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

Traylor, Matthew; Farrall, Martin; Holliday, Elizabeth G.; Sudlow, Cathie; Hopewell, Jemma C.; Cheng, Yu‐Ching; Fornage, Myriam; Ikram, M. Arfan; Malik, Rainer; Bevan, Steve; Þorsteinsdóttir, Unnur; Nalls, Mike A.; Longstreth, W. T.; Wiggins, Kerri L.; Yadav, Sunaina; Parati, Eugenio; DeStefano, Anita L.; Worrall, Bradford B.; Kittner, Steven J.; Khan, Muhammad Saleem; Reiner, Alex P.; Helgadóttir, Anna; Achterberg, Sefanja; Fernández-Cadenas, Israel; Abboud, Shérine; Schmidt, Reinhold; Walters, Matthew; Chen, Weimin; Ringelstein, E. B.; O’Donnell, Martin J.; Ho, Weang Kee; Pera, Joanna; Lemmens, Robin; Norrving, Bo; Higgins, Peter; Benn, Marianne; Sale, Michèle M.; Kuhlenbäumer, Gregor; Doney, Alex S.F.; Vicente, Astrid M.; Delavaran, Hossein; Algra, Ale; Davies, Gail; Oliveira, Sofia A.; Palmer, Colin N.A.; Deary, Ian J.; Schmidt, Helena; Pandolfo, Massimo; Montaner, Joan; Carty, Cara L.; Bakker, Paul I. W. de; Kostulas, Konstantinos; Ferro, José M.; Zuydam, Natalie R. van; Valdimarsson, Einar Már; Nordestgaard, Børge G.; Lindgren, Arne; Thijs, Vincent; Słowik, Agnieszka; Saleheen, Danish; Paré, Guillaume; Berger, Klaus; Þorleifsson, Guðmar; Hofman, Albert; Mosley, Thomas H.; Mitchell, Braxton D.; Furie, Karen L.; Clarke, Robert; Levi, Christopher; Seshadri, Sudha; Gschwendtner, Andreas; Boncoraglio, Giorgio B.; Sharma, Pankaj; Bis, Joshua C.; Grétarsdóttir, Sólveig; Psaty, Bruce M.; Rothwell, Peter M.; Rosand, Jonathan; Meschia, James F.; Stefánsson, Kāri; Dichgans, Martin; Markus, Hugh S.

doi:10.1016/s1474-4422(12)70234-x

Cited by 433 publications

(396 citation statements)

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“…Importantly, our study validated an association of chromosome 12q24.12. This locus was reported to be associated with CAD, 5 intracranial aneurysm, 14 ischemic stroke, 15 blood pressure, 16 kidney function, 17 type 1 diabetes, 18 serum urate 19 and lipid concentration, 20 and drinking behavior, 21 suggesting that this locus is an important genetic component of cardiovascular diseases and their risk factors. Because top associated SNP (rs3782886:A4G) is closely linked to two functional variants in this region (rs671:A4G in ALDH2 and rs11066001:C4T in BRAP), 22 we confirmed that the risk haplotype, which contains several functional variants, will affect the susceptibility of cardiovascular disease and its risk factors.…”

Section: Discussionmentioning

confidence: 99%

A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese

et al. 2014

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Despite considerable progress in preventive and therapeutic strategies, myocardial infarction (MI) is one of the leading causes of death throughout the world. A total of 55 susceptibility genes have been identified mostly in European genome-wide association studies (GWAS). Nevertheless, large-scale GWAS from other population could possibly find additional susceptibility loci. To identify as many MI susceptibility loci as possible, we performed a large-scale genomic analysis in Japanese population. To identify MI susceptibility loci in Japanese, we conducted a GWAS using 1666 cases and 3198 controls using the Illumina Human610-Quad BeadChip and HumanHap550v3 Genotyping BeadChip. We performed replication studies using a total of 11 412 cases and 28 397 controls in the Japanese population. Our study identified two novel susceptibility loci for MI: PLCL2 on chromosome 3p24.3 (rs4618210:A4G, P ¼ 2.60 Â 10 À9 , odds ratio (OR) ¼ 0.91) and AP3D1-DOT1L-SF3A2 on chromosome 19p13.3 (rs3803915:A4C, P ¼ 3.84 Â 10 À9 , OR ¼ 0.89). Besides, a total of 14 previously reported MI susceptibility loci were replicated in our study. In particular, we validated a strong association on chromosome 12q24 (rs3782886:A4G: P ¼ 1.14 Â 10 À14 , OR ¼ 1.46). Following pathway analysis using 265 genes related to MI or coronary artery disease, we found that these loci might be involved in the pathogenesis of MI via the promotion of atherosclerosis. In the present large-scale genomic analysis, we identified PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for MI in the Japanese population. Our findings will add novel findings for MI susceptibility loci. INTRODUCTIONMyocardial infarction (MI), the severest form of coronary artery disease (CAD), is characterized by the occlusion of the coronary artery, resulting in ischemic damage of the myocardium. The occlusion of the coronary artery is characterized by abrupt plaque rupture with thrombogenesis 1 following the atherosclerotic process, which has recently been regarded as a chronic inflammatory condition involving lipid accumulation, abnormal extracellular matrix metabolism, innate immunity with macrophages, and the adaptive immune response with T and B lymphocytes. 2 Despite recent dramatic advances in preventive and/or therapeutic strategies, MI is still one of the leading causes of death in Asian populations as well as European populations.The pathogenesis of MI is considered to be the cumulative effect of multiple genetic and environmental factors. For the genetic aspect, a

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Section: Discussionmentioning

confidence: 99%

A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese

et al. 2014

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“…In selecting IS associated SNPs, we considered the five loci (9p21, HDAC9, PITX2, ZFHX3 , and 12q24.12 ) associated with stroke in METASTROKE and in a recent publication 38, 39. We set a p ‐value threshold of p = 0.01 to determine significance, using the Bonferroni method to correct for five independent tests.…”

Section: Participants and Methodsmentioning

confidence: 99%

Shared genetic contribution to ischemic stroke and Alzheimer's disease

Traylor¹,

Adib-Samii²,

Harold³

et al. 2016

Annals of Neurology

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ObjectiveIncreasing 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.MethodsUsing 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.ResultsWe 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.InterpretationOur 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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“…109 For us it was also an unfortunate surprise that the large METASTROKE collaboration identified interesting candidate genes for cardioembolic (PITX2 and ZFHX3) and for large-vessel stroke (HDAC9) but no signal was found for small-vessel stroke. 110 Finally, linkage studies have identified several chromosomes with shared loci associated with WMH volumes and also with blood pressure parameters, suggesting pleiotropic genes might exist in these locations. 111,112 New genetic technology including exome sequencing and epigenetics will probably be used in the coming years and might add new players to the field.…”

Section: Genome-wide Association Studiesmentioning

confidence: 99%

Blood and CSF biomarkers in brain subcortical ischemic vascular disease: Involved pathways and clinical applicability

Vilar-Bergua

Riba‐Llena

Nafría

et al. 2015

J Cereb Blood Flow Metab

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Vascular dementia is the second most common type of dementia after Alzheimer's disease (AD). Subcortical ischemic vascular disease refers to a form of vascular cognitive impairment characterized by the presence of diffuse white matter hyperintensities (WMHs) and multiple lacunar infarcts. These neuroimaging findings are mainly caused by cerebral smallvessel disease (cSVD) and relate to aging and cognitive impairment, but they can also be silent and highly prevalent in otherwise healthy individuals. We aimed to review studies on blood and cerebrospinal fluid (CSF) markers related to the presence of WMHs and lacunar infarcts that have been conducted in the past in large population-based studies and in high-risk selected patients (such as those with vascular risk factors, vascular cognitive impairment, or AD). Relevant associations with the presence and progression of cSVD have been described in the blood for markers related to inflammatory processes, endothelial damage and coagulation/fibrinolysis processes, etc. Also, different combinations of CSF markers might help to differentiate between etiologic types of dementia. In the future, to translate these findings into clinical practice and use biomarkers to early diagnosis and monitoring vascular cognitive impairment would require the replication of candidate markers in large-scale, multicenter, and prospectively designed studies.

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

Cited by 433 publications

References 31 publications

A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese

A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese

Shared genetic contribution to ischemic stroke and Alzheimer's disease

Blood and CSF biomarkers in brain subcortical ischemic vascular disease: Involved pathways and clinical applicability

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