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International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery.

ABSTRACT: Numerous biological mechanisms contribute to outcome after stroke, including brain injury, inflammation, and repair mechanisms. Clinical genetic studies have the potential to discover biological mechanisms affecting stroke recovery in humans and identify intervention targets. Large sample sizes are needed to detect commonly occurring genetic variations related to stroke brain injury and recovery. However, this usually requires combining data from multiple studies where consistent terminology, methodology, and data collection timelines are essential. Our group of expert stroke and rehabilitation clinicians and researchers with knowledge in genetics of stroke recovery here present recommendations for harmonizing phenotype data with focus on measures suitable for multicenter genetic studies of ischemic stroke brain injury and recovery. Our recommendations have been endorsed by the International Stroke Genetics Consortium.

SUBMITTER: Lindgren AG

PROVIDER: S-EPMC8864333 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery.

Lindgren Arne G AG Braun Robynne G RG Juhl Majersik Jennifer J Clatworthy Philip P Mainali Shraddha S Derdeyn Colin P CP Maguire Jane J Jern Christina C Rosand Jonathan J Cole John W JW Lee Jin-Moo JM Khatri Pooja P Nyquist Paul P Debette Stéphanie S Keat Wei Loo L Rundek Tatjana T Leifer Dana D Thijs Vincent V Lemmens Robin R Heitsch Laura L Prasad Kameshwar K Jimenez Conde Jordi J Dichgans Martin M Rost Natalia S NS Cramer Steven C SC Bernhardt Julie J Worrall Bradford B BB Fernandez-Cadenas Israel I

International journal of stroke : official journal of the International Stroke Society 20210426 3

Numerous biological mechanisms contribute to outcome after stroke, including brain injury, inflammation, and repair mechanisms. Clinical genetic studies have the potential to discover biological mechanisms affecting stroke recovery in humans and identify intervention targets. Large sample sizes are needed to detect commonly occurring genetic variations related to stroke brain injury and recovery. However, this usually requires combining data from multiple studies where consistent terminology, me ...[more]

PMID: 33739214

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Project description:ObjectiveTo develop a research priority list for the International Stroke Genetics Consortium (ISGC).BackgroundPreviously, 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.Design/methodsWe 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.ResultsDeeper 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.ConclusionsTo 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.

Project description:BackgroundAlthough human leukocyte antigen (HLA) DQ and DR loci appear to confer the strongest genetic risk for type 1 diabetes, more detailed information is required for other loci within the HLA region to understand causality and stratify additional risk factors. The Type 1 Diabetes Genetics Consortium (T1DGC) study design included high-resolution genotyping of HLA-A, B, C, DRB1, DQ, and DP loci in all affected sibling pair and trio families, and cases and controls, recruited from four networks worldwide, for analysis with clinical phenotypes and immunological markers.PurposeIn this article, we present the operational strategy of training, classification, reporting, and quality control of HLA genotyping in four laboratories on three continents over nearly 5 years.MethodsMethods to standardize HLA genotyping at eight loci included: central training and initial certification testing; the use of uniform reagents, protocols, instrumentation, and software versions; an automated data transfer; and the use of standardized nomenclature and allele databases. We implemented a rigorous and consistent quality control process, reinforced by repeated workshops, yearly meetings, and telephone conferences.ResultsA total of 15,246 samples have been HLA genotyped at eight loci to four-digit resolution; an additional 6797 samples have been HLA genotyped at two loci. The genotyping repeat rate decreased significantly over time, with an estimated unresolved Mendelian inconsistency rate of 0.21%. Annual quality control exercises tested 2192 genotypes (4384 alleles) and achieved 99.82% intra-laboratory and 99.68% inter-laboratory concordances.LimitationsThe chosen genotyping platform was unable to distinguish many allele combinations, which would require further multiple stepwise testing to resolve. For these combinations, a standard allele assignment was agreed upon, allowing further analysis if required.ConclusionsHigh-resolution HLA genotyping can be performed in multiple laboratories using standard equipment, reagents, protocols, software, and communication to produce consistent and reproducible data with minimal systematic error. Many of the strategies used in this study are generally applicable to other large multi-center studies.

Project description:IntroductionGenome-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.MethodsThe 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.ResultsWe 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.ConclusionGenetics 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.

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International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery.

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International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery.

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