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 Jr; Christopher G Goetz; Gary W Small; Frank Mastaglia; Jeffrey M Stajich; Adam C McLaurin; Lefkos T Middleton; Burton L Scott; Donald E Schmechel; Margaret A Pericak-Vance; Jeffery M Vance

doi:10.1086/373937

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Mitochondrial Polymorphisms Significantly Reduce the Risk of Parkinson Disease

Journal article

Open access

Peer reviewed

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, …

American journal of human genetics, Vol.72(4), pp.804-811

2003-04

DOI: https://doi.org/10.1086/373937

PMCID: PMC1180345

PMID: 12618962

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.

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.197 Molecular & Cell Biology - Mitochondria; 1.197.564 Mitochondrial DNA
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Title: Mitochondrial Polymorphisms Significantly Reduce the Risk of Parkinson Disease
Creators: Joelle M van der Walt - Department of Medicine, and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC
Kristin K Nicodemus - Department of Medicine, and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC
Eden R Martin - Department of Medicine, and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC
William K Scott - Department of Medicine, and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC
Martha A Nance - Struthers Parkinson Center, Golden Valley, MN
Ray L Watts - Department of Neurology, Emory University School of Medicine, Atlanta
Jean P Hubble - Department of Neurology, Ohio State University, Columbus, OH
Jonathan L Haines - Program in Human Genetics, Vanderbilt University Medical Center, Nashville, TN
William C Koller - Department of Neurology, University of Miami School of Medicine, Miami
Kelly Lyons - Department of Neurology, University of Miami School of Medicine, Miami
Rajesh Pahwa - Department of Neurology, University of Kansas Medical Center, Kansas City, KS
Matthew B Stern - Department of Neurology, University of Pennsylvania Health System, Philadelphia
Amy Colcher - Department of Neurology, University of Pennsylvania Health System, Philadelphia
Bradley C Hiner - Department of Neurology, Marshfield Clinic, Marshfield, WI
Joseph Jankovic - Department of Neurology, Baylor College of Medicine, Houston
William G Ondo - Department of Neurology, Baylor College of Medicine, Houston
Fred H Allen Jr - Carolina Neurologic Clinic, Charlotte, NC
Christopher G Goetz - Department of Neurological Sciences, Rush-Presbyterian–St. Luke’s Hospital, Chicago; Departments of Psychiatry and Biobehavioral Science and Neurology, University of California, Los Angeles
Gary W Small - Department of Neurological Sciences, Rush-Presbyterian–St. Luke’s Hospital, Chicago; Departments of Psychiatry and Biobehavioral Science and Neurology, University of California, Los Angeles
Frank Mastaglia - Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, Australia
Jeffrey M Stajich - Department of Medicine, and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC
Adam C McLaurin - Department of Medicine, and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC
Lefkos T Middleton - GlaxoSmithKline Research and Development, Greenford, United Kingdom
Burton L Scott - Struthers Parkinson Center, Golden Valley, MN
Donald E Schmechel - Department of Medicine, and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC
Margaret A Pericak-Vance - Department of Medicine, and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC
Jeffery M Vance - Department of Medicine, and Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC
Publication Details: American journal of human genetics, Vol.72(4), pp.804-811
Publisher: Elsevier Inc
Academic Unit: Miller School of Medicine; John P. Hussman Institute for Human Genomics; UMMG Dept of Human Genetics - Clinical and Translational Genetics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 12618962
PMCID: PMC1180345
Record Identifier: 991031559699202976