Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies
| Autor: | Traylor, M, Persyn, E, Tomppo, L, Klasson, S, Abedi, V, Bakker, MK, Torres, N, Li, LX, Bell, S, Rutten-Jacobs, L, Tozer, DJ, Griessenauer, CJ, Zhang, YF, Pedersen, A, Sharma, P, Jimenez-Conde, J, Rundek, T, Grewal, RP, Lindgren, A, Meschia, JF, Salomaa, V, Havulinna, A, Kourkoulis, C, Crawford, K, Marini, S, Mitchell, BD, Kittner, SJ, Rosand, J, Dichgans, M, Jern, C, Strbian, D, Fernandez-Cadenas, I, Zand, R, Ruigrok, Y, Rost, N, Lemmens, R, Rothwell, PM, Anderson, CD, Wardlaw, J, Lewis, CM, Markus, HS, Helsinki Stroke Study, Dutch Parelsnoer Inst Cerebrovasc, Natl Inst Neurological Disorders, UK DNA Lacunar Stroke Study, Int Stroke Genetics Consortium |
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| Přispěvatelé: | University of St Andrews. School of Biology, Bell, Steven [0000-0001-6774-3149], Tozer, Daniel [0000-0002-0404-3214], Markus, Hugh [0000-0002-9794-5996], Apollo - University of Cambridge Repository, HUS Neurocenter, Helsinki University Hospital Area, Neurologian yksikkö, Medicum, Institute for Molecular Medicine Finland, University of Helsinki |
| Rok vydání: | 2021 |
| Předmět: |
Oncology
PATHOGENESIS LOCI Genome-wide association study Disease VARIANTS 3124 Neurology and psychiatry SUBTYPES 0302 clinical medicine SMALL VESSEL DISEASE Stroke RISK 0303 health sciences Magnetic Resonance Imaging 3. Good health Europe ISCHEMIC-STROKE Meta-analysis Medical genetics Life Sciences & Biomedicine RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry medicine.medical_specialty Lacunar stroke Clinical Neurology QH426 Genetics CLASSIFICATION 03 medical and health sciences SDG 3 - Good Health and Well-being Internal medicine medicine Humans Genetic Predisposition to Disease cardiovascular diseases QH426 METAANALYSIS 030304 developmental biology Genetic association Science & Technology business.industry 3112 Neurosciences Australia DAS medicine.disease Hyperintensity United States ONSET Stroke Lacunar RC0321 Neurology (clinical) Neurosciences & Neurology business 030217 neurology & neurosurgery Genome-Wide Association Study |
| Zdroj: | Traylor, M, Persyn, E, Tomppo, L, Klasson, S, Abedi, V, Bakker, M K, Torres, N, Li, L, Bell, S, Rutten-jacobs, L, Tozer, D J, Griessenauer, C J, Zhang, Y, Pedersen, A, Sharma, P, Jimenez-conde, J, Rundek, T, Grewal, R P, Lindgren, A, Meschia, J F, Salomaa, V, Havulinna, A, Kourkoulis, C, Crawford, K, Marini, S, Mitchell, B D, Kittner, S J, Rosand, J, Dichgans, M, Jern, C, Strbian, D, Fernandez-cadenas, I, Zand, R, Ruigrok, Y, Rost, N, Lemmens, R, Rothwell, P M, Anderson, C D, Wardlaw, J, Lewis, C M & Markus, H S 2021, ' Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies ', The Lancet Neurology . https://doi.org/10.1016/S1474-4422(21)00031-4 Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona LANCET NEUROLOGY r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau Instituto de Salud Carlos III (ISCIII) |
| ISSN: | 1474-4422 |
| DOI: | 10.17863/cam.66561 |
| Popis: | Funding: 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). 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 |
| Databáze: | OpenAIRE |
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