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 C. Bis, Bruce M. Psaty, Sudha Seshadri, Mike A. Nalls, William J. Devan, Giorgio Boncoraglio, Rainer Malik, Braxton D. Mitchell, Steven J. Kittner, M. Arfan IkramRobert Clarke, Jonathan Rosand, James F. Meschia, Cathie Sudlow, Peter M. Rothwell, Christopher Levi, Steve Bevan, Laura L. Kilarski, Matthew Walters, Vincent Thijs, Agnieszka Slowik, Arne Lindgren, Paul I W De Bakker, Jean Charles Lambert, Carla A. Ibrahim-Verbaas, Adam C. Naj, Rebecca Sims, Céline Bellenguez, Gyungah Jun, Anita L. Destefano, Gary W. Beecham, Benjamin 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 Kunkle, Melanie L. Dunstan, Agustin Ruiz, Marie Thçrèse Bihoreau, Seung Hoan Choi, Christiane Reitz, Florence 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 Craig, Najaf Amin, Claudine Berr, Oscar L. Lopez, Philip L. De Jager, Vincent Deramecourt, Janet A. Johnston, Denis Evans, Simon Lovestone, Luc Letenneur, Francisco J. Morón, David C. Rubinsztein, Gudny Eiriksdottir, Kristel Sleegers, Alison M. Goate, Nathalie Fiçvet, Matthew J. Huentelman, Michael Gill, Kristelle Brown, M. Ilyas Kamboh, Lina Keller, Pascale Barberger-Gateau, Bernadette McGuinness, Eric B. Larson, Robert Green, Amanda J. Myers, Carole Dufouil, Stephen Todd, David Wallon, Seth Love, Ekaterina Rogaeva, John Gallacher, Peter St George-Hyslop, Jordi Clarimon, Alberto Lleo, Anthony Bayer, Debby W. Tsuang, Lei Yu, Magda Tsolaki, Paola Bossù, Gianfranco Spalletta, Petroula Proitsi, John Collinge, Sandro Sorbi, Florentino Sanchez-Garcia, Nick C. Fox, John Hardy, Maria Candida Deniz Naranjo, Paolo Bosco, Carol Brayne, Daniela Galimberti, Michelangelo Mancuso, Fiona Matthews, Susanne Moebus, Patrizia Mecocci, Maria Del Zompo, Wolfgang Maier, Harald Hampel, Alberto Pilotto, Maria Bullido, Francesco Panza, Paolo Caffarra, Benedetta 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 H. Mosley, David A. Bennett, Tamara B. Harris, Laura Fratiglioni, Clive Holmes, Renee 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 F. Powell, Michael A. Nalls, Karen Ritchie, Kathryn L. Lunetta, John S K Kauwe, Eric Boerwinkle, Matthias Riemenschneider, Mercè Boada, Mikko Hiltunen, Eden R. Martin, Reinhold Schmidt, Dan Rujescu, Li San Wang, Jean François Dartigues, Richard Mayeux, Christophe Tzourio, Albert Hofman, Markus M. Nöthen, Caroline Graff, Lesley Jones, Jonathan L. Haines, Peter A. Holmans, Mark Lathrop, Margaret A. Pericak-Vance, Lenore J. Launer, Lindsay A. Farrer, Cornelia M. Van Duijn, Christine Van Broeckhoven, Valentina Moskvina, Gerard D. Schellenberg, Philippe Amouyel

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 (US)
Pages (from-to)739-747
Number of pages9
JournalAnnals of Neurology
Volume79
Issue number5
DOIs
StatePublished - May 1 2016

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Alzheimer Disease
Stroke
Genome-Wide Association Study
Single Nucleotide Polymorphism
Meta-Analysis
Genome
Genetic Predisposition to Disease
Genomics
Cholesterol
Genotype

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Traylor, M., Adib-Samii, P., Harold, D., Dichgans, M., Williams, J., Lewis, C. M., ... 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

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 journalArticle

Traylor, M, Adib-Samii, P, Harold, D, Dichgans, M, Williams, J, Lewis, CM, Markus, HS, Fornage, M, Holliday, EG, Sharma, P, Bis, JC, Psaty, BM, Seshadri, S, Nalls, MA, Devan, WJ, Boncoraglio, G, Malik, R, Mitchell, BD, Kittner, SJ, Ikram, MA, Clarke, R, Rosand, J, Meschia, JF, Sudlow, C, Rothwell, PM, Levi, C, Bevan, S, Kilarski, LL, Walters, M, Thijs, V, Slowik, A, Lindgren, A, De Bakker, PIW, Lambert, JC, Ibrahim-Verbaas, CA, Naj, AC, Sims, R, Bellenguez, C, Jun, G, Destefano, AL, Beecham, GW, Grenier-Boley, B, Russo, G, Thornton-Wells, TA, Jones, N, Smith, AV, Chouraki, V, Thomas, C, Zelenika, D, Vardarajan, BN, Kamatani, Y, Lin, CF, Gerrish, A, Schmidt, H, Kunkle, B, Dunstan, ML, Ruiz, A, Bihoreau, MT, Choi, SH, Reitz, C, Pasquier, F, Hollingworth, P, Ramirez, A, Hanon, O, Fitzpatrick, AL, Buxbaum, JD, Campion, D, Crane, PK, Baldwin, C, Becker, T, Gudnason, V, Cruchaga, C, Craig, D, Amin, N, Berr, C, Lopez, OL, De Jager, PL, Deramecourt, V, Johnston, JA, Evans, D, Lovestone, S, Letenneur, L, Morón, FJ, Rubinsztein, DC, Eiriksdottir, G, Sleegers, K, Goate, AM, Fiçvet, N, Huentelman, MJ, Gill, M, Brown, K, Kamboh, MI, Keller, L, Barberger-Gateau, P, McGuinness, B, Larson, EB, Green, R, Myers, AJ, Dufouil, C, Todd, S, Wallon, D, Love, S, Rogaeva, E, Gallacher, J, St George-Hyslop, P, Clarimon, J, Lleo, A, Bayer, A, Tsuang, DW, Yu, L, Tsolaki, M, Bossù, P, Spalletta, G, Proitsi, P, Collinge, J, Sorbi, S, Sanchez-Garcia, F, Fox, NC, Hardy, J, Deniz Naranjo, MC, Bosco, P, Brayne, C, Galimberti, D, Mancuso, M, Matthews, F, Moebus, S, Mecocci, P, Del Zompo, M, Maier, W, Hampel, H, Pilotto, A, Bullido, M, Panza, F, Caffarra, P, Nacmias, B, Gilbert, JR, Mayhaus, M, Lannfelt, L, Hakonarson, H, Pichler, S, Carrasquillo, MM, Ingelsson, M, Beekly, D, Alvarez, V, Zou, F, Valladares, O, Younkin, SG, Coto, E, Hamilton-Nelson, KL, Gu, W, Razquin, C, Pastor, P, Mateo, I, Owen, MJ, Faber, KM, Jonsson, PV, Combarros, O, O'Donovan, MC, Cantwell, LB, Soininen, H, Blacker, D, Mead, S, Mosley, TH, Bennett, DA, Harris, TB, Fratiglioni, L, Holmes, C, De Bruijn, RFAG, Passmore, P, Montine, TJ, Bettens, K, Rotter, JI, Brice, A, Morgan, K, Foroud, TM, Kukull, WA, Hannequin, D, Powell, JF, Nalls, MA, Ritchie, K, Lunetta, KL, Kauwe, JSK, Boerwinkle, E, Riemenschneider, M, Boada, M, Hiltunen, M, Martin, ER, Schmidt, R, Rujescu, D, Wang, LS, Dartigues, JF, Mayeux, R, Tzourio, C, Hofman, A, Nöthen, MM, Graff, C, Jones, L, Haines, JL, Holmans, PA, Lathrop, M, Pericak-Vance, MA, Launer, LJ, Farrer, LA, Van Duijn, CM, Van Broeckhoven, C, Moskvina, V, Schellenberg, GD & Amouyel, P 2016, 'Shared genetic contribution to ischemic stroke and Alzheimer's disease', Annals of Neurology, vol. 79, no. 5, pp. 739-747. https://doi.org/10.1002/ana.24621
Traylor M, Adib-Samii P, Harold D, Dichgans M, Williams J, Lewis CM et al. Shared genetic contribution to ischemic stroke and Alzheimer's disease. Annals of Neurology. 2016 May 1;79(5):739-747. https://doi.org/10.1002/ana.24621
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. / Shared genetic contribution to ischemic stroke and Alzheimer's disease. In: Annals of Neurology. 2016 ; Vol. 79, No. 5. pp. 739-747.
@article{d93a43f561614cee96bf21f378e435b3,
title = "Shared genetic contribution to ischemic stroke and Alzheimer's disease",
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",
author = "Matthew Traylor and Poneh Adib-Samii and Denise Harold and Martin Dichgans and Julie Williams and Lewis, {Cathryn M.} and Markus, {Hugh S.} and Myriam Fornage and Holliday, {Elizabeth G.} and Pankaj Sharma and Bis, {Joshua C.} and Psaty, {Bruce M.} and Sudha Seshadri and Nalls, {Mike A.} and Devan, {William J.} and Giorgio Boncoraglio and Rainer Malik and Mitchell, {Braxton D.} and Kittner, {Steven J.} and Ikram, {M. Arfan} and Robert Clarke and Jonathan Rosand and Meschia, {James F.} and Cathie Sudlow and Rothwell, {Peter M.} and Christopher Levi and Steve Bevan and Kilarski, {Laura L.} and Matthew Walters and Vincent Thijs and Agnieszka Slowik and Arne Lindgren and {De Bakker}, {Paul I W} and Lambert, {Jean Charles} and Ibrahim-Verbaas, {Carla A.} and Naj, {Adam C.} and Rebecca Sims and C{\'e}line Bellenguez and Gyungah Jun and Destefano, {Anita L.} and Beecham, {Gary W.} and Benjamin Grenier-Boley and Giancarlo Russo and Thornton-Wells, {Tricia A.} and Nicola Jones and Smith, {Albert V.} and Vincent Chouraki and Charlene Thomas and Diana Zelenika and Vardarajan, {Badri N.} and Yoichiro Kamatani and Lin, {Chiao Feng} and Amy Gerrish and Helena Schmidt and Brian Kunkle and Dunstan, {Melanie L.} and Agustin Ruiz and Bihoreau, {Marie Th{\cc}r{\`e}se} and Choi, {Seung Hoan} and Christiane Reitz and Florence Pasquier and Paul Hollingworth and Alfredo Ramirez and Olivier Hanon and Fitzpatrick, {Annette L.} and Buxbaum, {Joseph D.} and Dominique Campion and Crane, {Paul K.} and Clinton Baldwin and Tim Becker and Vilmundur Gudnason and Carlos Cruchaga and David Craig and Najaf Amin and Claudine Berr and Lopez, {Oscar L.} and {De Jager}, {Philip L.} and Vincent Deramecourt and Johnston, {Janet A.} and Denis Evans and Simon Lovestone and Luc Letenneur and Mor{\'o}n, {Francisco J.} and Rubinsztein, {David C.} and Gudny Eiriksdottir and Kristel Sleegers and Goate, {Alison M.} and Nathalie Fi{\cc}vet and Huentelman, {Matthew J.} and Michael Gill and Kristelle Brown and Kamboh, {M. Ilyas} and Lina Keller and Pascale Barberger-Gateau and Bernadette McGuinness and Larson, {Eric B.} and Robert Green and Myers, {Amanda J.} and Carole Dufouil and Stephen Todd and David Wallon and Seth Love and Ekaterina Rogaeva and John Gallacher and {St George-Hyslop}, Peter and Jordi Clarimon and Alberto Lleo and Anthony Bayer and Tsuang, {Debby W.} and Lei Yu and Magda Tsolaki and Paola Boss{\`u} and Gianfranco Spalletta and Petroula Proitsi and John Collinge and Sandro Sorbi and Florentino Sanchez-Garcia and Fox, {Nick C.} and John Hardy and {Deniz Naranjo}, {Maria Candida} and Paolo Bosco and Carol Brayne and Daniela Galimberti and Michelangelo Mancuso and Fiona Matthews and Susanne Moebus and Patrizia Mecocci and {Del Zompo}, Maria and Wolfgang Maier and Harald Hampel and Alberto Pilotto and Maria Bullido and Francesco Panza and Paolo Caffarra and Benedetta Nacmias and Gilbert, {John R.} and Manuel Mayhaus and Lars Lannfelt and Hakon Hakonarson and Sabrina Pichler and Carrasquillo, {Minerva M.} and Martin Ingelsson and Duane Beekly and Victoria Alvarez and Fanggeng Zou and Otto Valladares and Younkin, {Steven G.} and Eliecer Coto and Hamilton-Nelson, {Kara L.} and Wei Gu and Cristina Razquin and Pau Pastor and Ignacio Mateo and Owen, {Michael J.} and Faber, {Kelley M.} and Jonsson, {Palmi V.} and Onofre Combarros and O'Donovan, {Michael C.} and Cantwell, {Laura B.} and Hilkka Soininen and Deborah Blacker and Simon Mead and Mosley, {Thomas H.} and Bennett, {David A.} and Harris, {Tamara B.} and Laura Fratiglioni and Clive Holmes and {De Bruijn}, {Renee F A G} and Peter Passmore and Montine, {Thomas J.} and Karolien Bettens and Rotter, {Jerome I.} and Alexis Brice and Kevin Morgan and Foroud, {Tatiana M.} and Kukull, {Walter A.} and Didier Hannequin and Powell, {John F.} and Nalls, {Michael A.} and Karen Ritchie and Lunetta, {Kathryn L.} and Kauwe, {John S K} and Eric Boerwinkle and Matthias Riemenschneider and Merc{\`e} Boada and Mikko Hiltunen and Martin, {Eden R.} and Reinhold Schmidt and Dan Rujescu and Wang, {Li San} and Dartigues, {Jean Fran{\cc}ois} and Richard Mayeux and Christophe Tzourio and Albert Hofman and N{\"o}then, {Markus M.} and Caroline Graff and Lesley Jones and Haines, {Jonathan L.} and Holmans, {Peter A.} and Mark Lathrop and Pericak-Vance, {Margaret A.} and Launer, {Lenore J.} and Farrer, {Lindsay A.} and {Van Duijn}, {Cornelia M.} and {Van Broeckhoven}, Christine and Valentina Moskvina and Schellenberg, {Gerard D.} and Philippe Amouyel",
year = "2016",
month = "5",
day = "1",
doi = "10.1002/ana.24621",
language = "English (US)",
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pages = "739--747",
journal = "Annals of Neurology",
issn = "0364-5134",
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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.

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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

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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 -