Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies

M Traylor; M Farrall; EG Holliday; C Sudlow; JC Hopewell; YC Cheng; M Fomage; Arfan Ikram; R Malik; S Bevan; U Thorsteinsdottir; MA Nalls; WT Longstreth; KL Wiggins; S Yadav; EA Parati; AL DeStefano; BB Worrall; S Kittner; MS Khan; AP Reiner; A Helgadottir; S Achterberg; I Fernandez-Cadenas; S Abboud; R Schmidt; M Walters; WM Chen; EB Ringelstein; M O'Donnell; WK Ho; J Pera; R Lemmens; B Norrving; P Higgins; M Benn; M Sale; G Kuhlenbaumer; ASF Doney; AM Vicente; H Delavaran; A Algra; G Davies; SA Oliveira; CNA Palmer; I Deary; Heléna Schmidt; M Pandolfo; J Montaner; C Carty; PIW de Bakker; K Kostulas; JM Ferro; NR van Zuydam; E Valdimarsson; BG Nordestgaard; A Lindgren; V Thijs; A Slowik; D Saleheen; G Pare; K Berger; G Thorleifsson; Bert Hofman; TH Mosley; BD Mitchell; K Furie; R Clarke; C Levi; S Seshadri; A Gschwendtner; GB Boncoraglio; P Sharma; JC Bis; S Gretarsdottir; BM Psaty; PM Rothwell; J Rosand; JF Meschia; K Stefansson; M Dichgans; HS Markus

doi:10.1016/S1474-4422(12)70234-X

Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies

M Traylor, M Farrall, EG Holliday, C Sudlow, JC Hopewell, YC Cheng, M Fomage, Arfan Ikram, R Malik, S Bevan, U Thorsteinsdottir, MA Nalls, WT Longstreth, KL Wiggins, S Yadav, EA Parati, AL DeStefano, BB Worrall, S Kittner, MS KhanAP Reiner, A Helgadottir, S Achterberg, I Fernandez-Cadenas, S Abboud, R Schmidt, M Walters, WM Chen, EB Ringelstein, M O'Donnell, WK Ho, J Pera, R Lemmens, B Norrving, P Higgins, M Benn, M Sale, G Kuhlenbaumer, ASF Doney, AM Vicente, H Delavaran, A Algra, G Davies, SA Oliveira, CNA Palmer, I Deary, Heléna Schmidt, M Pandolfo, J Montaner, C Carty, PIW de Bakker, K Kostulas, JM Ferro, NR van Zuydam, E Valdimarsson, BG Nordestgaard, A Lindgren, V Thijs, A Slowik, D Saleheen, G Pare, K Berger, G Thorleifsson, Bert Hofman, TH Mosley, BD Mitchell, K Furie, R Clarke, C Levi, S Seshadri, A Gschwendtner, GB Boncoraglio, P Sharma, JC Bis, S Gretarsdottir, BM Psaty, PM Rothwell, J Rosand, JF Meschia, K Stefansson, M Dichgans, HS Markus

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Abstract

Background Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes. Methods We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nudeotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls. Findings We verified previous associations for cardioembolic stroke near PITX2 (p=2.8x10(-16)) and ZFHX3 (p=2.28x10(-8)), and for large-vessel stroke at a 9p21 locus (p=3.32x10(-5)) and HDAC9 (p=2.03x10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We Interpretation Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.

Original language	Undefined/Unknown
Pages (from-to)	951-962
Number of pages	12
Journal	Lancet Neurology
Volume	11
Issue number	11
DOIs	https://doi.org/10.1016/S1474-4422(12)70234-X
Publication status	Published - 2012

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Traylor, M., Farrall, M., Holliday, EG., Sudlow, C., Hopewell, JC., Cheng, YC., Fomage, M., Ikram, A., Malik, R., Bevan, S., Thorsteinsdottir, U., Nalls, MA., Longstreth, WT., Wiggins, KL., Yadav, S., Parati, EA., DeStefano, AL., Worrall, BB., Kittner, S., ... Markus, HS. (2012). Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies. Lancet Neurology, 11(11), 951-962. https://doi.org/10.1016/S1474-4422(12)70234-X

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title = "Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies",

abstract = "Background Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes. Methods We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nudeotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls. Findings We verified previous associations for cardioembolic stroke near PITX2 (p=2.8x10(-16)) and ZFHX3 (p=2.28x10(-8)), and for large-vessel stroke at a 9p21 locus (p=3.32x10(-5)) and HDAC9 (p=2.03x10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We Interpretation Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.",

author = "M Traylor and M Farrall and EG Holliday and C Sudlow and JC Hopewell and YC Cheng and M Fomage and Arfan Ikram and R Malik and S Bevan and U Thorsteinsdottir and MA Nalls and WT Longstreth and KL Wiggins and S Yadav and EA Parati and AL DeStefano and BB Worrall and S Kittner and MS Khan and AP Reiner and A Helgadottir and S Achterberg and I Fernandez-Cadenas and S Abboud and R Schmidt and M Walters and WM Chen and EB Ringelstein and M O'Donnell and WK Ho and J Pera and R Lemmens and B Norrving and P Higgins and M Benn and M Sale and G Kuhlenbaumer and ASF Doney and AM Vicente and H Delavaran and A Algra and G Davies and SA Oliveira and CNA Palmer and I Deary and Hel{\'e}na Schmidt and M Pandolfo and J Montaner and C Carty and {de Bakker}, PIW and K Kostulas and JM Ferro and {van Zuydam}, NR and E Valdimarsson and BG Nordestgaard and A Lindgren and V Thijs and A Slowik and D Saleheen and G Pare and K Berger and G Thorleifsson and Bert Hofman and TH Mosley and BD Mitchell and K Furie and R Clarke and C Levi and S Seshadri and A Gschwendtner and GB Boncoraglio and P Sharma and JC Bis and S Gretarsdottir and BM Psaty and PM Rothwell and J Rosand and JF Meschia and K Stefansson and M Dichgans and HS Markus",

year = "2012",

doi = "10.1016/S1474-4422(12)70234-X",

language = "Undefined/Unknown",

volume = "11",

pages = "951--962",

journal = "The Lancet Neurology",

issn = "1474-4422",

publisher = "Lancet Publishing Group",

number = "11",

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Traylor, M, Farrall, M, Holliday, EG, Sudlow, C, Hopewell, JC, Cheng, YC, Fomage, M, Ikram, A, Malik, R, Bevan, S, Thorsteinsdottir, U, Nalls, MA, Longstreth, WT, Wiggins, KL, Yadav, S, Parati, EA, DeStefano, AL, Worrall, BB, Kittner, S, Khan, MS, Reiner, AP, Helgadottir, A, Achterberg, S, Fernandez-Cadenas, I, Abboud, S, Schmidt, R, Walters, M, Chen, WM, Ringelstein, EB, O'Donnell, M, Ho, WK, Pera, J, Lemmens, R, Norrving, B, Higgins, P, Benn, M, Sale, M, Kuhlenbaumer, G, Doney, ASF, Vicente, AM, Delavaran, H, Algra, A, Davies, G, Oliveira, SA, Palmer, CNA, Deary, I, Schmidt, H, Pandolfo, M, Montaner, J, Carty, C, de Bakker, PIW, Kostulas, K, Ferro, JM, van Zuydam, NR, Valdimarsson, E, Nordestgaard, BG, Lindgren, A, Thijs, V, Slowik, A, Saleheen, D, Pare, G, Berger, K, Thorleifsson, G, Hofman, B, Mosley, TH, Mitchell, BD, Furie, K, Clarke, R, Levi, C, Seshadri, S, Gschwendtner, A, Boncoraglio, GB, Sharma, P, Bis, JC, Gretarsdottir, S, Psaty, BM, Rothwell, PM, Rosand, J, Meschia, JF, Stefansson, K, Dichgans, M & Markus, HS 2012, 'Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies', Lancet Neurology, vol. 11, no. 11, pp. 951-962. https://doi.org/10.1016/S1474-4422(12)70234-X

TY - JOUR

T1 - Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies

AU - Traylor, M

AU - Farrall, M

AU - Holliday, EG

AU - Sudlow, C

AU - Hopewell, JC

AU - Cheng, YC

AU - Fomage, M

AU - Ikram, Arfan

AU - Malik, R

AU - Bevan, S

AU - Thorsteinsdottir, U

AU - Nalls, MA

AU - Longstreth, WT

AU - Wiggins, KL

AU - Yadav, S

AU - Parati, EA

AU - DeStefano, AL

AU - Worrall, BB

AU - Kittner, S

AU - Khan, MS

AU - Reiner, AP

AU - Helgadottir, A

AU - Achterberg, S

AU - Fernandez-Cadenas, I

AU - Abboud, S

AU - Schmidt, R

AU - Walters, M

AU - Chen, WM

AU - Ringelstein, EB

AU - O'Donnell, M

AU - Ho, WK

AU - Pera, J

AU - Lemmens, R

AU - Norrving, B

AU - Higgins, P

AU - Benn, M

AU - Sale, M

AU - Kuhlenbaumer, G

AU - Doney, ASF

AU - Vicente, AM

AU - Delavaran, H

AU - Algra, A

AU - Davies, G

AU - Oliveira, SA

AU - Palmer, CNA

AU - Deary, I

AU - Schmidt, Heléna

AU - Pandolfo, M

AU - Montaner, J

AU - Carty, C

AU - de Bakker, PIW

AU - Kostulas, K

AU - Ferro, JM

AU - van Zuydam, NR

AU - Valdimarsson, E

AU - Nordestgaard, BG

AU - Lindgren, A

AU - Thijs, V

AU - Slowik, A

AU - Saleheen, D

AU - Pare, G

AU - Berger, K

AU - Thorleifsson, G

AU - Hofman, Bert

AU - Mosley, TH

AU - Mitchell, BD

AU - Furie, K

AU - Clarke, R

AU - Levi, C

AU - Seshadri, S

AU - Gschwendtner, A

AU - Boncoraglio, GB

AU - Sharma, P

AU - Bis, JC

AU - Gretarsdottir, S

AU - Psaty, BM

AU - Rothwell, PM

AU - Rosand, J

AU - Meschia, JF

AU - Stefansson, K

AU - Dichgans, M

AU - Markus, HS

PY - 2012

Y1 - 2012

N2 - Background Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes. Methods We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nudeotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls. Findings We verified previous associations for cardioembolic stroke near PITX2 (p=2.8x10(-16)) and ZFHX3 (p=2.28x10(-8)), and for large-vessel stroke at a 9p21 locus (p=3.32x10(-5)) and HDAC9 (p=2.03x10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We Interpretation Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.

AB - Background Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes. Methods We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nudeotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls. Findings We verified previous associations for cardioembolic stroke near PITX2 (p=2.8x10(-16)) and ZFHX3 (p=2.28x10(-8)), and for large-vessel stroke at a 9p21 locus (p=3.32x10(-5)) and HDAC9 (p=2.03x10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We Interpretation Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.

U2 - 10.1016/S1474-4422(12)70234-X

DO - 10.1016/S1474-4422(12)70234-X

M3 - Article

SN - 1474-4422

VL - 11

SP - 951

EP - 962

JO - The Lancet Neurology

JF - The Lancet Neurology

IS - 11

ER -