher, Bradley C. Hiner, Joseph Jankovic, William G. Ondo, Fred H. Allen, Christopher G. Goetz, Gary W. Small, Frank MastagliaJeffrey M. Stajich, Adam C. McLaurin, Lefkos T. Middleton, Burton L. Scott, Donald E. Schmechel, Margaret A. Pericak-Vance, Jeffery M. Vance

Research output: Contribution to journalArticle

449 Scopus citations

Abstract

Mitochondrial (mt) impairment, particularly within complex I of the electron transport system, has been implicated in the pathogenesis of Parkinson disease (PD). More than half of mitochondrially encoded polypeptides form part of the reduced nicotinamide adenine dinucleotide dehydrogenase (NADH) complex I enzyme. To test the hypothesis that mtDNA variation contributes to PD expression, we genotyped 10 single-nucleotide polymorphisms (SNPs) that define the European mtDNA haplogroups in 609 white patients with PD and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J (odds ratio [OR] 0.55; 95% confidence interval [CI] 0.34-0.91; P = .02) or K (OR 0.52; 95% CI 0.30-0.90; P = .02) demonstrated a significant decrease in risk of PD versus individuals carrying the most common haplogroup, H. Furthermore, a specific SNP that defines these two haplogroups, 10398G, is strongly associated with this protective effect (OR 0.53; 95% CI 0.39-0.73; P = .0001). SNP 10398G causes a nonconservative amino acid change from threonine to alanine within the NADH dehydrogenase 3 (ND3) of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men (OR 0.43; 95% CI 0.27-0.71; P = .0009). In addition, SNP 9055A of ATP6 demonstrated a protective effect for women (OR 0.45; 95% CI 0.22-0.93; P = .03). Our results suggest that ND3 is an important factor in PD susceptibility among white individuals and could help explain the role of complex I in PD expression.

Original languageEnglish (US)
Pages (from-to)804-811
Number of pages8
JournalAmerican journal of human genetics
Volume72
Issue number4
DOIs
StatePublished - Apr 1 2003

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Van Der Walt, J. M., Nicodemus, K. K., Martin, E. R., Scott, W. K., Nance, M. A., Watts, R. L., Hubble, J. P., Haines, J. L., Koller, W. C., Lyons, K., Pahwa, R., Stern, M. B., Colcher, A., Hiner, B. C., Jankovic, J., Ondo, W. G., Allen, F. H., Goetz, C. G., Small, G. W., ... Vance, J. M. (2003). Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease. American journal of human genetics, 72(4), 804-811. https://doi.org/10.1086/373937