Siblings With Ischemic Stroke Study (SWISS)
Principal Investigator: JAMES MESCHIA
Abstract: Stroke is the third leading cause of death in industrialized countries and a leading cause of acquired disability in adults. Each year, about 700,000 people experience stroke in the United States. Ischemic stroke constitutes about 85% of all strokes. Ischemic stroke is a complex genetic disorder, the result of interactions between multiple genes and multiple environmental exposures. Several epidemiological lines of evidence suggest an important genetic component to the overall risk of acquiring stroke. Cohort studies show that a positive family history for stroke increases stroke risk by 30%. The affected sibling pair methodology has been used successfully in other neurological and non-neurological disorders to define risk factor loci and has lead to the discovery of novel risk factor genes that would not have been assumed a priority to be key to the pathogenesis of these disorders. The affected sibling pair approach to risk factor locus discovery should be applied to ischemic stroke. The broad long-term objective of the application is to search for regions of interest in the human genome that may harbor stroke susceptibility genes. This is a competing continuation of the multicenter Siblings With Ischemic Stroke Study (SWISS). As of October 2004, DMA samples have been obtained from 170 affected sibling pairs (174 probands and 240 full siblings). The primary aims are: (1) to collect DMA samples from 300 sibling pairs concordant for ischemic stroke and 200 siblings discordant for ischemic stroke (total number of study subjects = 800), and (2) to perform a genome-wide screen for genetic risk factors for ischemic stroke using microsatellite markers spaced at 20 centimorgan intervals. Secondary aims include the identification of genetic regions of interest associated with ischemic stroke in adults below the age of 50 years and the identification of genetic regions of interest that are independent of the status of diabetes, hypertension, cigarette smoking, and atrial fibrillation among study subjects. Probands will be screened from patients who present with acute ischemic stroke to 1 of about 50 centers. A centralized stroke verification committee will assure accuracy in phenotyping. Ischemic strokes are classified in all affected individuals using the Trial of ORG10172 Acute Stroke Treatment (TOAST) criteria. DNA banking and the creation of permanent lymphoblastoid cell lines will be done to permit future collaborative efforts to study the genetic basis for stroke risk.
Funding Period: 2000-09-30 - 2010-06-30
more information: NIH RePORT
- Multilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studiesRainer Malik
From the Institute for Stroke and Dementia Research, Klinikum der Universitat Munchen, Ludwig Maximilians Universitat, Munich, Germany R M, M D Stroke and Dementia Research Centre, St George s University of London, London, United Kingdom S B, H S M Laboratory of Neurogenetics M A N and Laboratory of Epidemiology and Population Sciences L J L, National Institute on Aging, National Institutes of Health, Bethesda, MD Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health E G H and Center for Translational Neuroscience and Mental Health Research C L, University of Newcastle, Callaghan, NSW, Australia Center for Bioinformatics, Biomarker Discovery and Information Based Medicine, Hunter Medical Research Institute, New Lambton, NSW, Australia E G H Department of Neurology, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA W J D, J R Department of Medicine, University of Maryland School of Medicine, Baltimore, MD Y C C, B D M Department of Veterans Affairs and Veterans Affairs Medical Center, Baltimore Geriatric Research, Education, and Clinical Center GRECC, Baltimore, MD Y C C, B D M Department of Epidemiology C A I V, B F J V, Baltimore
Stroke 45:394-402. 2014..We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts...
- Genetic variants associated with myocardial infarction in the PSMA6 gene and Chr9p21 are also associated with ischaemic strokeM G Heckman
Biostatistics Unit, Mayo Clinic, Jacksonville, FL 32224, USA
Eur J Neurol 20:300-8. 2013..This study evaluated whether genetic risk factors for CAD and MI also affect susceptibility to ischaemic stroke in Caucasians and African Americans...
- Ischemic stroke is associated with the ABO locus: the EuroCLOT studyFrances M K Williams
Department of Twin Research and Genetic Epidemiology, King s College London, United Kingdom
Ann Neurol 73:16-31. 2013..We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype...
- Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathyNadine Norton
Cardiovascular Division, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
Circ Cardiovasc Genet 6:144-53. 2013..However, the lack of segregation of all identified TTN truncating variants illustrates the challenge of determining variant pathogenicity even with full exome sequencing...
- Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke: systematic review and meta-analysis of 14,015 stroke cases and pooled analysis of primary biomarker data from up to 60,883 individualsTauseef A Khan
Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK
Int J Epidemiol 42:475-92. 2013..We evaluated the association of APOE genotype with risk of ischaemic stroke and assessed whether the observed effect was consistent with the effects of APOE genotype on LDL-C or other lipids and biomarkers of cardiovascular risk...
- Genome-wide analysis of blood pressure variability and ischemic strokeSunaina Yadav
From the Imperial College Cerebrovascular Research Unit ICCRU S Y, I C, M S K, N H, M P, P E R, P S and International Centre for Circulatory Health P S, Imperial College London, London, United Kingdom Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health E G H, M M, J A, School of Nursing and Midwifery J M M, and School of Biomedical Sciences and Pharmacy R J S, University of Newcastle, Newcastle, New South Wales, Australia Hunter Medical Research Institute, Newcastle, New South Wales, Australia E G H, J M M, M M, R J S, J A Institute for Stroke and Dementia Research ISD, Medical Centre, Klinikum der Universitat Munchen, Ludwig Maximilians University, Munich, Germany R M, M D Munich Cluster for Systems Neurology SyNergy, Munich, Germany R M, M D Stroke and Dementia Research Centre, St George s University of London, London, Germany
Stroke 44:2703-9. 2013..We sought to determine whether such variability has genetic causes and whether genetic variants associated with BP variability are also associated with ischemic stroke...
- Stroke Genetics Network (SiGN) study: design and rationale for a genome-wide association study of ischemic stroke subtypesJames F Meschia
From the Mayo Clinic Jacksonville, FL J F M University of Alabama at Birmingham D K A, L A M Mayo Clinic Rochester, MN R D B Massachusetts General Hospital, Boston, MA H A, J R, O W University of British Columbia, Vancouver, British Columbia, Canada O R B University of Maryland School of Medicine and Veterans Administration Medical Center, Baltimore, MD J W C, P F M, B D M, A R S, S J K University Medical Center Utrecht, Utrecht, The Netherlands P I W d B Brigham and Women s Hospital, Harvard Medical School, Boston, MA P I W d B Broad Institute of Harvard, MIT, Cambridge, MA P I W d B Klinikum der Universität München, Ludwig Maximilians University, Munich, Germany M D Johns Hopkins University, Baltimore, MD K F D University of Texas Health Science Center at Houston M F Saint Francis Medical Center, Lynwood, CA R P G NINDS Neurogenetics Cluster, Bethesda, MD K G IMIM Hospital Universitari del Mar, Barcelona, Spain J J C University of Florida, College of Pharmacy, Gainesville, FL J A J Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Germany
Stroke 44:2694-702. 2013..The National Institute of Neurological Disorders and Stroke SiGN (Stroke Genetics Network) contributes substantially to meta-analyses that focus on specific subtypes of stroke...
- NOTCH3 variants and risk of ischemic strokeOwen A Ross
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America
PLoS ONE 8:e75035. 2013..The role of other exonic NOTCH3 variation not involving cysteine residues and mutations in exons 25-33 in ischemic stroke remains unresolved...
- Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variantsMartin Dichgans
From the Institute for Stroke and Dementia Research, Klinikum der Universitat Munchen, Ludwig Maximilians Universitat, Munich, Germany M D, R Malik Munich Cluster for Systems Neurology SyNergy, Munich, Germany M D Institut für Medizinische Biometrie und Statistik I R K, and Institut für integrative und experimentelle Genomik J E, Universitat zu Lubeck, Lubeck, Germany Universitätsklinikum Schleswig Holstein, Campus Lubeck, Germany I R K Department of Neurology and Center for Human Genetic Research J R, and Cardiology Division C J O D, Massachusetts General Hospital, Boston Harvard Medical School, Boston, MA J R Program in Medical and Population Genetics J R, and Program in Medical and Population Genetics S K, Broad Institute of Harvard and MIT, Cambridge, MA Clinical Trial Service Unit and Epidemiological Studies Unit R C, J C H, Wellcome Trust Centre for Human Genetics H W, M Farrall, Department of Cardiovascular Medicine M Farrall, and Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience P M R, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom deCODE Genetics, Reykjavik, Iceland S G, G T, U T
Stroke 45:24-36. 2014..Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases...
- Common mitochondrial sequence variants in ischemic strokeChristopher D Anderson
Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, USA
Ann Neurol 69:471-80. 2011..We investigated whether common mitochondrial genetic variants influence risk of sporadic ischemic stroke and, in patients with stroke, the volume of white matter hyperintensity (WMHV)...
- New information on the genetics of strokeJames F Meschia
Cerebrovascular Division, Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
Curr Neurol Neurosci Rep 11:35-41. 2011....
- Genetic susceptibility to ischemic strokeJames F Meschia
Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
Nat Rev Neurol 7:369-78. 2011....
- Siblings with ischemic stroke study: results of a genome-wide scan for stroke lociJames F Meschia
Department of Neurology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, USA
Stroke 42:2726-32. 2011..The Siblings With Ischemic Stroke Study was conducted to examine the associations between single-nucleotide polymorphisms (SNPs) and risk of stroke and stroke subtypes within pairs...
- Genomic risk profiling of ischemic stroke: results of an international genome-wide association meta-analysisJames F Meschia
Department of Neurology, Mayo Clinic, Jacksonville, Florida, United States of America
PLoS ONE 6:e23161. 2011..We present a meta-analysis of genome-wide association scans (GWAS) from 3 cohorts to identify the contribution of common variants to ischemic stroke risk...
- Are myocardial infarction--associated single-nucleotide polymorphisms associated with ischemic stroke?Yu Ching Cheng
Department of Medicine, University of Maryland School of Medicine, 660 W Redwood St, Howard Hall, Room 492, Baltimore, MD 21201, USA
Stroke 43:980-6. 2012..To test this hypothesis, we evaluated whether single-nucleotide polymorphisms (SNPs) at 11 different loci recently associated with MI or CAD through genome-wide association studies were associated with IS...
- Rare variants in ischemic stroke: an exome pilot studyJohn W Cole
Veterans Administration Medical Center, Baltimore, Maryland, United States of America
PLoS ONE 7:e35591. 2012..Our study demonstrates the complexities of such research and highlights that while exome data can be obtained, the optimal analytical methods have yet to be determined...
- Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trialsMichael V Holmes
Research Department of Epidemiology and Public Health, University College London, London, UK
Lancet 378:584-94. 2011..We aimed to reduce the effect of small-study bias and investigate whether folate status modifies the association between MTHFR 677C→T and stroke in a genetic analysis and meta-analysis of randomised controlled trials...
- Pharmacogenetics and strokeJames F Meschia
Mayo Clinic, Jacksonville, Fla 32224, USA
Stroke 40:3641-5. 2009..Physicians, pharmaceutical companies, regulatory agencies, and health insurers continue to grapple with how best to translate this burgeoning field into effective individualized medicine...
- IL1RN VNTR polymorphism in ischemic stroke: analysis in 3 populationsBradford B Worrall
Department of Neurology, University of Virginia Health System, Charlottesville, VA, USA
Stroke 38:1189-96. 2007..The purpose of this study was to confirm our earlier finding of an association between allele 2 of a variable number tandem repeat of the IL-1 receptor antagonist gene (IL1RN) and cerebrovascular disease...
- Lack of aggregation of ischemic stroke subtypes within affected sibling pairsP G Wiklund
Department of Medicine, Umea University, Umea, Sweden
Neurology 68:427-31. 2007..To establish whether subtypes of ischemic stroke aggregate within ischemic stroke-affected sibling pairs more than expected by chance alone...
- PDE4D and stroke: a real advance or a case of the Emperor's new clothes?Bradford B Worrall
Stroke 37:1955-7. 2006
- The Siblings With Ischemic Stroke Study (SWISS): a progress reportJames F Meschia
Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224, USA
Clin Med Res 4:12-21. 2006..This report updates the progress of enrollment in the SWISS protocol, discusses barriers to pedigree completion and describes innovative approaches used by the SWISS investigators to enhance enrollment...
- Ischemic stroke as a complex genetic disorderJames F Meschia
Department of Neurology, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA
Semin Neurol 26:49-56. 2006..Family history studies suggest that some subphenotypes like cardioembolic stroke may be less heritable than others...
- Phosphodiesterase 4D and 5-lipoxygenase activating protein in ischemic strokeJames F Meschia
Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA
Ann Neurol 58:351-61. 2005..There was no evidence of association between variants of ALOX5AP and ischemic stroke. These data suggest that common variants in PDE4D may contribute to the genetic risk for ischemic stroke in multiple populations...
- A survey of the SWISS researchers on the impact of sibling privacy protections on pedigree recruitmentBradford B Worrall
Department of Neurology, University of Virginia, Charlottesville, VA, USA
Neuroepidemiology 25:32-41. 2005..A substantial minority of researchers (37%) said the strategy impeded enrollment, and 44% said it was overly burdensome to probands...
- Correlation of proband and sibling stroke latency: the SWISS StudyJ F Meschia
Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
Neurology 64:1061-3. 2005..68; p < 0.0001), diabetes (r = 0.73; p < 0.0001), and hypertension (r = 0.63; p < 0.0001). In the authors' cohort of affected sibling pairs, inherited factors were important determinants of incident ischemic stroke latency...
- Association of integrin alpha2 gene variants with ischemic strokeMar Matarin
Neurogenetics Laboratory, National Institute on Aging, Bethesda, Maryland, USA
J Cereb Blood Flow Metab 28:81-9. 2008..These results provide additional support for a role for platelet receptor genes in the pathogenesis of ischemic stroke of diverse subtypes...
- Advancing stroke therapeutics through genetic understandingO A Ross
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
Curr Drug Targets 8:850-9. 2007..Identifying possible genetic determinants of outcome will also open new avenues of research into stroke therapeutics beyond thrombolysis...
- Stroke genetic research and adults with impaired decision-making capacity: a survey of IRB and investigator practicesDonna T Chen
Department of Neurology, Center for Biomedical Ethics and Humanities, University of Virginia, Charlottesville, VA 22908, USA
Stroke 39:2732-5. 2008..This study was conducted to obtain data on how investigators and IRBs handle surrogate authorization to enroll probands into a genetic study where some may lack capacity because of ischemic stroke...
- Candidate gene polymorphisms for ischemic strokeMar Matarin
Molecular Genetics Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
Stroke 40:3436-42. 2009..We investigated the contribution of 67 candidate genes (369 single nucleotide polymorphisms [SNPs]) on the risk of IS in a North American population of European descent...
- Joint Commission primary stroke center certification does not affect proband enrollment: the siblings with ischemic stroke studyAlexa N Richie
Department of Neurology, Mayo Clinic, Jacksonville, Florida 32224, USA
J Stroke Cerebrovasc Dis 18:363-6. 2009..Whether certification promotes enrollment of study subjects into stroke research studies is not known. We examined whether enrollment performance of centers was related to JC certification status...
- Association of higher diastolic blood pressure levels with cognitive impairmentG Tsivgoulis
Comprehensive Stroke Center, University of Alabama at Birmingham, RWUH M226, 1530 3rd Avenue S, Birmingham, AL 35294 3280, USA
Neurology 73:589-95. 2009..We evaluated the cross-sectional relationship of blood pressure (BP) components with cognitive impairment after adjusting for potential confounders...
- Education research: Bias and poor interrater reliability in evaluating the neurology clinical skills examinationL A Schuh
Department of Neurology, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202, USA
Neurology 73:904-8. 2009..The ABPN postulated the experience with the NEX would be similar to the Mini-Clinical Evaluation Exercise, a reliable and valid assessment tool. The reliability and validity of the NEX has not been established...
- Whole genome approaches in ischemic strokeJames F Meschia
Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
Stroke 40:S61-3. 2009..The field of ischemic stroke genetics is moving beyond candidate gene studies into the realm of genomewide association studies. Such studies have resulted in discoveries in diverse, complex disorders...
- Proband race/ethnicity affects pedigree completion rate in a genetic study of ischemic strokeBrett M Kissela
Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA
J Stroke Cerebrovasc Dis 17:299-302. 2008..However, little is known about the predictors of enrollment in family-based observational genetic studies. We tested the hypothesis that proband race/ethnicity is a significant predictor of enrolling a pedigree...
- The impact of privacy protections on recruitment in a multicenter stroke genetics studyD T Chen
Department of Health Evaluation Sciences, University of Virginia, Charlottesville, USA
Neurology 64:721-4. 2005..The sibling response rate was 30.6%, for a pedigree response rate of 58%. Of the siblings who replied, 96% authorized further contact. Median time from proband enrollment to pedigree DNA banking, which required 3+ probands, was 134 days...