Shared genetic contribution to ischemic stroke and Alzheimer's disease. Issue 5 (30th March 2016)

• Record Type: Journal Article
• Authors: Traylor, Matthew; Adib‐Samii, Poneh; Harold, Denise; Dichgans, Martin; Williams, Julie; Lewis, Cathryn M.; Markus, Hugh S.
• Other Names: Fornage Myriam investigator.; Holliday Elizabeth G investigator.; Sharma Pankaj investigator.; Bis Joshua C investigator.; Psaty Bruce M investigator.; Seshadri Sudha investigator.; Nalls Mike A investigator.; Devan William J investigator.; Boncoraglio Giorgio investigator.; Malik Rainer investigator.; Mitchell Braxton D investigator.; Kittner Steven J investigator.; Ikram M Arfan investigator.; Clarke Robert investigator.; Rosand Jonathan investigator.; Meschia James F investigator.; Sudlow Cathie investigator.; Rothwell Peter M investigator.; Levi Christopher investigator.; Bevan Steve investigator.; Kilarski Laura L investigator.; Walters Matthew investigator.; Thijs Vincent investigator.; Slowik Agnieszka investigator.; Lindgren Arne investigator.; de Bakker Paul I W investigator.; Lambert Jean‐Charles investigator.; Ibrahim‐Verbaas Carla A investigator.; Harold Denise investigator.; Naj Adam C investigator.; Sims Rebecca investigator.; Bellenguez Céline investigator.; Jun Gyungah investigator.; DeStefano Anita L investigator.; Bis Joshua C investigator.; Beecham Gary W investigator.; Grenier‐Boley Benjamin investigator.; Russo Giancarlo investigator.; Thornton‐Wells Tricia A investigator.; Jones Nicola investigator.; Smith Albert V investigator.; Chouraki Vincent investigator.; Thomas Charlene investigator.; Ikram M Arfan investigator.; Zelenika Diana investigator.; Vardarajan Badri N investigator.; Kamatani Yoichiro investigator.; Lin Chiao‐Feng investigator.; Gerrish Amy investigator.; Schmidt Helena investigator.; Kunkle Brian investigator.; Dunstan Melanie L investigator.; Ruiz Agustin investigator.; Bihoreau Marie‐Thçrèse investigator.; Choi Seung‐Hoan investigator.; Reitz Christiane investigator.; Pasquier Florence investigator.; Hollingworth Paul investigator.; Ramirez Alfredo investigator.; Hanon Olivier investigator.; Fitzpatrick Annette L investigator.; Buxbaum Joseph D investigator.; Campion Dominique investigator.; Crane Paul K investigator.; Baldwin Clinton investigator.; Becker Tim investigator.; Gudnason Vilmundur investigator.; Cruchaga Carlos investigator.; Craig David investigator.; Amin Najaf investigator.; Berr Claudine investigator.; Lopez Oscar L investigator.; De Jager Philip L investigator.; Deramecourt Vincent investigator.; Johnston Janet A investigator.; Evans Denis investigator.; Lovestone Simon investigator.; Letenneur Luc investigator.; Morón Francisco J investigator.; Rubinsztein David C investigator.; Eiriksdottir Gudny investigator.; Sleegers Kristel investigator.; Goate Alison M investigator.; Fiçvet Nathalie investigator.; Huentelman Matthew J investigator.; Gill Michael investigator.; Brown Kristelle investigator.; Kamboh M Ilyas investigator.; Keller Lina investigator.; Barberger‐Gateau Pascale investigator.; McGuinness Bernadette investigator.; Larson Eric B investigator.; Green Robert investigator.; Myers Amanda J investigator.; Dufouil Carole investigator.; Todd Stephen investigator.; Wallon David investigator.; Love Seth investigator.; Rogaeva Ekaterina investigator.; Gallacher John investigator.; St George‐Hyslop Peter investigator.; Clarimon Jordi investigator.; Lleo Alberto investigator.; Bayer Anthony investigator.; Tsuang Debby W investigator.; Yu Lei investigator.; Tsolaki Magda investigator.; Bossù Paola investigator.; Spalletta Gianfranco investigator.; Proitsi Petroula investigator.; Collinge John investigator.; Sorbi Sandro investigator.; Sanchez‐Garcia Florentino investigator.; Fox Nick C investigator.; Hardy John investigator.; Deniz Naranjo Maria Candida investigator.; Bosco Paolo investigator.; Clarke Robert investigator.; Brayne Carol investigator.; Galimberti Daniela investigator.; Mancuso Michelangelo investigator.; Matthews Fiona investigator.; investigator.; investigator.; investigator.; investigator.; Moebus Susanne investigator.; Mecocci Patrizia investigator.; Del Zompo Maria investigator.; Maier Wolfgang investigator.; Hampel Harald investigator.; Pilotto Alberto investigator.; Bullido Maria investigator.; Panza Francesco investigator.; Caffarra Paolo investigator.; Nacmias Benedetta investigator.; Gilbert John R investigator.; Mayhaus Manuel investigator.; Lannfelt Lars investigator.; Hakonarson Hakon investigator.; Pichler Sabrina investigator.; Carrasquillo Minerva M investigator.; Ingelsson Martin investigator.; Beekly Duane investigator.; Alvarez Victoria investigator.; Zou Fanggeng investigator.; Valladares Otto investigator.; Younkin Steven G investigator.; Coto Eliecer investigator.; Hamilton‐Nelson Kara L investigator.; Gu Wei investigator.; Razquin Cristina investigator.; Pastor Pau investigator.; Mateo Ignacio investigator.; Owen Michael J investigator.; Faber Kelley M investigator.; Jonsson Palmi V investigator.; Combarros Onofre investigator.; O'Donovan Michael C investigator.; Cantwell Laura B investigator.; Soininen Hilkka investigator.; Blacker Deborah investigator.; Mead Simon investigator.; Mosley Thomas H investigator.; Bennett David A investigator.; Harris Tamara B investigator.; Fratiglioni Laura investigator.; Holmes Clive investigator.; de Bruijn Renee F A G investigator.; Passmore Peter investigator.; Montine Thomas J investigator.; Bettens Karolien investigator.; Rotter Jerome I investigator.; Brice Alexis investigator.; Morgan Kevin investigator.; Foroud Tatiana M investigator.; Kukull Walter A investigator.; Hannequin Didier investigator.; Powell John F investigator.; Nalls Michael A investigator.; Ritchie Karen investigator.; Lunetta Kathryn L investigator.; Kauwe John S K investigator.; Boerwinkle Eric investigator.; Riemenschneider Matthias investigator.; Boada Mercè investigator.; Hiltunen Mikko investigator.; Martin Eden R investigator.; Schmidt Reinhold investigator.; Rujescu Dan investigator.; Wang Li‐San investigator.; Dartigues Jean‐François investigator.; Mayeux Richard investigator.; Tzourio Christophe investigator.; Hofman Albert investigator.; Nöthen Markus M investigator.; Graff Caroline investigator.; Psaty Bruce M investigator.; Jones Lesley investigator.; Haines Jonathan L investigator.; Holmans Peter A investigator.; Lathrop Mark investigator.; Pericak‐Vance Margaret A investigator.; Launer Lenore J investigator.; Farrer Lindsay A investigator.; van Duijn Cornelia M investigator.; Van Broeckhoven Christine investigator.; Moskvina Valentina investigator.; Seshadri Sudha investigator.; Williams Julie investigator.; Schellenberg Gerard D investigator.; Amouyel Philippe investigator.;
• Is Part Of: Annals of neurology. Volume 79:Issue 5(2016:May)
• Page Start: 739
• Page End: 747
• Publication Date: 2016-03-30
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.24621
• Languages: English
• ISSNs: 0364-5134

Abstract

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