TY - JOUR
T1 - Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease
AU - Van Der Walt, Joelle M.
AU - Nicodemus, Kristin K.
AU - Martin, Eden R.
AU - Scott, William K.
AU - Nance, Martha A.
AU - Watts, Ray L.
AU - Hubble, Jean P.
AU - Haines, Jonathan L.
AU - Koller, William C.
AU - Lyons, Kelly
AU - Pahwa, Rajesh
AU - Stern, Matthew B.
AU - Colcher, Amy
AU - Hiner, Bradley C.
AU - Jankovic, Joseph
AU - Ondo, William G.
AU - Allen, Fred H.
AU - Goetz, Christopher G.
AU - Small, Gary W.
AU - Mastaglia, Frank
AU - Stajich, Jeffrey M.
AU - McLaurin, Adam C.
AU - Middleton, Lefkos T.
AU - Scott, Burton L.
AU - Schmechel, Donald E.
AU - Pericak-Vance, Margaret A.
AU - Vance, Jeffery M.
N1 - Funding Information:
We are grateful to the families who participated in this study. We also thank the personnel at the Center for Human Genetics, Institute for Genome Sciences and Policy, Duke University Medical Center, for excellent clinical, technical, and administrative support. This research was supported, in part, by NIH program project grants 2 P50 NS39764-02 and P01 NS26630, National Institute on Aging grant 1R01-AG-20135-01, the McKnight Foundation (McKnight Neuroscience of Brain Disorders Award), and GlaxoSmithKline. J.M.vdW. is supported by a postdoctoral fellowship award from the American Parkinson’s Disease Association.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2003/4/1
Y1 - 2003/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0037385480&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037385480&partnerID=8YFLogxK
U2 - 10.1086/373937
DO - 10.1086/373937
M3 - Article
C2 - 12618962
AN - SCOPUS:0037385480
VL - 72
SP - 804
EP - 811
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 4
ER -