Large-scale replication and heterogeneity in Parkinson disease genetic loci.
OBJECTIVE
Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.


METHODS
Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry.


RESULTS
In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD.


CONCLUSIONS
Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.
Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. manu.sharma@uni-tuebingen.de
Manu
M
Sharma
John P A
JP
Ioannidis
Jan O
JO
Aasly
Grazia
G
Annesi
Alexis
A
Brice
Christine
C
Van Broeckhoven
Lars
L
Bertram
Maria
M
Bozi
David
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Crosiers
Carl
C
Clarke
Maurizio
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Facheris
Matthew
M
Farrer
Gaetan
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Garraux
Suzana
S
Gispert
Georg
G
Auburger
Carles
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Vilariño-Güell
Georgios M
GM
Hadjigeorgiou
Andrew A
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Hicks
Nobutaka
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Hattori
Beom
B
Jeon
Suzanne
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Lesage
Christina M
CM
Lill
Juei-Jueng
JJ
Lin
Timothy
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Lynch
Peter
P
Lichtner
Anthony E
AE
Lang
Vincent
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Mok
Barbara
B
Jasinska-Myga
George D
GD
Mellick
Karen E
KE
Morrison
Grzegorz
G
Opala
Peter P
PP
Pramstaller
Irene
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Pichler
Sung Sup
SS
Park
Aldo
A
Quattrone
Ekaterina
E
Rogaeva
Owen A
OA
Ross
Leonidas
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Stefanis
Joanne D
JD
Stockton
Wataru
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Satake
Peter A
PA
Silburn
Jessie
J
Theuns
Eng-King
EK
Tan
Tatsushi
T
Toda
Hiroyuki
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Tomiyama
Ryan J
RJ
Uitti
Karin
K
Wirdefeldt
Zbigniew
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Wszolek
Georgia
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Xiromerisiou
Kuo-Chu
KC
Yueh
Yi
Y
Zhao
Thomas
T
Gasser
Demetrius
D
Maraganore
Rejko
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Krüger
D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide