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Original Investigation |

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, PhD1; Denise Harold, PhD1; GianCarlo Russo, PhD1; Alexey Vedernikov, MSc1; Manu Sharma, PhD2; Mohamad Saad3,4; Peter Holmans, PhD1; Jose M. Bras, PhD5; Francesco Bettella, PhD6; Margaux F. Keller, BS7; Nayia Nicolaou, MSc8; Javier Simón-Sánchez, PhD8; J. Raphael Gibbs, MS5,7; Claudia Schulte, PhD2,9; Alexandra Durr, MD, PhD3,10,11; Rita Guerreiro, PhD5; Dena Hernandez, MS5,7; Alexis Brice, MD, PhD10,11,12,13; Hreinn Stefánsson, PhD6; Kari Majamaa, MD, PhD14; Thomas Gasser, MD, PhD2,9; Peter Heutink, PhD8; Nick Wood, PhD, FRCP, FMedSci5,15; Maria Martinez, PhD3,4; Andrew B. Singleton, PhD7; Michael A. Nalls, PhD7; John Hardy, PhD5; Michael J. Owen, PhD, FRCPsych, FMedSci1; Michael C. O’Donovan, FRCPsych, PhD1; Julie Williams, PhD1; Huw R. Morris, PhD, FRCP1; Nigel M. Williams, PhD1 ; for the IPDGC and GERAD Investigators
[+] Author Affiliations
1Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Wales
2Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, and Insitute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Germany
3Institut National de la Sante et de la Recherche Medicale, UMR 1043, Centre de Physiopathologie de Toulouse–Purpan, Toulouse, France
4Paul Sabatier University, Toulouse, France
5Department of Molecular Neuroscience, Institute of Neurology, University College London, England
6deCODE Genetics, Scientific Services, Reykjavik Iceland
7Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland
8Department of Clinical Genetics, Section of Medical Genomics, VU University Medical Centre, Amsterdam, the Netherlands
9German Center for Neurodegenerative Diseases, Tübingen, Germany
10Université Pierre et Marie Curie-Paris, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, UMR S975, Paris, France
11Assistance Publique Hôpitaux de Paris, Hôpital de la Salpêtrière, Département de Génétique, France
12Institut National de la Sante et de la Recherche Medicale, Paris, France
13Centre National de la Recherche Scientifique, UMR 7225, Paris, France
14Department of Neurology, Institute of Clinical Medicine, University of Oulu, Finland
15University College London Genetics Institute, London, England
JAMA Neurol. 2013;70(10):1268-1276. doi:10.1001/jamaneurol.2013.448.
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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.

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Comparison of the Association Signals in the Combined Genome-Wide Association (GWA) Analysis With the Lowest Signals in the Primary GWA Studies

The association signals are compared in terms of the difference in −log10P values: −log10 (combined PD-AD P value) − −log10 [min(AD GWA P value, PD GWA P value)], where AD indicates Alzheimer disease and PD indicates Parkinson disease. Only single-nucleotide polymorphisms (SNPs) that were genome-wide significant SNPs in either the PD GWA study15 or the AD GWA study9 were included.

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