Shared genetic contribution to Ischaemic Stroke and Alzheimer's Disease.

Matthew Traylor; Poneh Adib-Samii; Denise Harold; the Alzheimer's Disease Neuroimaging Alzheimer's Disease Neuroimaging Initiative; The International Stroke Genetics Consortium International Stroke Genetics Consortium (ISGC), UK Young Lacunar Stroke DNA resource; Martin Dichgans; Julie Williams; Cathryn M Lewis; Hugh S Markus; Hugh S. METASTROKE; and the METASTROKE and International Genomics of Alzheimer's Project (IGAP) International Genomics of Alzheimer's Project (IGAP), investigators; 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 Ikram; Robert 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; Denise Harold; Adam C Naj; Rebecca Sims; Céline Bellenguez; Gyungah Jun; Anita L DeStefano; Joshua C Bis; Gary W Beecham; Benjamin Grenier‐Boley; Giancarlo Russo; Tricia A Thornton‐Wells; Nicola Jones; Albert Vernon Smith; Vincent Chouraki; Charlene Thomas; M Arfan Ikram; 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 S 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 J 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; Robert Clarke; Carol Brayne; Daniela Galimberti; Michelangelo Mancuso; Fiona E Matthews; European Alzheimer's Disease Initiative (EADI); Genetic and Environmental Risk in Alzheimer's Disease (GERAD); Alzheimer's Disease Genetic Consortium (ADGC); Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE); 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

doi:10.1002/ana.24621

Shared genetic contribution to Ischaemic Stroke and Alzheimer's Disease.

Matthew Traylor, Poneh Adib-Samii, Denise Harold, the Alzheimer's Disease Neuroimaging Alzheimer's Disease Neuroimaging Initiative, The International Stroke Genetics Consortium International Stroke Genetics Consortium (ISGC), UK Young Lacunar Stroke DNA resource, Martin Dichgans, Julie Williams, Cathryn M Lewis, Hugh S Markus, Hugh S. METASTROKE, and the METASTROKE and International Genomics of Alzheimer's Project (IGAP) International Genomics of Alzheimer's Project (IGAP), investigators, Myriam Fornage, Elizabeth G Holliday, Pankaj Sharma, Joshua C Bis, Bruce M Psaty, Sudha Seshadri, Mike A Nalls, William J Devan, Giorgio BoncoraglioRainer Malik, Braxton D Mitchell, Steven J Kittner, M Arfan Ikram, Robert 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, Denise Harold, Adam C Naj, Rebecca Sims, Céline Bellenguez, Gyungah Jun, Anita L DeStefano, Joshua C Bis, Gary W Beecham, Benjamin Grenier‐Boley, Giancarlo Russo, Tricia A Thornton‐Wells, Nicola Jones, Albert Vernon Smith, Vincent Chouraki, Charlene Thomas, M Arfan Ikram, 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 S 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 J 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, Robert Clarke, Carol Brayne, Daniela Galimberti, Michelangelo Mancuso, Fiona E Matthews, European Alzheimer's Disease Initiative (EADI), Genetic and Environmental Risk in Alzheimer's Disease (GERAD), Alzheimer's Disease Genetic Consortium (ADGC), Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), 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

Research output: Contribution to journal › Article › peer-review

53 Citations (Scopus)

Abstract

OBJECTIVE Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and Ischaemic 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 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, large vessel), using genome-wide SNP data. We then performed a meta-analysis and pathway analysis in the combined AD and small vessel stroke datasets 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(SE)=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=1.8x10(-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. This article is protected by copyright. All rights reserved.

Original language	English
Pages (from-to)	739
Number of pages	1
Journal	Annals of neurology
DOIs	https://doi.org/10.1002/ana.24621
Publication status	Published - 23 Feb 2016

Access to Document

10.1002/ana.24621

Bernadette McGuinness
- B.McGuinnessqub.acuk
- School of Medicine, Dentistry and Biomedical Sciences - Clinical Professor
- Centre for Public Health
Person: Academic

Cite this

Traylor, M., Adib-Samii, P., Harold, D., Alzheimer's Disease Neuroimaging Initiative, T. A. D. N., International Stroke Genetics Consortium (ISGC), UK Young Lacunar Stroke DNA resource, T. I. S. G. C., Dichgans, M., Williams, J., Lewis, C. M., Markus, H. S., METASTROKE, H. S., International Genomics of Alzheimer's Project (IGAP), investigators, A. T. METASTROKE. A. I. G. O. A. P., Fornage, M., Holliday, E. G., Sharma, P., Bis, J. C., Psaty, B. M., Seshadri, S., Nalls, M. A., Devan, W. J., ... Mosley, T. H. (2016). Shared genetic contribution to Ischaemic Stroke and Alzheimer's Disease. Annals of neurology, 739. https://doi.org/10.1002/ana.24621

@article{8f29676bed6345f8b4921bc2d4bde9b5,

title = "Shared genetic contribution to Ischaemic Stroke and Alzheimer's Disease.",

abstract = "OBJECTIVE Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and Ischaemic 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 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, large vessel), using genome-wide SNP data. We then performed a meta-analysis and pathway analysis in the combined AD and small vessel stroke datasets 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(SE)=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=1.8x10(-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. This article is protected by copyright. All rights reserved.",

author = "Matthew Traylor and Poneh Adib-Samii and Denise Harold and {Alzheimer's Disease Neuroimaging Initiative}, {the Alzheimer's Disease Neuroimaging} and {International Stroke Genetics Consortium (ISGC), UK Young Lacunar Stroke DNA resource}, {The International Stroke Genetics Consortium} and Martin Dichgans and Julie Williams and Lewis, {Cathryn M} and Markus, {Hugh S} and METASTROKE, {Hugh S.} and {International Genomics of Alzheimer's Project (IGAP), investigators}, {and the METASTROKE and International Genomics of Alzheimer's Project (IGAP)} 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 Jean-Charles Lambert and Ibrahim-Verbaas, {Carla A.} and Denise Harold and Naj, {Adam C} and Rebecca Sims and C{\'e}line Bellenguez and Gyungah Jun and DeStefano, {Anita L} and Bis, {Joshua C} and Beecham, {Gary W} and Benjamin Grenier‐Boley and Giancarlo Russo and Thornton‐Wells, {Tricia A} and Nicola Jones and Smith, {Albert Vernon} and Vincent Chouraki and Charlene Thomas and Ikram, {M Arfan} and Diana Zelenika and Vardarajan, {Badri N} and Yoichiro Kamatani and Chiao‐Feng Lin and Amy Gerrish and Helena Schmidt and Brian Kunkle and Dunstan, {Melanie L} and Agustin Ruiz and Marie‐Th{\c c}r{\`e}se Bihoreau and Seung-Hoan Choi 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 Jager, {Philip L De} 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{\c c}vet and Huentelman, {Matthew J} and Michael Gill and Brown, {Kristelle S} 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 George‐Hyslop, {Peter St} and Jordi Clarimon and Alberto Lleo and Bayer, {Anthony J} 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 Naranjo, {Maria Candida Deniz} and Paolo Bosco and Robert Clarke and Carol Brayne and Daniela Galimberti and Michelangelo Mancuso and Matthews, {Fiona E} and (EADI), {European Alzheimer's Disease Initiative} and (GERAD), {Genetic and Environmental Risk in Alzheimer's Disease} and (ADGC), {Alzheimer's Disease Genetic Consortium} and (CHARGE), {Cohorts for Heart and Aging Research in Genomic Epidemiology} and Susanne Moebus and Patrizia Mecocci and Zompo, {Maria Del} 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}",

year = "2016",

month = feb,

day = "23",

doi = "10.1002/ana.24621",

language = "English",

pages = "739",

journal = "Annals of neurology",

issn = "1531-8249",

publisher = "John Wiley & Sons Inc.",

}

Traylor, M, Adib-Samii, P, Harold, D, Alzheimer's Disease Neuroimaging Initiative, TADN, International Stroke Genetics Consortium (ISGC), UK Young Lacunar Stroke DNA resource, TISGC, Dichgans, M, Williams, J, Lewis, CM, Markus, HS, METASTROKE, HS, International Genomics of Alzheimer's Project (IGAP), investigators, ATMETASTROKEAIGOAP, 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, J-C, Ibrahim-Verbaas, CA, Harold, D, Naj, AC, Sims, R, Bellenguez, C, Jun, G, DeStefano, AL, Bis, JC, Beecham, GW, Grenier‐Boley, B, Russo, G, Thornton‐Wells, TA, Jones, N, Smith, AV, Chouraki, V, Thomas, C, Ikram, MA, Zelenika, D, Vardarajan, BN, Kamatani, Y, Lin, CF, Gerrish, A, Schmidt, H, Kunkle, B, Dunstan, ML, Ruiz, A, Bihoreau, MT, Choi, S-H, 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, Jager, PLD, 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, KS, 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, George‐Hyslop, PS, Clarimon, J, Lleo, A, Bayer, AJ, Tsuang, DW, Yu, L, Tsolaki, M, Bossù, P, Spalletta, G, Proitsi, P, Collinge, J, Sorbi, S, Sanchez‐Garcia, F, Fox, NC, Hardy, J, Naranjo, MCD, Bosco, P, Clarke, R, Brayne, C, Galimberti, D, Mancuso, M, Matthews, FE, (EADI), EADI, (GERAD), GAERIAD, (ADGC), ADGC, (CHARGE), CFHAARIGE, Moebus, S, Mecocci, P, Zompo, MD, 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 2016, 'Shared genetic contribution to Ischaemic Stroke and Alzheimer's Disease.', Annals of neurology, pp. 739. https://doi.org/10.1002/ana.24621

TY - JOUR

T1 - Shared genetic contribution to Ischaemic Stroke and Alzheimer's Disease.

AU - Traylor, Matthew

AU - Adib-Samii, Poneh

AU - Harold, Denise

AU - Alzheimer's Disease Neuroimaging Initiative, the Alzheimer's Disease Neuroimaging

AU - International Stroke Genetics Consortium (ISGC), UK Young Lacunar Stroke DNA resource, The International Stroke Genetics Consortium

AU - Dichgans, Martin

AU - Williams, Julie

AU - Lewis, Cathryn M

AU - Markus, Hugh S

AU - METASTROKE, Hugh S.

AU - International Genomics of Alzheimer's Project (IGAP), investigators, and the METASTROKE and International Genomics of Alzheimer's Project (IGAP)

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 - Harold, Denise

AU - Naj, Adam C

AU - Sims, Rebecca

AU - Bellenguez, Céline

AU - Jun, Gyungah

AU - DeStefano, Anita L

AU - Bis, Joshua C

AU - Beecham, Gary W

AU - Grenier‐Boley, Benjamin

AU - Russo, Giancarlo

AU - Thornton‐Wells, Tricia A

AU - Jones, Nicola

AU - Smith, Albert Vernon

AU - Chouraki, Vincent

AU - Thomas, Charlene

AU - Ikram, M Arfan

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 - Jager, Philip L De

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 S

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 - George‐Hyslop, Peter St

AU - Clarimon, Jordi

AU - Lleo, Alberto

AU - Bayer, Anthony J

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 - Naranjo, Maria Candida Deniz

AU - Bosco, Paolo

AU - Clarke, Robert

AU - Brayne, Carol

AU - Galimberti, Daniela

AU - Mancuso, Michelangelo

AU - Matthews, Fiona E

AU - (EADI), European Alzheimer's Disease Initiative

AU - (GERAD), Genetic and Environmental Risk in Alzheimer's Disease

AU - (ADGC), Alzheimer's Disease Genetic Consortium

AU - (CHARGE), Cohorts for Heart and Aging Research in Genomic Epidemiology

AU - Moebus, Susanne

AU - Mecocci, Patrizia

AU - Zompo, Maria Del

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

PY - 2016/2/23

Y1 - 2016/2/23

N2 - OBJECTIVE Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and Ischaemic 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 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, large vessel), using genome-wide SNP data. We then performed a meta-analysis and pathway analysis in the combined AD and small vessel stroke datasets 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(SE)=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=1.8x10(-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. This article is protected by copyright. All rights reserved.

AB - OBJECTIVE Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and Ischaemic 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 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, large vessel), using genome-wide SNP data. We then performed a meta-analysis and pathway analysis in the combined AD and small vessel stroke datasets 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(SE)=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=1.8x10(-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. This article is protected by copyright. All rights reserved.

U2 - 10.1002/ana.24621

DO - 10.1002/ana.24621

M3 - Article

C2 - 26913989

SN - 1531-8249

SP - 739

JO - Annals of neurology

JF - Annals of neurology

ER -

Shared genetic contribution to Ischaemic Stroke and Alzheimer's Disease.

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Bernadette McGuinness

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