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 |
|---|---|
| Pages (from-to) | 739-747 |
| Number of pages | 9 |
| Journal | Annals of Neurology |
| Volume | 79 |
| Issue number | 5 |
| DOIs | |
| Publication status | 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; Psaty, Bruce M.; Seshadri, Sudha; Nalls, Mike A.; Devan, William; Boncoraglio, Giorgio Battista; Malik, Rainer; Mitchell, Braxton D.; Kittner, Steve J.; Ikram, M. Arfan; Clarke, R.; Rosand, Jonathan; Meschia, James; Sudlow, Cathie; Rothwell, Peter M.; Levi, Christopher; Bevan, Steve; Kilarski, Laura L.; Walters, Matthew; Thijs, Vincent; Slowik, Agnieszka; Lindgren, Arne; De Bakker, P. I W; Lambert, Jean Charles; Ibrahim-Verbaas, Carla A.; Naj, Adam C.; Sims, Rebecca; Bellenguez, Céline; Jun, G.; DeStefano, Anita L.; Beecham, Gary W.; Grenier-Boley, B.; 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 W.; Dunstan, Melanie L.; Ruiz, Agustín; Bihoreau, Marie Thçrèse; Choi, Seung Hoan; Reitz, C.; Pasquier, F.; 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 W.; Amin, Najaf; Berr, C.; Lopez, Oscar L.; de Jager, Philip; Deramecourt, Vincent; Johnston, Janet A.; Evans, Denis; Lovestone, Simon; Letenneur, Luc; Morón, Francisco J.; Rubinsztein, D. C.; Eiriksdottir, Gudny; Sleegers, Kristel; Goate, Alison M.; Fiçvet, Nathalie; Huentelman, Matthew J.; Gill, Michael; Brown, Kristelle S.; Kamboh, M. Ilyas; Keller, Lina; Barberger-Gateau, Pascale; McGuinness, Bernadette M.; Larson, Eric B.; Green, Robert C.; Myers, Amanda J.; Dufouil, Carole; Todd, Stephen; Wallon, David; Love, Seth; Rogaeva, E.; Gallacher, J.; St. George-Hyslop, P. H.; Clarimon, Jordi; Lleó, Alberto; Bayer, Anthony; Tsuang, Debby W.; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petroula; Collinge, J.; Sorbi, S.; Sanchez-Garcia, F.; Fox, Nick C.; Hardy, J.; Deniz Naranjo, Maria Candida; Bosco, P.; Brayne, Carol; Galimberti, Daniela; Mancuso, M.; Matthews, Fiona; Moebus, Susanne; Mecocci, Patrizia; Del Zompo, M.; Maier, W.; Hampel, Harald; Pilotto, A.; Bullido, Maria J.; Panza, Francesco; Caffarra, Paolo; Nacmias, B.; 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; Bennett, David A.; Harris, Tamara B.; Fratiglioni, L.; Holmes, Clive; De Bruijn, Renée 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; Nalls, Michael A.; Ritchie, K.; Lunetta, Kathryn L.; Kauwe, John S K; Boerwinkle, Eric; Riemenschneider, Matthias; Boada, M.; Hiltunen, Mikko; Martin, Eden R.; Schmidt, Reinhold; Rujescu, Dan; Wang, Li San; Dartigues, Jean François; Mayeux, Richard; Tzourio, Christopher; Hofman, Albert; Nöthen, Markus M.; Graff, Caroline; Jones, Lesley; Haines, Jonathan; Holmans, Peter A.; Lathrop, Mark; Pericak-Vance, Margaret A.; Launer, Lenore J.; Farrer, L.; Van Duijn, Cornelia; Van Broeckhoven, C.; 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
AU - Psaty, Bruce M.
AU - Seshadri, Sudha
AU - Nalls, Mike A.
AU - Devan, William
AU - Boncoraglio, Giorgio Battista
AU - Malik, Rainer
AU - Mitchell, Braxton D.
AU - Kittner, Steve J.
AU - Ikram, M. Arfan
AU - Clarke, R.
AU - Rosand, Jonathan
AU - Meschia, James
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, P. I W
AU - Lambert, Jean Charles
AU - Ibrahim-Verbaas, Carla A.
AU - Naj, Adam C.
AU - Sims, Rebecca
AU - Bellenguez, Céline
AU - Jun, G.
AU - DeStefano, Anita L.
AU - Beecham, Gary W.
AU - Grenier-Boley, B.
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 W.
AU - Dunstan, Melanie L.
AU - Ruiz, Agustín
AU - Bihoreau, Marie Thçrèse
AU - Choi, Seung Hoan
AU - Reitz, C.
AU - Pasquier, F.
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 W.
AU - Amin, Najaf
AU - Berr, C.
AU - Lopez, Oscar L.
AU - de Jager, Philip
AU - Deramecourt, Vincent
AU - Johnston, Janet A.
AU - Evans, Denis
AU - Lovestone, Simon
AU - Letenneur, Luc
AU - Morón, Francisco J.
AU - Rubinsztein, D. C.
AU - Eiriksdottir, Gudny
AU - Sleegers, Kristel
AU - Goate, Alison M.
AU - Fiçvet, Nathalie
AU - Huentelman, Matthew J.
AU - Gill, Michael
AU - Brown, Kristelle S.
AU - Kamboh, M. Ilyas
AU - Keller, Lina
AU - Barberger-Gateau, Pascale
AU - McGuinness, Bernadette M.
AU - Larson, Eric B.
AU - Green, Robert C.
AU - Myers, Amanda J.
AU - Dufouil, Carole
AU - Todd, Stephen
AU - Wallon, David
AU - Love, Seth
AU - Rogaeva, E.
AU - Gallacher, J.
AU - St. George-Hyslop, P. H.
AU - Clarimon, Jordi
AU - Lleó, 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, J.
AU - Sorbi, S.
AU - Sanchez-Garcia, F.
AU - Fox, Nick C.
AU - Hardy, J.
AU - Deniz Naranjo, Maria Candida
AU - Bosco, P.
AU - Brayne, Carol
AU - Galimberti, Daniela
AU - Mancuso, M.
AU - Matthews, Fiona
AU - Moebus, Susanne
AU - Mecocci, Patrizia
AU - Del Zompo, M.
AU - Maier, W.
AU - Hampel, Harald
AU - Pilotto, A.
AU - Bullido, Maria J.
AU - Panza, Francesco
AU - Caffarra, Paolo
AU - Nacmias, B.
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
AU - Bennett, David A.
AU - Harris, Tamara B.
AU - Fratiglioni, L.
AU - Holmes, Clive
AU - De Bruijn, Renée 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
AU - Nalls, Michael A.
AU - Ritchie, K.
AU - Lunetta, Kathryn L.
AU - Kauwe, John S K
AU - Boerwinkle, Eric
AU - Riemenschneider, Matthias
AU - Boada, M.
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, Christopher
AU - Hofman, Albert
AU - Nöthen, Markus M.
AU - Graff, Caroline
AU - Jones, Lesley
AU - Haines, Jonathan
AU - Holmans, Peter A.
AU - Lathrop, Mark
AU - Pericak-Vance, Margaret A.
AU - Launer, Lenore J.
AU - Farrer, L.
AU - Van Duijn, Cornelia
AU - Van Broeckhoven, C.
AU - Moskvina, Valentina
AU - Schellenberg, Gerard D.
AU - Amouyel, Philippe
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
VL - 79
SP - 739
EP - 747
JO - Annals of Neurology
JF - Annals of Neurology
SN - 0364-5134
IS - 5
ER -