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Lack of replication of thirteen single-nucleotide polymorphisms implicated in Parkinson's disease: a large-scale international study.

Alexis Elbaz 1 Lorene Nelson 2 Haydeh Payami 3 John Ioannidis 4 Brian Fiske 5, * Grazia Annesi 6 Andrea Carmine Belin 7 Stewart Factor 8 Carlo Ferrarese 9 Georgios Hadjigeorgiou 10 Donald Higgins 11 Hideshi Kawakami 12 Rejko Krüger 13 Karen Marder 14 Richard Mayeux 14 George Mellick 15 John Nutt 16 Beate Ritz 17 Ali Samii 18 Caroline Tanner 19 Christine van Broeckhoven 20 Stephen van den Eeden 21 Karin Wirdefeldt 22 Cyrus Zabetian 23, 24 Marie Dehem 25 Jennifer Montimurro 3 Audrey Southwick 26 Richard Myers 26 Thomas Trikalinos 4
* Corresponding author
1 Neuroépidémiologie
2 Division of Epidemiology, Department of Health Research and Policy
3 New York State Department of Health [Albany]
4 Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology
5 The Michael J Fox Foundation for Parkinson's Research
6 Institute of Neurological Sciences
7 Neuroscience Department
8 Department of Neurology
9 Department of Neuroscience-Section of Neurology
10 School of Medicine, Larissa
11 Parkinson's Disease and Movement Disorder Clinic
12 Department of Epidemiology, Research Institute for Radiation Biology and Medicine
13 Center of Neurology and Hertie-Institute for Clinical Brain Research
14 The Gertrude H Sergivesky Center
15 Eskitis Institute for Cell and Molecular Therapies
16 Department of Neurology
17 Department of Epidemiology
18 Parkinson Disease Research Education and Clinical Center
19 The Parkinson's Institute
20 Neurodegenerative Brain Diseases Group, Department of Molecular Genetics
21 Division of Research
22 MEB - Department of Medical Epidemiology and Biostatistics
23 Geriatric Research Education and Clinical Center
24 Department of Neurology
25 Genoscreen
26 Department of Genetics [Stanford]
Abstract : BACKGROUND: A genome-wide association study identified 13 single-nucleotide polymorphisms (SNPs) significantly associated with Parkinson's disease. Small-scale replication studies were largely non-confirmatory, but a meta-analysis that included data from the original study could not exclude all SNP associations, leaving relevance of several markers uncertain. METHODS: Investigators from three Michael J Fox Foundation for Parkinson's Research-funded genetics consortia-comprising 14 teams-contributed DNA samples from 5526 patients with Parkinson's disease and 6682 controls, which were genotyped for the 13 SNPs. Most (88%) participants were of white, non-Hispanic descent. We assessed log-additive genetic effects using fixed and random effects models stratified by team and ethnic origin, and tested for heterogeneity across strata. A meta-analysis was undertaken that incorporated data from the original genome-wide study as well as subsequent replication studies. FINDINGS: In fixed and random-effects models no associations with any of the 13 SNPs were identified (odds ratios 0.89 to 1.09). Heterogeneity between studies and between ethnic groups was low for all SNPs. Subgroup analyses by age at study entry, ethnic origin, sex, and family history did not show any consistent associations. In our meta-analysis, no SNP showed significant association (summary odds ratios 0.95 to 1.08); there was little heterogeneity except for SNP rs7520966. INTERPRETATION: Our results do not lend support to the finding that the 13 SNPs reported in the original genome-wide association study are genetic susceptibility factors for Parkinson's disease.
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Alexis Elbaz, Lorene Nelson, Haydeh Payami, John Ioannidis, Brian Fiske, et al.. Lack of replication of thirteen single-nucleotide polymorphisms implicated in Parkinson's disease: a large-scale international study.. The Lancet Neurology, Elsevier, 2006, 5 (11), pp.917-23. ⟨10.1016/S1474-4422(06)70579-8⟩. ⟨inserm-00177203⟩

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