International Stroke Genetics Consortium Research Articles

Abstract P663: Polygenic Risk Scores for Plasma Levels of Fibrin D-Dimer and Tissue Plasminogen Activator Are Associated With Non-Lacunar Stroke

Introduction: Plasma concentrations of prothrombotic factors such as fibrinogen have previously been associated with ischemic stroke risk. To extend this observation, we examined the association of polygenic risk scores (PRS) for increased plasma levels of thrombosis-related factors with ischemic stroke. Our hypotheses were that these PRS would be more associated with early than late onset stroke and with non-lacunar than lacunar stroke. Methods: We identified 9053 late onset (≥ 60 years) stroke cases from the NINDS International Stroke Genetics Consortium (SiGN) with 24804 controls and 6594 early onset (< 60 years) stroke cases from the Genetics of Early Onset Ischemic Stroke Consortium with 30561 controls. We identified previously known loci associated with plasma levels of four thrombosis-related factors: fibrinogen, fibrin D-dimer, tPA and PAI-1 from prior GWAS studies and developed genome-wide PRS for plasma concentrations of these factors. We then used logistic regression to test the association of these scores with risk of stroke and stroke subtype. Results: PRS for fibrin D dimer levels were associated with increased risk for all stroke and specifically for older (p = 0.019), but not younger (p = 0.22) onset stroke. PRS for tPA levels were also marginally associated with older (p = 0.06), but not younger (p = 0.24) onset stroke. Genetic risk scores for both D dimer and tPA were associated with non-lacunar stroke (Table 1). Further analyses stratified by age revealed PRS for D dimer to be significantly associated with non-lacunar stroke (but not lacunar stroke) in both late and early onset cohorts. PRS for fibrinogen and PAI-1 were not associated with stroke. Conclusion: Genomic risk scores for thrombosis-related factors including D dimer and tPA levels were associated with risk for ischemic stroke, and specifically, non-lacunar stroke.

The Role of C-Reactive Protein and Fibrinogen in the Development of Intracerebral Hemorrhage: A Mendelian Randomization Study in European Population.

Background: The causal association of C-reactive protein (CRP) and fibrinogen on intracerebral hemorrhage (ICH) remains uncertain. We investigated the causal associations of CRP and fibrinogen with ICH using two-sample Mendelian randomization.Method: We used single-nucleotide polymorphisms associated with CRP and fibrinogen as instrumental variables. The summary data on ICH were obtained from the International Stroke Genetics Consortium (1,545 cases and 1,481 controls). Two-sample Mendelian randomization estimates were performed to assess with inverse-variance weighted and sensitive analyses methods including the weighted median, the penalized weighted median, pleiotropy residual sum and outlier (MR-PRESSO) approaches. MR-Egger regression was used to explore the pleiotropy.Results: The MR analyses indicated that genetically predicted CRP concentration was not associated with ICH, with an odds ratio (OR) of 1.263 (95% CI = 0.935–1.704, p = 0.127). Besides, genetically predicted fibrinogen concentration was not associated with an increased risk of ICH, with an OR of 0.879 (95% CI = 0.060–18.281; p = 0.933). No evidence of pleiotropic bias was detected by MR-Egger. The findings were overall robust in sensitivity analyses.Conclusions: Our findings did not support that CRP and fibrinogen are causally associated with the risk of ICH.

Proceedings of the 26th International Stroke Genetics Consortium Workshop: St. Louis, MO

The 26th workshop of the International Stroke Genetics Consortium (ISGC) was held at the Four Seasons Hotel on November 2–4, 2019 in St. Louis, MO, and was hosted by Jin-Moo Lee, MD, PhD and Carlos Cruchaga, PhD, and co-hosted by Stephanie Debette, MD, PhD. The ISGC is an international collaboration of physicians and scientists who have agreed to pool resources and expertise in an effort to unravel the genetic basis of stroke and its comorbidities. Founded in 2007 by a small group of stroke genetics investigators, the ISGC has grown to over 200 members representing over 50 countries in North and South America, Europe, Australia, Africa, and Asia. ISGC workshops are held semi-annually and provide a forum for ISGC investigators to report on progress of ongoing scientific projects and discuss new ideas that help advance the ISGC's research mission. The ISGC nurtures junior investigators by offering several travel awards to young investigators interested in stroke genetics. Many abstracts in these Proceedings reflect the contributions of active junior investigators. Herein, we present the Proceedings and official published abstracts of the 26th ISGC Workshop.

Proceedings of the 25th International Stroke Genetics Consortium Workshop: Cambridge, UK

The 25th workshop of the International Stroke Genetics Consortium (ISGC) was held at the beautiful and historic Queens' College, University of Cambridge, UK on April 10–12, 2019, and was hosted by Associate Professor Jemma C Hopewell, Dr Matthew Traylor, and Professor Hugh Markus, and co-hosted by Professor Jin-Moo Lee and Associate Professor Carlos Cruchaga. Herein, we present the Proceedings and official published abstracts of the 25th ISGC Workshop.

Effects of Genetic Variants on Stroke Risk.

Effects of Genetic Variants on Stroke Risk.

Highlights From the Circulation Family of Journals.

Highlights From the Circulation Family of Journals.

Proceedings of the 23rd International Stroke Genetics Consortium Workshop: Kyoto, Japan

The 23rd Workshop of the International Stroke Genetics Consortium (ISGC) was held on April 12–13 in Kyoto, Japan, and was hosted by Yoichiro Kamatani, Stephanie Debette, Paul Nyquist and John Cole. The ISGC is an international collaboration of physicians and scientists who have agreed to pool resources and expertise in an effort to unravel the genetic basis of stroke and its comorbidities ([strokegenetics.org][1]). It was formed in 2007 by a small group of scientists and has since grown to over 200 members representing over 50 countries in North and South America, Europe, Australia, Asia, and Africa. ISGC workshops are held semi-annually and provide a forum for ISGC scientists and researchers to report on progress of ongoing scientific projects and discuss new ideas that help advance the ISGC's research mission. Herein, we present the Proceedings and official published abstracts of the 23rd Workshop of the ISGC, which was the first ISGC Workshop held in Asia. [1]: http://www.strokegenetics.org

Proceedings of the 24th International Stroke Genetics Consortium Workshop: Washington, DC, USA

The 24th workshop of the International Stroke Genetics Consortium (ISGC) was held at the beautiful National Museum of the American Indian on November 8–9, 2018 in Washington, DC, and was hosted by Paul Nyquist, MD, MPH and John Cole, MD, MS, and co-hosted by Jemma Hopewell, PhD and Matthew Traylor, PhD. The ISGC is an international collaboration of physicians and scientists who have agreed to pool resources and expertise in an effort to unravel the genetic basis of stroke and its comorbidities. It was formed in 2007 by a small group of scientists and has since grown to over 200 members representing over 50 countries in North and South America, Europe, Australia, Africa, and Asia. ISGC workshops are held semi-annually and provide a forum for ISGC scientists and researchers to report on progress of ongoing scientific projects and discuss new ideas that help advance the ISGC's research mission. The ISGC nurtures its junior members by offering several travel awards to young investigators. Many abstracts in these Proceedings reflect the contributions of active junior investigators. Herein, we present the Proceedings and official published abstracts of the 24th ISGC workshop.

Proceedings of the 21st International Stroke Genetics Consortium Workshop

The 21st workshop and 10th anniversary of the International Stroke Genetics Consortium (ISGC) was held on June 1–2, 2017 in Houston, TX, hosted by Myriam Fornage and Ynte Ruigrok. The ISGC is an international collaboration of physicians and scientists who have agreed to pool resources and expertise in an effort to unravel the genetic basis of stroke and its comorbidities ([http://www.strokegenetics.org][1]). It was formed in 2007 by a small group of scientists and has since grown to over 200 members representing over 50 countries in North and South America, Europe, Australia, and Africa. ISGC workshops are held semi-annually and provide a forum for ISGC scientists and researchers to report on progress of ongoing scientific projects and discuss new ideas that help advance the ISGC's research mission. The ISGC nurtures its junior members offering up to 2 travel awards to young investigators. Many abstracts in these Proceedings reflect the contributions of active junior investigators. Herein, we present the Proceedings and official published abstracts of the 21st ISGC workshop. [1]: https://www.strokegenetics.org

Proceedings of the 22nd International Stroke Genetics Consortium Workshops

The 22nd Workshop of the International Stroke Genetics Consortium (ISGC) was held on November 2–3 in Utrecht, the Netherlands, and was hosted by Ynte Ruigrok and Yoichiro Kamatani. The Workshops are a semiannual tradition of the ISGC, where ISGC scientists meet to share their ideas and results. The ISGC is an international collaboration of physicians and scientists who have agreed to pool resources and expertise in an effort to unravel the genetic basis of stroke and its comorbidities ([http://www.strokegenetics.org][1]). It was formed in 2007 by a small group of scientists and has since grown to over 200 members representing over 50 countries in North and South America, Europe, Australia, and Africa. The success of this initiative stems from the collaboration and engagement of its members who pursue their own research as well as come together under the ISGC banner to conduct larger, collaborative studies. Herein, we present the Proceedings and official published abstracts of the 22nd Workshop of the ISGC. [1]: https://www.strokegenetics.org

Abstract TP161: The Cerebrovascular Disease Knowledge Portal: an Open Access Data Resource to Accelerate Genomic Discoveries in Stroke

Introduction: High throughput genotyping technologies and large collaborative consortia have revolutionized the field of medical genetics. Open data access is the final barrier capitalizing fully on the opportunities available in stroke genetics research. The International Stroke Genetics Consortium (ISGC) has created the Cerebrovascular Disease Knowledge Portal (CDKP), a platform to explore and access genetic data related to cerebrovascular diseases. Methods: Funded by the NIH, the CDKP has been developed by the ISGC and the American Heart Association (AHA) Institute for Precision Cardiovascular Medicine. The CDKP seeks to democratize access to genomic data and potentiate stroke genomics research by providing open access to genetic, phenotypic and imaging data on patients with stroke. Within the CDKP, data are aggregated, integrated, and harmonized according to a pre-specified standardized pipeline. Any institution or investigator working with stroke genomic data is welcome to deposit their data or use available data. Results: The CDKP houses two types of data, for different regulatory and analytical needs: summary level data and individual level data. The CDKP offers three main features: (1) a web-based graphical user interphase that allows the exploration of genomic information through a wide menu of integrated tools for analysis and data visualization; (2) a repository of full sets of genome-wide summary statistics produced by published landmark studies in the field; and (3) a repository of individual level data, accessible through a secure cloud working space provided by the AHA Platform for Precision Medicine. The CDKP can be accessed at www.cerebrovascularportal.org . Conclusion: The CDKP advances the ISGC’s goal of liberal data sharing in stroke genomics and other areas of cardiovascular research that may benefit from genomic analyses. In the future, phenotypic datasets can be added to further enrich sharing of non-genetic data as well.

GISCOME - Genetics of Ischaemic Stroke Functional Outcome network: A protocol for an international multicentre genetic association study.

Genome-wide association studies have identified several novel genetic loci associated with stroke risk, but how genetic factors influence stroke outcome is less studied. The Genetics of Ischaemic Stroke Functional outcome network aims at performing genetic studies of stroke outcome. We here describe the study protocol and methods basis of Genetics of Ischaemic Stroke Functional outcome. The Genetics of Ischaemic Stroke Functional outcome network has assembled patients from 12 ischaemic stroke projects with genome-wide genotypic and outcome data from the International Stroke Genetics Consortium and the National Institute of Neurological Diseases Stroke Genetics Network initiatives. We have assessed the availability of baseline variables, outcome metrics and time-points for collection of outcome data. We have collected 8831 ischaemic stroke cases with genotypic and outcome data. Modified Rankin score was the outcome metric most readily available. We detected heterogeneity between cohorts for age and initial stroke severity (according to the NIH Stroke Scale), and will take this into account in analyses. We intend to conduct a first phase genome-wide association outcome study on ischaemic stroke cases with data on initial stroke severity and modified Rankin score within 60-190 days. To date, we have assembled 5762 such cases and are currently seeking additional cases meeting these criteria for second phase analyses. Genetics of Ischaemic Stroke Functional outcome is a unique collection of ischaemic stroke cases with detailed genetic and outcome data providing an opportunity for discovery of genetic loci influencing functional outcome. Genetics of Ischaemic Stroke Functional outcome will serve as an exploratory study where the results as well as the methodological observations will provide a basis for future studies on functional outcome. Genetics of Ischaemic Stroke Functional outcome can also be used for candidate gene replication or assessing stroke outcome non-genetic association hypotheses.

Proceedings of the 19th and 20th International Stroke Genetics Consortium Workshops

The 19th and 20th Workshops of the International Stroke Genetics Consortium (ISGC) were held on April 28–29 in Cambridge, Massachusetts, hosted by Christopher Anderson and Steven Lubitz, and on November 3–4 in Milan, Italy, hosted by Giorgio Boncoraglio. These Workshops are a semiannual tradition of the ISGC, dating back to the founding meeting of the Consortium in Cambridge, Massachusetts, in April 2007. The ISGC is a worldwide collaboration of stroke physicians and scientists who have agreed to pool resources and expertise in an effort to unravel the genetic basis of stroke ([http://www.strokegenetics.org][1]). As such, members pursue their own research as well as come together under the ISGC banner to conduct larger, collaborative studies. Herein, we present the Proceedings and official published abstracts of the 19th and 20th Workshops of the ISGC. Where topics were presented twice in one year, the latter abstract was included. Steering Committee: Daniel Woo, MD; Scientific Committee: Christopher D. Anderson, MD, MMSc; Outreach Committee: Jennifer Majersik, MD; Analysis Committee: Rainer Malik, PhD; Imaging Committee: Natalia Rost, MD, MSc; Translational Research Committee: Christopher D. Anderson, MD, MMSc. [1]: http://www.strokegenetics.org/

20th Workshop of the International Stroke Genetics Consortium, November 3-4, 2016, Milan, Italy: 2016.036 ISGC research priorities.

To develop a research priority list for the International Stroke Genetics Consortium (ISGC). Previously, stroke progress review groups and other activities provided an opportunity for members within the field to develop priorities for research. These filtered into larger categories which then published the top research priorities of their given field. However, these review groups are no longer forming and thus there has been no clear direction on what the research priorities and needs for stroke genetics research. We polled members of the stroke genetics community from around the world including collaborations of the major stroke genetics research efforts currently under way asking each respondent to provide their top 3 research priorities. Each priority was then sorted by the authors into major categories based upon the type of suggestion made. The results were presented for commentary and feedback during the presentation. Deeper Phenotyping related topics were presented in 84% of respondent top research priorities. These included topics related to ethnic/racial variation, third world countries, deeper evaluation of subtypes of stroke. Translational science related topics were present in 40% of respondent top research priorities and consisted of translating our current findings into a greater understanding of their relationship to stroke and clinical pathophysiology. Pooling of our resources through data banking and sample banking was a topic in 36% of respondents. Recovery/outcome related topics were suggested in 32% of respondents and utilizing novel techniques such as epigenetics, whole genome sequencing, proteomics and metabolomics were present in 28% of respondents. Other topics were not present in more than 25% of the responses for top research priorities. To summarize, greater sample size and research within subtypes and endophenotypes of stroke was the top research priority of the ISGC. In addition, translating our existing findings, pooling our resources, recovery/outcomes research and utilization of novel techniques were among the top research priorities of the ISGC. A working group will be assembled to draft the ISGC Research Priorities paper.

19th Workshop of the International Stroke Genetics Consortium, April 28-29, 2016, Boston, Massachusetts, USA: 2016.001 MRI-defined cerebrovascular genomics-The CHARGE consortium.

19th Workshop of the International Stroke Genetics Consortium, April 28-29, 2016, Boston, Massachusetts, USA: 2016.001 MRI-defined cerebrovascular genomics-The CHARGE consortium.

International Stroke Genetics Consortium Update.

Created in April 2007, the International Stroke Genetics Consortium (ISGC) has grown into scientific community’s global organizing force for stroke genetics, open to all who can contribute to its mission. Stroke is a leading cause of death worldwide,1 with 15 million people suffering a stroke per year.1 Intracerebral hemorrhage, which makes up 15% of all stroke in the United States,2 results in a 50% rate of severe disability or death.3,4 Although the major cerebrovascular risk factors of hypertension, cardiac disease, diabetes mellitus, and the influence of hyperlipidemia have been well established, a substantial portion of stroke is not explained by these risk factors alone and biological susceptibility to known risk factors remains to be discovered. The ISGC …

Stroke Genetics: A Review and Update

Stroke genetics includes several topics of clinical interest, including (1) molecular genetic variations affecting risk of monogenic stroke syndromes; (2) molecular genetic variations affecting risk of common stroke syndromes, sometimes with specific effects on risk of specific main types of stroke or subtypes of ischemic and hemorrhagic stroke; (3) genetics of conditions associated with stroke risk e.g. white matter hyperintensities, atrial fibrillation and hypertension; (4) hereditary causes of familial aggregation of stroke; (5) epigenetic impact on protein expression during acute brain injury; (6) genetic influence on stroke recovery; and (7) pharmacogenetics. Genetic research methods include candidate gene studies; Genome Wide Association Studies; family studies; RNA and protein analyses; and advanced computer-aided analytical methods to detect statistically significant associations. Several methods that could improve our knowledge of stroke genetics are being developed e.g.: Exome content analysis; Next-generation sequencing; Whole genome sequencing; and Epigenetics. During 2012-2014, several Single Nucleotide Polymorphisms (SNPs) have been related to common ischemic stroke risk. Certain SNPs have been associated with risk of specific ischemic stroke subtypes such as large vessel disease and cardiac embolism, particular subtypes of intracerebral hemorrhage (ICH), especially lobar ICH, and with prognosis after ICH. Large international studies on stroke recovery and exome content are ongoing. Advanced mathematical models have been used to study how several SNPs can act together and increase stroke risk burden. Such efforts require large numbers of patients and controls, which is achieved by co-operation in large international consortia such as the International Stroke Genetics Consortium. This overview includes an introduction to genetics, stroke genetics in general, and different genetic variations that may influence stroke risk. It presents some of the latest reports on stroke genetics published in high impact journals. The role of pharmacogenetics, the current clinical situation, and future prospects will also be discussed.

Stroke : Highlights of Selected Articles

<i>Stroke</i> : Highlights of Selected Articles

Abstract TMP50: A Polymorphism in HDAC9 was Associated with Large Vessel Stroke in the Vienna and German Stroke Studies

Introduction The International Stroke Genetics Consortium (ISGC) and the Wellcome Trust Case Control Consortium 2 (WTCCC2) performed a large genome wide association study of ischemic stroke and its subtypes (large vessel stroke (LVD), small vessel stroke (SVD), cardioembolic stroke (CE)), and identified a polymorphism in HDAC9 (rs11984041) associated with the LVD subtype of ischemic stroke. Hypothesis We assessed the hypothesis that rs11984041 is associated with LVD in two additional studies. Methods The genotype of rs11984041 was determined for participants of the Vienna Study (815 controls, 122 LVD, 165 SVD, 202 CE) and of the German Study (1040 controls, 495 LVD, 230 SVD, 462 CE). The association of rs11984041 with LVD was assessed by logistic regression. Heterogeneity of the effect of rs11984041 on LVD, CE or SVD was assessed by testing the equality of the corresponding regression coefficients from a multinomial logistic regression model. Results Carriers of the minor (T) allele of rs11984041 (23.3% of LVD cases and 17.4% of controls), compared with noncarriers, had increased risk for LVD: the odds ratios (OR) were 1.92 (95%CI 1.25-2.96) for the Vienna Study and 1.33 (95%CI 1.02-1.74) for the German Study. Adjusting for covariates including sex, age, diabetes, and hypertension did not materially change the ORs. Heterogeneity of the effects of rs11984041 on LVD vs CE was significant in the Vienna Study (p = 0.009) and in the German Study (p = 0.005). Heterogeneity of the effects of rs11984041 on LVD vs SVD trended toward significance in the Vienna Study (p = 0.088) and was significant in the German Study (p = 0.047). Adjusting for covariates did not materially change the heterogeneity test p values. Conclusions The HDAC9 polymorphism rs11984041 was associated with the LVD stroke subtype in the Vienna Study and the German Study. These results replicated the ISGC/WTCCC2 findings.

Advances in Stroke

The field of stroke genetics continues to make substantive advances. Large-scale partnerships have led to meta-analyses in ischemic and hemorrhagic stroke, which are yielding reproducible genetic risk factors. Most ischemic stroke risk factors seem to be specific to type, for example, large-vessel stroke. Progress is being made in understanding the pathophysiology of single-gene stroke syndromes. Genetics is also being used to potentially advance pharmacotherapeutics. In the genome-wide association study (GWAS) era, several themes are emerging. First, heritability seems to vary by ischemic stroke subtype. Using complex trait analysis on a GWAS data set of >3000 individuals, Bevan et al1 found a 37.9% heritability for ischemic stroke overall, but the heritability varied widely by subtype from a high of 40.3% for large-vessel stroke to a low of 16.1% for small-vessel stroke.1 Second, genetic risk factors seem to be subtype-selective. Third, GWAS have yielded more reliable discoveries than candidate gene studies uninformed by GWAS. In the previously cited study by Bevan,1 no candidate gene previously reported as associated with ischemic stroke could be replicated using GWAS data, but 3 loci from related cardiovascular GWAS were significant even after rigorous correction for multiple comparisons. In the area of ischemic stroke genetics, a partnership between the International Stroke Genetics Consortium and the Wellcome Trust Case Control Consortium 2, which included GWAS data from 5859 cases and 6281 controls, replicated associations …