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 MajamaaThomas 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

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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 - Oct 2013

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ASJC Scopus subject areas

  • Clinical Neurology

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Moskvina, V., Harold, D., Russo, G. C., Vedernikov, A., Sharma, M., Saad, M., Holmans, P., Bras, J. M., Bettella, F., Keller, M. F., Nicolaou, N., Simón-Sánchez, J., Raphael Gibbs, J., Schulte, C., Durr, A., Guerreiro, R., Hernandez, D., Brice, A., Stefánsson, H., ... Williams, N. M. (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, 70(10), 1268-1276. https://doi.org/10.1001/jamaneurol.2013.448