Analysis of genome-wide association studies of Alzheimer disease and of Parkinson disease to determine if these 2 diseases share a common genetic risk.
OBJECTIVE
Despite Alzheimer disease (AD) and Parkinson disease (PD) being clinically distinct entities, there is a possibility of a pathological overlap, with some genome-wide association (GWA) studies suggesting that the 2 diseases represent a biological continuum. The application of GWA studies to idiopathic forms of AD and PD have identified a number of loci that contain genetic variants that increase the risk of these disorders.


OBJECTIVE
To assess the genetic overlap between PD and AD by testing for the presence of potentially pleiotropic loci in 2 recent GWA studies of PD and AD.


METHODS
Combined GWA analysis.


METHODS
Data sets from the United Kingdom, Germany, France, and the United States.


METHODS
Thousands of patients with AD or PD and their controls.


METHODS
Meta-analysis of GWA studies of AD and PD.


METHODS
To identify evidence for potentially pleiotropic alleles that increased the risk for both PD and AD, we performed a combined PD-AD meta-analysis and compared the results with those obtained in the primary GWA studies.We also tested for a net effect of potentially polygenic alleles that were shared by both disorders by performing a polygenic score analysis. Finally, we also performed a gene-based association analysis that was aimed at detecting genes that harbor multiple disease-causing single-nucleotide polymorphisms, some of which confer a risk of PD and some a risk of AD.


RESULTS
Detailed interrogation of the single-nucleotide polymorphism, polygenic, and gene-based analyses resulted in no significant evidence that supported the presence of loci that increase the risk of both PD and AD.


CONCLUSIONS
Our findings therefore imply that loci that increase the risk of both PD and AD are not widespread and that the pathological overlap could instead be “downstream” of the primary susceptibility genes that increase the risk of each disease.
Valentina
V
Moskvina
Denise
D
Harold
GianCarlo
G
Russo
Alexey
A
Vedernikov
Manu
M
Sharma
Mohamed
M
Saad
Peter
P
Holmans
Jose M
JM
Bras
Francesco
F
Bettella
Margaux F
MF
Keller
Nayia
N
Nicolaou
Javier
J
Simón-Sánchez
J Raphael
JR
Gibbs
Claudia
C
Schulte
Alexandra
A
Durr
Rita
R
Guerreiro
Dena
D
Hernandez
Alexis
A
Brice
Hreinn
H
Stefánsson
Kari
K
Majamaa
Thomas
T
Gasser
Peter
P
Heutink
Nick
N
Wood
Maria
M
Martinez
Andrew B
AB
Singleton
Michael A
MA
Nalls
John
J
Hardy
Michael J
MJ
Owen
Michael C
MC
O'Donovan
Julie
J
Williams
Huw R
HR
Morris
Nigel M
NM
Williams
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D016208:Databases, Factual / Q000706:statistics & numerical data; D005060:Europe; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D014481:United States