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 language | English (US) |
|---|---|
| Pages (from-to) | 739-747 |
| Number of pages | 9 |
| Journal | Annals of neurology |
| Volume | 79 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2016 |
ASJC Scopus subject areas
- Neurology
- Clinical Neurology
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Shared genetic contribution to ischemic stroke and Alzheimer's disease. / Traylor, Matthew; Adib-Samii, Poneh; Harold, Denise; Dichgans, Martin; Williams, Julie; Lewis, Cathryn M.; Markus, Hugh S.; Fornage, Myriam; Holliday, Elizabeth G.; Sharma, Pankaj; Bis, Joshua C.; Psaty, Bruce M.; Seshadri, Sudha; Nalls, Mike A.; Devan, William J.; Boncoraglio, Giorgio; Malik, Rainer; Mitchell, Braxton D.; Kittner, Steven J.; Ikram, M. Arfan; Clarke, Robert; Rosand, Jonathan; Meschia, James F.; Sudlow, Cathie; Rothwell, Peter M.; Levi, Christopher; Bevan, Steve; Kilarski, Laura L.; Walters, Matthew; Thijs, Vincent; Slowik, Agnieszka; Lindgren, Arne; De Bakker, Paul I.W.; Lambert, Jean Charles; Ibrahim-Verbaas, Carla A.; Naj, Adam C.; Sims, Rebecca; Bellenguez, Céline; Jun, Gyungah; Destefano, Anita L.; Beecham, Gary W.; Grenier-Boley, Benjamin; Russo, Giancarlo; Thornton-Wells, Tricia A.; Jones, Nicola; Smith, Albert V.; Chouraki, Vincent; Thomas, Charlene; Zelenika, Diana; Vardarajan, Badri N.; Kamatani, Yoichiro; Lin, Chiao Feng; Gerrish, Amy; Schmidt, Helena; Kunkle, Brian; Dunstan, Melanie L.; Ruiz, Agustin; Bihoreau, Marie Thçrèse; Choi, Seung Hoan; Reitz, Christiane; Pasquier, Florence; Hollingworth, Paul; Ramirez, Alfredo; Hanon, Olivier; Fitzpatrick, Annette L.; Buxbaum, Joseph D.; Campion, Dominique; Crane, Paul K.; Baldwin, Clinton; Becker, Tim; Gudnason, Vilmundur; Cruchaga, Carlos; Craig, David; Amin, Najaf; Berr, Claudine; Lopez, Oscar L.; De Jager, Philip L.; Deramecourt, Vincent; Johnston, Janet A.; Evans, Denis; Lovestone, Simon; Letenneur, Luc; Morón, Francisco J.; Rubinsztein, David C.; Eiriksdottir, Gudny; Sleegers, Kristel; Goate, Alison M.; Fiçvet, Nathalie; Huentelman, Matthew J.; Gill, Michael; Brown, Kristelle; Kamboh, M. Ilyas; Keller, Lina; Barberger-Gateau, Pascale; McGuinness, Bernadette; Larson, Eric B.; Green, Robert; Myers, Amanda J.; Dufouil, Carole; Todd, Stephen; Wallon, David; Love, Seth; Rogaeva, Ekaterina; Gallacher, John; St George-Hyslop, Peter; Clarimon, Jordi; Lleo, Alberto; Bayer, Anthony; Tsuang, Debby W.; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petroula; Collinge, John; Sorbi, Sandro; Sanchez-Garcia, Florentino; Fox, Nick C.; Hardy, John; Deniz Naranjo, Maria Candida; Bosco, Paolo; Brayne, Carol; Galimberti, Daniela; Mancuso, Michelangelo; Matthews, Fiona; Moebus, Susanne; Mecocci, Patrizia; Del Zompo, Maria; Maier, Wolfgang; Hampel, Harald; Pilotto, Alberto; Bullido, Maria; Panza, Francesco; Caffarra, Paolo; Nacmias, Benedetta; Gilbert, John R.; Mayhaus, Manuel; Lannfelt, Lars; Hakonarson, Hakon; Pichler, Sabrina; Carrasquillo, Minerva M.; Ingelsson, Martin; Beekly, Duane; Alvarez, Victoria; Zou, Fanggeng; Valladares, Otto; Younkin, Steven G.; Coto, Eliecer; Hamilton-Nelson, Kara L.; Gu, Wei; Razquin, Cristina; Pastor, Pau; Mateo, Ignacio; Owen, Michael J.; Faber, Kelley M.; Jonsson, Palmi V.; Combarros, Onofre; O'Donovan, Michael C.; Cantwell, Laura B.; Soininen, Hilkka; Blacker, Deborah; Mead, Simon; Mosley, Thomas H.; Bennett, David A.; Harris, Tamara B.; Fratiglioni, Laura; Holmes, Clive; De Bruijn, Renee F.A.G.; Passmore, Peter; Montine, Thomas J.; Bettens, Karolien; Rotter, Jerome I.; Brice, Alexis; Morgan, Kevin; Foroud, Tatiana M.; Kukull, Walter A.; Hannequin, Didier; Powell, John F.; Nalls, Michael A.; Ritchie, Karen; Lunetta, Kathryn L.; Kauwe, John S.K.; Boerwinkle, Eric; Riemenschneider, Matthias; Boada, Mercè; Hiltunen, Mikko; Martin, Eden R.; Schmidt, Reinhold; Rujescu, Dan; Wang, Li San; Dartigues, Jean François; Mayeux, Richard; Tzourio, Christophe; Hofman, Albert; Nöthen, Markus M.; Graff, Caroline; Jones, Lesley; Haines, Jonathan L.; Holmans, Peter A.; Lathrop, Mark; Pericak-Vance, Margaret A.; Launer, Lenore J.; Farrer, Lindsay A.; Van Duijn, Cornelia M.; Van Broeckhoven, Christine; Moskvina, Valentina; Schellenberg, Gerard D.; Amouyel, Philippe.
In: Annals of neurology, Vol. 79, No. 5, 01.05.2016, p. 739-747.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Shared genetic contribution to ischemic stroke and Alzheimer's disease
AU - Traylor, Matthew
AU - Adib-Samii, Poneh
AU - Harold, Denise
AU - Dichgans, Martin
AU - Williams, Julie
AU - Lewis, Cathryn M.
AU - Markus, Hugh S.
AU - Fornage, Myriam
AU - Holliday, Elizabeth G.
AU - Sharma, Pankaj
AU - Bis, Joshua C.
AU - Psaty, Bruce M.
AU - Seshadri, Sudha
AU - Nalls, Mike A.
AU - Devan, William J.
AU - Boncoraglio, Giorgio
AU - Malik, Rainer
AU - Mitchell, Braxton D.
AU - Kittner, Steven J.
AU - Ikram, M. Arfan
AU - Clarke, Robert
AU - Rosand, Jonathan
AU - Meschia, James F.
AU - Sudlow, Cathie
AU - Rothwell, Peter M.
AU - Levi, Christopher
AU - Bevan, Steve
AU - Kilarski, Laura L.
AU - Walters, Matthew
AU - Thijs, Vincent
AU - Slowik, Agnieszka
AU - Lindgren, Arne
AU - De Bakker, Paul I.W.
AU - Lambert, Jean Charles
AU - Ibrahim-Verbaas, Carla A.
AU - Naj, Adam C.
AU - Sims, Rebecca
AU - Bellenguez, Céline
AU - Jun, Gyungah
AU - Destefano, Anita L.
AU - Beecham, Gary W.
AU - Grenier-Boley, Benjamin
AU - Russo, Giancarlo
AU - Thornton-Wells, Tricia A.
AU - Jones, Nicola
AU - Smith, Albert V.
AU - Chouraki, Vincent
AU - Thomas, Charlene
AU - Zelenika, Diana
AU - Vardarajan, Badri N.
AU - Kamatani, Yoichiro
AU - Lin, Chiao Feng
AU - Gerrish, Amy
AU - Schmidt, Helena
AU - Kunkle, Brian
AU - Dunstan, Melanie L.
AU - Ruiz, Agustin
AU - Bihoreau, Marie Thçrèse
AU - Choi, Seung Hoan
AU - Reitz, Christiane
AU - Pasquier, Florence
AU - Hollingworth, Paul
AU - Ramirez, Alfredo
AU - Hanon, Olivier
AU - Fitzpatrick, Annette L.
AU - Buxbaum, Joseph D.
AU - Campion, Dominique
AU - Crane, Paul K.
AU - Baldwin, Clinton
AU - Becker, Tim
AU - Gudnason, Vilmundur
AU - Cruchaga, Carlos
AU - Craig, David
AU - Amin, Najaf
AU - Berr, Claudine
AU - Lopez, Oscar L.
AU - De Jager, Philip L.
AU - Deramecourt, Vincent
AU - Johnston, Janet A.
AU - Evans, Denis
AU - Lovestone, Simon
AU - Letenneur, Luc
AU - Morón, Francisco J.
AU - Rubinsztein, David C.
AU - Eiriksdottir, Gudny
AU - Sleegers, Kristel
AU - Goate, Alison M.
AU - Fiçvet, Nathalie
AU - Huentelman, Matthew J.
AU - Gill, Michael
AU - Brown, Kristelle
AU - Kamboh, M. Ilyas
AU - Keller, Lina
AU - Barberger-Gateau, Pascale
AU - McGuinness, Bernadette
AU - Larson, Eric B.
AU - Green, Robert
AU - Myers, Amanda J.
AU - Dufouil, Carole
AU - Todd, Stephen
AU - Wallon, David
AU - Love, Seth
AU - Rogaeva, Ekaterina
AU - Gallacher, John
AU - St George-Hyslop, Peter
AU - Clarimon, Jordi
AU - Lleo, Alberto
AU - Bayer, Anthony
AU - Tsuang, Debby W.
AU - Yu, Lei
AU - Tsolaki, Magda
AU - Bossù, Paola
AU - Spalletta, Gianfranco
AU - Proitsi, Petroula
AU - Collinge, John
AU - Sorbi, Sandro
AU - Sanchez-Garcia, Florentino
AU - Fox, Nick C.
AU - Hardy, John
AU - Deniz Naranjo, Maria Candida
AU - Bosco, Paolo
AU - Brayne, Carol
AU - Galimberti, Daniela
AU - Mancuso, Michelangelo
AU - Matthews, Fiona
AU - Moebus, Susanne
AU - Mecocci, Patrizia
AU - Del Zompo, Maria
AU - Maier, Wolfgang
AU - Hampel, Harald
AU - Pilotto, Alberto
AU - Bullido, Maria
AU - Panza, Francesco
AU - Caffarra, Paolo
AU - Nacmias, Benedetta
AU - Gilbert, John R.
AU - Mayhaus, Manuel
AU - Lannfelt, Lars
AU - Hakonarson, Hakon
AU - Pichler, Sabrina
AU - Carrasquillo, Minerva M.
AU - Ingelsson, Martin
AU - Beekly, Duane
AU - Alvarez, Victoria
AU - Zou, Fanggeng
AU - Valladares, Otto
AU - Younkin, Steven G.
AU - Coto, Eliecer
AU - Hamilton-Nelson, Kara L.
AU - Gu, Wei
AU - Razquin, Cristina
AU - Pastor, Pau
AU - Mateo, Ignacio
AU - Owen, Michael J.
AU - Faber, Kelley M.
AU - Jonsson, Palmi V.
AU - Combarros, Onofre
AU - O'Donovan, Michael C.
AU - Cantwell, Laura B.
AU - Soininen, Hilkka
AU - Blacker, Deborah
AU - Mead, Simon
AU - Mosley, Thomas H.
AU - Bennett, David A.
AU - Harris, Tamara B.
AU - Fratiglioni, Laura
AU - Holmes, Clive
AU - De Bruijn, Renee F.A.G.
AU - Passmore, Peter
AU - Montine, Thomas J.
AU - Bettens, Karolien
AU - Rotter, Jerome I.
AU - Brice, Alexis
AU - Morgan, Kevin
AU - Foroud, Tatiana M.
AU - Kukull, Walter A.
AU - Hannequin, Didier
AU - Powell, John F.
AU - Nalls, Michael A.
AU - Ritchie, Karen
AU - Lunetta, Kathryn L.
AU - Kauwe, John S.K.
AU - Boerwinkle, Eric
AU - Riemenschneider, Matthias
AU - Boada, Mercè
AU - Hiltunen, Mikko
AU - Martin, Eden R.
AU - Schmidt, Reinhold
AU - Rujescu, Dan
AU - Wang, Li San
AU - Dartigues, Jean François
AU - Mayeux, Richard
AU - Tzourio, Christophe
AU - Hofman, Albert
AU - Nöthen, Markus M.
AU - Graff, Caroline
AU - Jones, Lesley
AU - Haines, Jonathan L.
AU - Holmans, Peter A.
AU - Lathrop, Mark
AU - Pericak-Vance, Margaret A.
AU - Launer, Lenore J.
AU - Farrer, Lindsay A.
AU - Van Duijn, Cornelia M.
AU - Van Broeckhoven, Christine
AU - Moskvina, Valentina
AU - Schellenberg, Gerard D.
AU - Amouyel, Philippe
N1 - Publisher Copyright: © 2016 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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
AB - 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
UR - http://www.scopus.com/inward/record.url?scp=84963579133&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84963579133&partnerID=8YFLogxK
U2 - 10.1002/ana.24621
DO - 10.1002/ana.24621
M3 - Article
AN - SCOPUS:84963579133
VL - 79
SP - 739
EP - 747
JO - Annals of Neurology
JF - Annals of Neurology
SN - 0364-5134
IS - 5
ER -