TY - JOUR
T1 - Genetic basis of lacunar stroke
T2 - a pooled analysis of individual patient data and genome-wide association studies
AU - Helsinki Stroke, Study Dutch Parelsnoer Institute-Cerebrovascular Accident (CVA) Study Group
AU - National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network
AU - UK DNA Lacunar Stroke Study Investigators
AU - International Stroke Genetics Consortium
AU - Traylor, Matthew
AU - Persyn, Elodie
AU - Tomppo, Liisa
AU - Klasson, Sofia
AU - Abedi, Vida
AU - Bakker, Mark K.
AU - Torres, Nuria
AU - Li, Linxin
AU - Bell, Steven
AU - Rutten-Jacobs, Loes
AU - Tozer, Daniel J.
AU - Griessenauer, Christoph J.
AU - Zhang, Yanfei
AU - Pedersen, Annie
AU - Sharma, Pankaj
AU - Jimenez-Conde, Jordi
AU - Rundek, Tatjana
AU - Grewal, Raji P.
AU - Lindgren, Arne
AU - Meschia, James F.
AU - Salomaa, Veikko
AU - Havulinna, Aki
AU - Kourkoulis, Christina
AU - Crawford, Katherine
AU - Marini, Sandro
AU - Mitchell, Braxton D.
AU - Kittner, Steven J.
AU - Rosand, Jonathan
AU - Dichgans, Martin
AU - Jern, Christina
AU - Strbian, Daniel
AU - Fernandez-Cadenas, Israel
AU - Zand, Ramin
AU - Ruigrok, Ynte
AU - Rost, Natalia
AU - Lemmens, Robin
AU - Rothwell, Peter M.
AU - Anderson, Christopher D.
AU - Wardlaw, Joanna
AU - Lewis, Cathryn M.
AU - Markus, Hugh S.
N1 - Funding Information:
The UK Household Longitudinal Study is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The survey was done by NatCen and the genome-wide scan data were analysed and deposited by the Wellcome Trust Sanger Institute. Information on how to access the data can be found on the Understanding Society website https://www.understandingsociety.ac.uk/. This research made use of the UK Biobank Resource under application number 36509. Ethical approval for UK Biobank was received from the research ethics committee (REC reference 11/NW/0382). We are grateful to deCODE genetics for providing data for this analysis. We acknowledge the contribution of Giorgio Boncoraglio (Fondazione IRCCS Instituto Neurologico Carlo Besta, Milan, Italy). This work, including collection and genotyping of the UK Young Lacunar Stroke DNA Study 2 (DNA Lacunar 2), was supported by a British Heart Foundation Programme Grant (RG/16/4/32218). The NINDS Stroke Genetics Network study was funded by the US National Institute of Neurological Disorders and Stroke, National Institutes of Health (U01 NS069208 and R01 NS100178). Collection of the UK Young Lacunar Stroke DNA Study 1 (DNA Lacunar) was primarily supported by the Wellcome Trust (WT072952), with additional support from the Stroke Association (TSA 2010/01). Genotyping of the DNA Lacunar samples was supported by a Stroke Association Grant (TSA 2013/01). The principal funding for the WTCCC2 stroke study was provided by the Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z and WT084724MA). Collection and genotyping of the Sahlgrenska Academy Study on Ischemic Stroke were primarily supported by the Swedish Research Council (grant #2018?02543), the Swedish Heart and Lung Foundation (20190203), and the Swedish state under the agreement between the Swedish government and the county councils (the ALF agreement, ALFGBG-720081). The genetic data from Geisinger was made available through the collaboration with Regeneron Genetic Centre. The Edinburgh Mild Stroke Study (MSS2) was funded by the Wellcome Trust (WT088134/Z/09/A). MT was supported by The Barts Charity and the National Institute of Health Research (NIHR) Barts Biomedical Research Centre. RL is a senior clinical investigator of FWO Flanders. PMR and the Oxford Vascular Study are funded by the NIHR Oxford Biomedical Research Centre and the Wellcome Trust. CDA is supported by the US National Institutes of Health (R01NS103924 and K23NS086873). CML is supported by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. HSM is supported by an NIHR Senior Investigator award, and his work is supported by the Cambridge Universities NIHR Comprehensive Biomedical Research Centre.
Funding Information:
The UK Household Longitudinal Study is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The survey was done by NatCen and the genome-wide scan data were analysed and deposited by the Wellcome Trust Sanger Institute. Information on how to access the data can be found on the Understanding Society website https://www.understandingsociety.ac.uk/ . This research made use of the UK Biobank Resource under application number 36509. Ethical approval for UK Biobank was received from the research ethics committee (REC reference 11/NW/0382). We are grateful to deCODE genetics for providing data for this analysis. We acknowledge the contribution of Giorgio Boncoraglio (Fondazione IRCCS Instituto Neurologico Carlo Besta, Milan, Italy). This work, including collection and genotyping of the UK Young Lacunar Stroke DNA Study 2 (DNA Lacunar 2), was supported by a British Heart Foundation Programme Grant (RG/16/4/32218) . The NINDS Stroke Genetics Network study was funded by the US National Institute of Neurological Disorders and Stroke, National Institutes of Health ( U01 NS069208 and R01 NS100178 ). Collection of the UK Young Lacunar Stroke DNA Study 1 (DNA Lacunar) was primarily supported by the Wellcome Trust (WT072952), with additional support from the Stroke Association (TSA 2010/01). Genotyping of the DNA Lacunar samples was supported by a Stroke Association Grant (TSA 2013/01). The principal funding for the WTCCC2 stroke study was provided by the Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z and WT084724MA). Collection and genotyping of the Sahlgrenska Academy Study on Ischemic Stroke were primarily supported by the Swedish Research Council (grant #2018–02543), the Swedish Heart and Lung Foundation (20190203), and the Swedish state under the agreement between the Swedish government and the county councils (the ALF agreement, ALFGBG-720081). The genetic data from Geisinger was made available through the collaboration with Regeneron Genetic Centre. The Edinburgh Mild Stroke Study (MSS2) was funded by the Wellcome Trust (WT088134/Z/09/A). MT was supported by The Barts Charity and the National Institute of Health Research (NIHR) Barts Biomedical Research Centre. RL is a senior clinical investigator of FWO Flanders. PMR and the Oxford Vascular Study are funded by the NIHR Oxford Biomedical Research Centre and the Wellcome Trust. CDA is supported by the US National Institutes of Health (R01NS103924 and K23NS086873). CML is supported by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. HSM is supported by an NIHR Senior Investigator award, and his work is supported by the Cambridge Universities NIHR Comprehensive Biomedical Research Centre.
Funding Information:
AL reports grants from the Swedish Heart and Lung Foundation, Region Skåne, Skåne University Hospital, Freemasons Lodge of Instruction Eos in Lund, Lund University, the Färs & Frosta Foundation (a Sparbanken Skåne Foundation), and the Swedish Research Council, during the conduct of the study; and personal fees from AstraZeneca, Bristol Myers Squibb/Pfizer, Portola, and Bayer, outside the submitted work. VS reports honoraria for consultation from Novo Nordisk and Sanofi and grants from Bayer, outside the submitted work. AH reports grants from the Academy of Finland, outside the submitted work. JR reports grants from the US National Institutes of Health and OneMind, during the conduct of the study, and personal fees from Boehringer Ingelheim, Pfizer, and New Beta Innovation, outside the submitted work. PMR reports personal fees from Bayer and Bristol Myers Squibb, outside the submitted work. CDA reports grants from the US National Institutes of Health, the American Heart Association, Massachusetts General Hospital, and Bayer, and personal fees from ApoPharma, outside the submitted work. JW reports grants from the Wellcome Trust, during the conduct of the study. HSM reports personal fees from BIBA Medical, outside the submitted work. All other authors declare no competing interests.
Publisher Copyright:
© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/5
Y1 - 2021/5
N2 - Background: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease. Methods: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation. Findings: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke. Interpretation: Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk. Funding: British Heart Foundation.
AB - Background: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease. Methods: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation. Findings: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke. Interpretation: Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk. Funding: British Heart Foundation.
UR - http://www.scopus.com/inward/record.url?scp=85103972083&partnerID=8YFLogxK
U2 - 10.1016/S1474-4422(21)00031-4
DO - 10.1016/S1474-4422(21)00031-4
M3 - Article
C2 - 33773637
AN - SCOPUS:85103972083
SN - 1474-4422
VL - 20
SP - 351
EP - 361
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 5
ER -
