Analysis of genome-wide association studies of alzheimer disease and of parkinson disease to determine if these 2 diseases share a common genetic risk

Valentina Moskvina, Denise Harold, Gian Carlo Russo, Alexey Vedernikov, Manu Sharma, Mohamad Saad, Peter Holmans, Jose M. Bras, Francesco Bettella, Margaux F. Keller, Nayia Nicolaou, Javier Simón-Sánchez, J. Raphael Gibbs, Claudia Schulte, Alexandra Durr, Rita Guerreiro, Dena Hernandez, Alexis Brice, Hreinn Stefánsson, Kari Majamaa & 12 others Thomas Gasser, Peter Heutink, Nick Wood, Maria Martinez, Andrew B. Singleton, Michael A. Nalls, John Hardy, Michael J. Owen, Michael C. O'Donovan, Julie Williams, Huw R. Morris, Nigel M. Williams

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Importance 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. DESIGN Combined GWA analysis. SETTING Data sets from the United Kingdom, Germany, France, and the United States. Participants Thousands of patients with AD or PD and their controls. Main Outcomes and Measures 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 and Relevance 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.

Original languageEnglish
Pages (from-to)1268-1276
Number of pages9
JournalJAMA Neurology
Volume70
Issue number10
DOIs
Publication statusPublished - 1 Jan 2013
Externally publishedYes

Fingerprint

Genome-Wide Association Study
Parkinson Disease
Alzheimer Disease
Genes
Single Nucleotide Polymorphism
Meta-Analysis
Alleles
Genetic Loci
France
Germany
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Analysis of genome-wide association studies of alzheimer disease and of parkinson disease to determine if these 2 diseases share a common genetic risk. / Moskvina, Valentina; Harold, Denise; Russo, Gian Carlo; Vedernikov, Alexey; Sharma, Manu; Saad, Mohamad; Holmans, Peter; Bras, Jose M.; Bettella, Francesco; Keller, Margaux F.; Nicolaou, Nayia; Simón-Sánchez, Javier; Raphael Gibbs, J.; Schulte, Claudia; Durr, Alexandra; Guerreiro, Rita; Hernandez, Dena; Brice, Alexis; Stefánsson, Hreinn; Majamaa, Kari; Gasser, Thomas; Heutink, Peter; Wood, Nick; Martinez, Maria; Singleton, Andrew B.; Nalls, Michael A.; Hardy, John; Owen, Michael J.; O'Donovan, Michael C.; Williams, Julie; Morris, Huw R.; Williams, Nigel M.

In: JAMA Neurology, Vol. 70, No. 10, 01.01.2013, p. 1268-1276.

Research output: Contribution to journalArticle

Moskvina, V, Harold, D, Russo, GC, Vedernikov, A, Sharma, M, Saad, M, Holmans, P, Bras, JM, Bettella, F, Keller, MF, Nicolaou, N, Simón-Sánchez, J, Raphael Gibbs, J, Schulte, C, Durr, A, Guerreiro, R, Hernandez, D, Brice, A, Stefánsson, H, Majamaa, K, Gasser, T, Heutink, P, Wood, N, Martinez, M, Singleton, AB, Nalls, MA, Hardy, J, Owen, MJ, O'Donovan, MC, Williams, J, Morris, HR & Williams, NM 2013, 'Analysis of genome-wide association studies of alzheimer disease and of parkinson disease to determine if these 2 diseases share a common genetic risk', JAMA Neurology, vol. 70, no. 10, pp. 1268-1276. https://doi.org/10.1001/jamaneurol.2013.448
Moskvina, Valentina ; Harold, Denise ; Russo, Gian Carlo ; Vedernikov, Alexey ; Sharma, Manu ; Saad, Mohamad ; Holmans, Peter ; Bras, Jose M. ; Bettella, Francesco ; Keller, Margaux F. ; Nicolaou, Nayia ; Simón-Sánchez, Javier ; Raphael Gibbs, J. ; Schulte, Claudia ; Durr, Alexandra ; Guerreiro, Rita ; Hernandez, Dena ; Brice, Alexis ; Stefánsson, Hreinn ; Majamaa, Kari ; Gasser, Thomas ; Heutink, Peter ; Wood, Nick ; Martinez, Maria ; Singleton, Andrew B. ; Nalls, Michael A. ; Hardy, John ; Owen, Michael J. ; O'Donovan, Michael C. ; Williams, Julie ; Morris, Huw R. ; Williams, Nigel M. / Analysis of genome-wide association studies of alzheimer disease and of parkinson disease to determine if these 2 diseases share a common genetic risk. In: JAMA Neurology. 2013 ; Vol. 70, No. 10. pp. 1268-1276.
@article{af9d338298e246aa91bc9443f018bb36,
title = "Analysis of genome-wide association studies of alzheimer disease and of parkinson disease to determine if these 2 diseases share a common genetic risk",
abstract = "Importance 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. DESIGN Combined GWA analysis. SETTING Data sets from the United Kingdom, Germany, France, and the United States. Participants Thousands of patients with AD or PD and their controls. Main Outcomes and Measures 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 and Relevance 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.",
author = "Valentina Moskvina and Denise Harold and Russo, {Gian Carlo} and Alexey Vedernikov and Manu Sharma and Mohamad Saad and Peter Holmans and Bras, {Jose M.} and Francesco Bettella and Keller, {Margaux F.} and Nayia Nicolaou and Javier Sim{\'o}n-S{\'a}nchez and {Raphael Gibbs}, J. and Claudia Schulte and Alexandra Durr and Rita Guerreiro and Dena Hernandez and Alexis Brice and Hreinn Stef{\'a}nsson and Kari Majamaa and Thomas Gasser and Peter Heutink and Nick Wood and Maria Martinez and Singleton, {Andrew B.} and Nalls, {Michael A.} and John Hardy and Owen, {Michael J.} and O'Donovan, {Michael C.} and Julie Williams and Morris, {Huw R.} and Williams, {Nigel M.}",
year = "2013",
month = "1",
day = "1",
doi = "10.1001/jamaneurol.2013.448",
language = "English",
volume = "70",
pages = "1268--1276",
journal = "JAMA Neurology",
issn = "2168-6149",
publisher = "American Medical Association",
number = "10",

}

TY - JOUR

T1 - Analysis of genome-wide association studies of alzheimer disease and of parkinson disease to determine if these 2 diseases share a common genetic risk

AU - Moskvina, Valentina

AU - Harold, Denise

AU - Russo, Gian Carlo

AU - Vedernikov, Alexey

AU - Sharma, Manu

AU - Saad, Mohamad

AU - Holmans, Peter

AU - Bras, Jose M.

AU - Bettella, Francesco

AU - Keller, Margaux F.

AU - Nicolaou, Nayia

AU - Simón-Sánchez, Javier

AU - Raphael Gibbs, J.

AU - Schulte, Claudia

AU - Durr, Alexandra

AU - Guerreiro, Rita

AU - Hernandez, Dena

AU - Brice, Alexis

AU - Stefánsson, Hreinn

AU - Majamaa, Kari

AU - Gasser, Thomas

AU - Heutink, Peter

AU - Wood, Nick

AU - Martinez, Maria

AU - Singleton, Andrew B.

AU - Nalls, Michael A.

AU - Hardy, John

AU - Owen, Michael J.

AU - O'Donovan, Michael C.

AU - Williams, Julie

AU - Morris, Huw R.

AU - Williams, Nigel M.

PY - 2013/1/1

Y1 - 2013/1/1

N2 - Importance 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. DESIGN Combined GWA analysis. SETTING Data sets from the United Kingdom, Germany, France, and the United States. Participants Thousands of patients with AD or PD and their controls. Main Outcomes and Measures 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 and Relevance 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.

AB - Importance 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. DESIGN Combined GWA analysis. SETTING Data sets from the United Kingdom, Germany, France, and the United States. Participants Thousands of patients with AD or PD and their controls. Main Outcomes and Measures 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 and Relevance 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.

UR - http://www.scopus.com/inward/record.url?scp=84885781056&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84885781056&partnerID=8YFLogxK

U2 - 10.1001/jamaneurol.2013.448

DO - 10.1001/jamaneurol.2013.448

M3 - Article

VL - 70

SP - 1268

EP - 1276

JO - JAMA Neurology

JF - JAMA Neurology

SN - 2168-6149

IS - 10

ER -