Shared genetic contribution to ischemic stroke and Alzheimer's disease

Matthew Traylor, Poneh Adib-Samii, Denise Harold, Martin Dichgans, Julie Williams, Cathryn M. Lewis, Hugh S. Markus, Myriam Fornage, Elizabeth G. Holliday, Pankaj Sharma, Joshua Bis, Bruce M. Psaty, Sudha Seshadri, Mike A. Nalls, William Devan, Giorgio Battista Boncoraglio, Rainer Malik, Braxton D. Mitchell, Steve J. Kittner, M. Arfan IkramR. Clarke, Jonathan Rosand, James Meschia, Cathie Sudlow, Peter M. Rothwell, Christopher Levi, Steve Bevan, Laura L. Kilarski, Matthew Walters, Vincent Thijs, Agnieszka Slowik, Arne Lindgren, P. I W De Bakker, Jean Charles Lambert, Carla A. Ibrahim-Verbaas, Adam C. Naj, Rebecca Sims, Céline Bellenguez, G. Jun, Anita L. DeStefano, Gary W. Beecham, B. Grenier-Boley, Giancarlo Russo, Tricia A. Thornton-Wells, Nicola Jones, Albert V. Smith, Vincent Chouraki, Charlene Thomas, Diana Zelenika, Badri N. Vardarajan, Yoichiro Kamatani, Chiao Feng Lin, Amy Gerrish, Helena Schmidt, Brian W. Kunkle, Melanie L. Dunstan, Agustín Ruiz, Marie Thçrèse Bihoreau, Seung Hoan Choi, C. Reitz, F. Pasquier, Paul Hollingworth, Alfredo Ramirez, Olivier Hanon, Annette L. Fitzpatrick, Joseph D. Buxbaum, Dominique Campion, Paul K. Crane, Clinton Baldwin, Tim Becker, Vilmundur Gudnason, Carlos Cruchaga, David W. Craig, Najaf Amin, C. Berr, Oscar L. Lopez, Philip de Jager, Vincent Deramecourt, Janet A. Johnston, Denis Evans, Simon Lovestone, Luc Letenneur, Francisco J. Morón, D. C. Rubinsztein, Gudny Eiriksdottir, Kristel Sleegers, Alison M. Goate, Nathalie Fiçvet, Matthew J. Huentelman, Michael Gill, Kristelle S. Brown, M. Ilyas Kamboh, Lina Keller, Pascale Barberger-Gateau, Bernadette M. McGuinness, Eric B. Larson, Robert C. Green, Amanda J. Myers, Carole Dufouil, Stephen Todd, David Wallon, Seth Love, E. Rogaeva, J. Gallacher, P. H. St. George-Hyslop, Jordi Clarimon, Alberto Lleó, Anthony Bayer, Debby W. Tsuang, Lei Yu, Magda Tsolaki, Paola Bossù, Gianfranco Spalletta, Petroula Proitsi, J. Collinge, S. Sorbi, F. Sanchez-Garcia, Nick C. Fox, J. Hardy, Maria Candida Deniz Naranjo, P. Bosco, Carol Brayne, Daniela Galimberti, M. Mancuso, Fiona Matthews, Susanne Moebus, Patrizia Mecocci, M. Del Zompo, W. Maier, Harald Hampel, A. Pilotto, Maria J. Bullido, Francesco Panza, Paolo Caffarra, B. Nacmias, John R. Gilbert, Manuel Mayhaus, Lars Lannfelt, Hakon Hakonarson, Sabrina Pichler, Minerva M. Carrasquillo, Martin Ingelsson, Duane Beekly, Victoria Alvarez, Fanggeng Zou, Otto Valladares, Steven G. Younkin, Eliecer Coto, Kara L. Hamilton-Nelson, Wei Gu, Cristina Razquin, Pau Pastor, Ignacio Mateo, Michael J. Owen, Kelley M. Faber, Palmi V. Jonsson, Onofre Combarros, Michael C. O'Donovan, Laura B. Cantwell, Hilkka Soininen, Deborah Blacker, Simon Mead, Thomas Mosley, David A. Bennett, Tamara B. Harris, L. Fratiglioni, Clive Holmes, Renée F A G De Bruijn, Peter Passmore, Thomas J. Montine, Karolien Bettens, Jerome I. Rotter, Alexis Brice, Kevin Morgan, Tatiana M. Foroud, Walter A. Kukull, Didier Hannequin, John Powell, Michael A. Nalls, K. Ritchie, Kathryn L. Lunetta, John S K Kauwe, Eric Boerwinkle, Matthias Riemenschneider, M. Boada, Mikko Hiltunen, Eden R. Martin, Reinhold Schmidt, Dan Rujescu, Li San Wang, Jean François Dartigues, Richard Mayeux, Christopher Tzourio, Albert Hofman, Markus M. Nöthen, Caroline Graff, Lesley Jones, Jonathan Haines, Peter A. Holmans, Mark Lathrop, Margaret A. Pericak-Vance, Lenore J. Launer, L. Farrer, Cornelia Van Duijn, C. Van Broeckhoven, Valentina Moskvina, Gerard D. Schellenberg, Philippe Amouyel

Research output: Contribution to journalArticle

Abstract

Objective Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and ischemic stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases. Methods Using genome-wide association study (GWAS) data from METASTROKE + (15,916 IS cases and 68,826 controls) and the International Genomics of Alzheimer's Project (IGAP; 17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype-level data (4,610 IS cases, 1,281 AD cases, and 14,320 controls), we estimated the genome-wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, and large vessel), using genome-wide single-nucleotide polymorphism (SNP) data. We then performed a meta-analysis and pathway analysis in the combined AD and small vessel stroke data sets to identify the SNPs and molecular pathways through which disease risk may be conferred. Results We found evidence of a shared genetic contribution between AD and small vessel stroke (rG [standard error] = 0.37 [0.17]; p = 0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta-analysis of AD IGAP and METASTROKE + small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1) associated with both diseases (p = 1.8 × 10-8). A pathway analysis identified four associated pathways involving cholesterol transport and immune response. Interpretation Our findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. Ann Neurol 2016;79:739-747

Original languageEnglish
Pages (from-to)739-747
Number of pages9
JournalAnnals of Neurology
Volume79
Issue number5
DOIs
Publication statusPublished - May 1 2016

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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    Traylor, M., Adib-Samii, P., Harold, D., Dichgans, M., Williams, J., Lewis, C. M., Markus, H. S., Fornage, M., Holliday, E. G., Sharma, P., Bis, J., Psaty, B. M., Seshadri, S., Nalls, M. A., Devan, W., Boncoraglio, G. B., Malik, R., Mitchell, B. D., Kittner, S. J., ... Amouyel, P. (2016). Shared genetic contribution to ischemic stroke and Alzheimer's disease. Annals of Neurology, 79(5), 739-747. https://doi.org/10.1002/ana.24621