Non-replication of association for six polymorphisms from meta-analysis of genome-wide association studies of Parkinson's disease: large-scale collaborative study.
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.
Evangelou
Evangelos
E
Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
Maraganore
Demetrius M
DM
Annesi
Grazia
G
Brighina
Laura
L
Brice
Alexis
A
Elbaz
Alexis
A
Ferrarese
Carlo
C
Hadjigeorgiou
Georgios M
GM
Krueger
Rejko
R
Lambert
Jean-Charles
JC
Lesage
Suzanne
S
Markopoulou
Katerina
K
Mellick
George D
GD
Meeus
Bram
B
Pedersen
Nancy L
NL
Quattrone
Aldo
A
Van Broeckhoven
Christine
C
Sharma
Manu
M
Silburn
Peter A
PA
Tan
Eng-King
EK
Wirdefeldt
Karin
K
Ioannidis
John P A
JP
D055106:Genome-Wide Association Study; D006801:Humans; D010300:Parkinson Disease / Q000235:genetics*; D011110:Polymorphism, Genetic