title: Non-replication of association for six polymorphisms from meta-analysis of genome-wide association studies of Parkinson's disease: large-scale collaborative study.
abstract: Early genome-wide association (GWA) studies on Parkinson's disease (PD) have not been able to yield conclusive, replicable signals of association, perhaps due to limited sample size. We aimed to investigate whether association signals derived from the meta-analysis of the first two GWA investigations might be replicable in different populations. We examined six single-nucleotide polymorphisms (SNPs) (rs1000291, rs1865997, rs2241743, rs2282048, rs2313982, and rs3018626) that had reached nominal significance with at least two of three different strategies proposed in a previous analysis of the original GWA studies. Investigators from the "Genetic Epidemiology of Parkinson's Disease" (GEOPD) consortium were invited to join in this study. Ten teams contributed replication data from 3,458 PD cases and 3,719 controls. The data from the two previously published GWAs (599 PD cases, 592 controls and 443 sibling pairs) were considered as well. All data were synthesized using both fixed and random effects models. The summary allelic odds ratios were ranging from 0.97 to 1.09 by random effects, when all data were included. The summary estimates of the replication data sets (excluding the original GWA data) were very close to 1.00 (range 0.98-1.09) and none of the effects were nominally statistically significant. The replication data sets had significantly different results than the GWA data. Our data do not support evidence that any of these six SNPs reflect susceptibility markers for PD. Much stronger signals of statistical significance in GWA platforms are needed to have substantial chances of replication. Specifically in PD genetics, this would require much larger GWA studies and perhaps novel analytical techniques.
authors.affiliation: Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Evangelou
authors.forename: Demetrius M
authors.initials: DM
authors.lastname: Maraganore
authors.forename: Grazia
authors.initials: G
authors.lastname: Annesi
authors.forename: Laura
authors.initials: L
authors.lastname: Brighina
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Alexis
authors.initials: A
authors.lastname: Elbaz
authors.forename: Carlo
authors.initials: C
authors.lastname: Ferrarese
authors.forename: Georgios M
authors.initials: GM
authors.lastname: Hadjigeorgiou
authors.forename: Rejko
authors.initials: R
authors.lastname: Krueger
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Lambert
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lesage
authors.forename: Katerina
authors.initials: K
authors.lastname: Markopoulou
authors.forename: George D
authors.initials: GD
authors.lastname: Mellick
authors.forename: Bram
authors.initials: B
authors.lastname: Meeus
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Pedersen
authors.forename: Aldo
authors.initials: A
authors.lastname: Quattrone
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: Manu
authors.initials: M
authors.lastname: Sharma
authors.forename: Peter A
authors.initials: PA
authors.lastname: Silburn
authors.forename: Eng-King
authors.initials: EK
authors.lastname: Tan
authors.forename: Karin
authors.initials: K
authors.lastname: Wirdefeldt
authors.forename: John P A
authors.initials: JP
authors.lastname: Ioannidis
mesh_terms: D055106:Genome-Wide Association Study; D006801:Humans; D010300:Parkinson Disease / Q000235:genetics*; D011110:Polymorphism, Genetic