RESEARCH ARTICLE OPEN ACCESS Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke Thomas Jaworek, MS,* Huichun Xu, MD, PhD,* Brady J. Gaynor, MS, John W. Cole, MD, MS, Correspondence Kristiina Rannikmae, MD, PhD, Tara M. Stanne, PhD, Liisa Tomppo, MD, PhD, Vida Abedi, PhD, Dr. Mitchell Philippe Amouyel, MD, PhD, Nicole D. Armstrong, MS, PhD, John Attia, MD, PhD, Steven Bell, PhD, bmitchel@ Oscar R. Benavente, MD, Giorgio B. Boncoraglio, MD, Adam Butterworth, PhD, som.umaryland.edu for the Cervical Artery Dissections and Ischemic Stroke Patients (CADSIP) Consortium Jara Carcel-Marquez, MSc, Zhengming Chen, DPhil, Michael Chong, PhD, MSc, Carlos Cruchaga, PhD, Mary Cushman, MD, MSc, John Danesh, FMedSci, DPhil, Stéphanie Debette, MD, PhD, David J. Duggan, PhD, Jon Peter Durda, PhD, Gunnar Engstrom, MD, PhD, Chris Enzinger, MD, Jessica D. Faul, PhD, MPH, Natalie S. Fecteau, MPH, Israel Fernandez-Cadenas, MD, PhD, Christian Gieger, PhD, Anne-Katrin Giese, MD, Raji P. Grewal, MD, Ulrike Grittner, PhD, Aki S. Havulinna, DSc, Laura Heitsch, MD, Marc C. Hochberg, MD, Elizabeth Holliday, BSc, MSc, PhD, Jie Hu, MD, PhD, Andreea Ilinca, MD, PhD, for the INVENT Consortium Marguerite R. Irvin, PhD, Rebecca D. Jackson, MD, Mina A. Jacob, MD, Raquel Rabionet, PhD, Jordi Jimenez-Conde, MD, PhD, Julie A. Johnson, PharmD, Yoichiro Kamatani, MD, PhD, Sharon L.R. Kardia, PhD, Masaru Koido, PhD, Michiaki Kubo, MD, PhD, Leslie Lange, PhD, Jin-Moo Lee, MD, PhD, Robin Lemmens, MD, PhD, Christopher R. Levi, MD, PhD, Jiang Li, PhD, Liming Li, MPH, Kuang Lin, PhD, Haley Lopez, BS, Sothear Luke, MPH, Jane Maguire, PhD, Patrick F. McArdle, PhD, Caitrin W. McDonough, PhD, James F. Meschia, MD, Tiina Metso, MD, PhD, Martina Müller-Nurasyid, PhD, Timothy D. O’Connor, PhD, Martin O’Donnell, PhD, Leema R. Peddareddygari, MBBS, MD, Joanna Pera, MD, PhD, James A. Perry, PhD, Annette Peters, PhD, Jukka Putaala, MD, PhD, Debashree Ray, BSc, MStat, PhD, Kathryn Rexrode, MD, MPH, Marta Ribases, BSc, PhD, Jonathan Rosand, MD, MSc, Peter M. Rothwell, MD, PhD, FMedSci, Tatjana Rundek, MD, PhD, Kathleen A. Ryan, MPH, Ralph L. Sacco, MD, MS, Veikko Salomaa, MD, PhD, Cristina Sanchez-Mora, BSc, PhD, Reinhold Schmidt, MD, Pankaj Sharma, MD, PhD, FRCP, Agnieszka Slowik, MD, PhD, Jennifer A. Smith, PhD, MPH, Nicholas L. Smith, PhD, MPH, Sylvia Wassertheil-Smoller, PhD, Martin Söderholm, MD, PhD, O. Colin Stine, PhD, Daniel Strbian, MD, PhD, Cathie L.M. Sudlow, DPhil, FRCP(E), Turgut Tatlisumak, MD, PhD, Chikashi Terao, MD, PhD, Vincent Thijs, MD, PhD, Nuria P. Torres-Aguila, PhD, David-Alexandre Trégouët, PhD, Anil M. Tuladhar, MD, Jan H. Veldink, MD, PhD, Robin G. Walters, PhD, David R. Weir, PhD, Daniel Woo, MD, Bradford B. Worrall, MD, MSc, Charles C. Hong, MD, PhD, Owen A. Ross, PhD, Ramin Zand, MD, MPH, Frank-Erik de Leeuw, MD, PhD, Arne G. Lindgren, MD, PhD, Guillaume Pare, MD, MSc, Christopher D. Anderson, MD, MMSc, Hugh S. Markus, DM, FMed Sci, Christina Jern, MD, PhD, Rainer Malik, PhD, Martin Dichgans, MD, Braxton D. Mitchell, PhD, MPH,† Steven J. Kittner, MD,† and the Early Onset Stroke Genetics Consortium of the International Stroke Genetics Consortium (ISGC) ® Neurology 2022;99:e1738-e1754. doi:10.1212/WNL.0000000000201006 Abstract RELATED ARTICLE Background and Objectives Editorial Current genome-wide association studies of ischemic stroke have focused primarily on late- Common Genetic Variants onset disease. As a complement to these studies, we sought to identify the contribution of and Early Onset Stroke: Clues but No Answers common genetic variants to risk of early-onset ischemic stroke. Page 683 Methods We performed a meta-analysis of genome-wide association studies of early-onset stroke (EOS), ages 18–59 years, using individual-level data or summary statistics in 16,730 cases and 599,237 From the Division of Endocrinology (T.J., H.X., B.J.G, B.D.M., K.A.R., J.A.P., P.F.M.), Diabetes and Nutrition, Department of Neurology (J.W.C., N.S.F., H.L., S.J.K.), Division of Rheumatology and Clinical Immunology (M.C.H.), Department of Medicine, Department of Epidemiology and Public Health (M.C.H.), and Institute for Genome Sciences (T.D.O.C.), University of Maryland School of Medicine; VA Maryland Health Care System (J.W.C.); Centre for Medical Informatics (K.R., C.L.M.S.), Usher Institute, University of Edinburgh, United Kingdom; Institute of Biomedicine (T.M.S., C.J.), Department of Laboratory Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden; Department of Neurology (L.T., J.P., D.S., T.T.), Helsinki University Hospital and University of Helsinki, Finland; Department of Molecular and Functional Genomics (V.A., J.L., R.Z.), Geisinger Health System, Danville, PA; LabEx DISTALZ-U1167 (P.A.), RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, University of Lille; Inserm U1167 (P.A.), Lille; Centre Hospitalier Universitaire Lille (P.A.); Institut Pasteur de Lille (P.A.), France; Department of Epidemiology (N.D.A., M.R.I.), University of Alabama at Birmingham; School of Medicine and Public Health (J.A., E.H.), University of Newcastle and Hunter Medical Research Institute, Australia; Stroke Research Group (S.B., H.S.M.), Department of Clinical Neurosciences, British Heart Foundation Cardiovascular Epidemiology Unit (A.B., J.D.), Department of Public Health and Primary Care, British Heart Foundation Centre of Research Excellence (A.B., J.D.), National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics (A.B., J.D.), University of Cambridge (A.B., J.D.), United Kingdom; Department of Neurology (Q.R.B.), University of British Columbia, Vancouver, Canada; Department of Cerebrovascular Diseases (G.B.B.), Fondazione IRCCS Istituto Neurologico “Carlo Besta,” Milan, Italy; Health Data Research UK Cambridge (A.B., J.D.); Wellcome Genome Campus (A.B., J.D.), Cambridge, United Kingdom; Stroke Pharmacogenomics and Genetics group (J.C.-M., I.F.-C., N.P.T.-A.), Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain; MRC Population Health Research Unit (Z.C., R.G.W.), Nuffield Department of Population Health, University of Oxford, United Kingdom; Nuffield Department of Clinical Neurosciences (P.M.R.), University of Oxford, United Kingdom; DBCVS Research Institute (M.C., G.P.), Department of Pathology and Molecular Medicine, Population Health Research Institute, McMaster University; Thrombosis & Atherosclerosis Research Institute (TaARI) (M.C., G.P.), Hamilton, Ontario, Canada; This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. e1738 Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. Glossary CI = confidence interval; EOS = early-onset stroke; EOSC = Early Onset Stroke Consortium; GWAS = genome-wide association study; ICD-9 = International Classification of Diseases–9; LD = linkage disequilibrium; LDSC = LD Score Regression analysis; LOS = late-onset stroke; MAF = minor allele frequency; OR = odds ratio; PRS = polygenic risk score; SiGN = Stroke Genetics Network; VTE = venous thromboembolism; VWF = von Willebrand factor. nonstroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late-onset stroke (LOS) and compared polygenic risk scores (PRS) for venous thromboembolism (VTE) between EOS and LOS. Results We observed genome-wide significant associations of EOS with 2 variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared with LOS. The odds ratio (OR) for rs529565, tagging O1, was 0.88 (95% confidence interval [CI]: 0.85–0.91) in EOS vs 0.96 (95% CI: 0.92–1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11–1.21) for EOS vs 1.05 (0.99–1.11) in LOS; p-values for Departments of Neurology (J.-M.L.) and Psychiatry (C.C.), Washington University School of Medicine, St. Louis, MO; Department of Medicine and Laboratory for Clinical Bio- chemistry Research (J.P.D.), Department of Medicine, (M.C.), University of Vermont Larner College of Medicine, Burlington, VT; Department of Human Genetics (J.D.), Wellcome Sanger Institute, Hinxton, United Kingdom; University of Bordeaux (S.D., D.-A.T.), Inserm, Bordeux Population Health Research Center, UMR 1219; Department of Neurology (S.D.), Institute for Neurodegenerative Disease, Bordeaux University Hospital, France; Quantitative Medicine and Systems Biology Division (D.J.D.), Translational Genomics Research Institute, An Affiliate of City of Hope, Phoenix, AZ; Laboratory for Clinical Biochemistry Research (J.P.D.), Department of Clinical Sciences (G.E., J.A.S., M.S., D.R.W.), Malmö and Department of Clinical Sciences (A.I., M.S., A.G.L.), Neurology, Lund, Lund University, Sweden; Department of Neurology (C.E., R.S.), Medical University Graz, Austria; Survey Research Center (J.D.F.), Institute for Social Research, University of Michigan, Ann Arbor; Stroke Pharmacogenomics and Genetics (I.F.-C.), Fundacio Docència i Recerca MutuaTerrassa, Spain; Unit of Molecular Epidemiology (C.G.), Institute of Epidemiology (C.G., A.P.), Helmholtz Zentrum München German Research Center for Environ- mental Health, Neuherberg; Klinik und Poliklinik für Neurologie (A.-K.G.), Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Germany; Neuroscience Institute (R.P.G., L.R.P.), Saint Francis Medical Center, Trenton, NJ; Department for Biostatistics and Clinical Epidemiology (U.G., ), Charité-University Medical Centre, Berlin, Germany; National Institute for Health and Welfare (A.S.H., V.S.), Helsinki, Finland; Departments of Emergency Medicine and Neurology (L.H.), Washington University School of Medicine, St. Louis, MO; Division of Women’s Health (K.R.), Department of Medicine and Department of Neurology (C.D.A.), Brigham and Women’s Hospital, Harvard Medical School; Department of Epidemiology (J.H.), Harvard T.H. Chan School of Public Health, Boston, MA; Department of Neurology and Rehabilitation Medicine (A.I.), Skane University Hospital, Lund, Sweden; Division of Endocrinology (R.D.J.), Diabetes and Metabolism, Department of Internal Medicine and the Center for Clinical and Translational Science, The Ohio State University, Columbus; Department of Neurology (M.A.J., A.M.T., F.E.d.L.), Radboud University Medical Center, Donders Medical Center for Neuroscience, Nijmegen, the Nether- lands; Department of Genetics, Microbiology and Statistics (R.R.J.), Institute of Biomedicine (IBUB), University of Barcelona; Institut de Recerca Sant Joan de Déu (R.R.J.), Esplugues de Llobregat; Centro de investigación biomédica en red (CIBERER) (R.R.J.); Neurovascular Research Group (NEUVAS) (J.J.-C.), Neurology Department, Institut Hospital del Mar d’Investigacio Medica, Universitat Autonoma de Barcelona, Spain; Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (J.A.J., C.W.M.), University of Florida, College of Pharmacy; Division of Cardiovascular Medicine (J.A.J.), College of Medicine, University of Florida, Gainesville; Laboratory of Complex Trait Genomics (Y.K.), Graduate School of Frontier Sciences and Department of Cancer Biology (M.K.), Institute of Medical Science, The University of Tokyo, Japan; Department of Epidemiology (S.L.R.K.), School of Public Health, University of Michigan, Ann Arbor; Department of Cancer Biology (M.K.), RIKEN Center for Integrative Medical Sciences (M.K., C.T.), Yokohama, Japan; Department of Medicine (L.L.), University of Colorado Denver, Anschutz Medical Campus, Aurora, CO; Department of Neurosciences, Experimental Neurology (R.L.), VIB Center, For Brain & Disease Research, KU Leuven–University of Leuven; Department of Neurology (R.L.), University Hospitals Leuven, Belgium; John Hunter Hospital (C.R.L.), Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia and Priority Research Centre for Stroke & Brain Injury, University of Newcastle, NSW, Australia; Peking University Health Science Center (L.L.), Department of Epidemiology and Biostatistics, Peking University, Beijing, China; Department of Neurology (S.L., J.F.M., O.A.R.), Mayo Clinic, Jacksonville, FL; Faculty of Health (J.M.), School of Nursing and Midwifery, University of Technology Sydney, NSW, Australia; Department of Neurology (T.M.), Helsinki University Central Hospital, Helsinki, Finland; Institute of Genetic Epidemiology (M.M.-N.), Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg; Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University Mainz, Germany; Department of Medicine I, Ludwig-Maximilians University Munich, Germany; Department of Medicine (C.C.H.) University of Maryland School of Medicine, Baltimore, MD; Health Research Board Clinical Research Facility (M.O.D.), Geata an Eolais, National University of Ireland, Galway; Department of Neurology (J.P., A.S.), Jagiellonian University, Krakow, Poland; Institute for Medical Information Sciences (A.P.), Biometry and Epidemiology, Ludwig-Maximilians-University, Munich, Germany; Department of Epidemiology (D.R.), Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD; Psychiatric Genetics Unit (M.R., C.S.-M.), Group of Psychiatry, Mental Health and Addiction, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona; Department of Psychiatry (C.S.-M.), Hospital Universitari Vall d’Hebron, Barcelona; Biomedical Network Research Centre on Mental Health (CIBERSAM) (M.R.), Instituto de Salud Carlos III, Madrid; Department of Genetics (M.R.), Microbiology, and Statistics, Faculty of Biology, Universitat de Barcelona, Spain; McCance Center for Brain Health (J.R., C.D.A.), Massachusetts General Hospital; Center for Genomic Medicine (J.R.), MGH; Department of Neurology (J.R.), MGH, Boston; Program in Medical and Population Genetics (J.R.), Broad Institute, Cambridge, MA; Department of Neurology and Evelin F. McKnight Brain Institute (T.R., R.L.S.), Miller School of Medicine, University of Miami, FL; Institute of Cardiovascular Research (P.S.), Royal Holloway University of London, and Ashford and St. Peters Hospital (P.S.), Surrey, United Kingdom; Group Health Research Institute (N.L.S.), Group Health Cooperative; Department of Epidemiology (N.L.S.), University of Washington; Seattle Epidemiologic Research and Information Center (N.L.S.), VA Office of Research and Development, Seattle, WA; Department of Epidemiology and Population Health (S.W.-S.), Albert Einstein College of Medicine, New York; BHF Data Science Centre (C.L.S.), Health Data Research UK, London, United Kingdom; Department of Neurology (T.T.) and Department of Clinical Genetics and Genomics (C.J.), Region Vastra Gotaland, Sahlgrenska University Hospital; Department of Clinical Neuroscience (T.T.), Institute of Neurosciences and Physiology, Sahlgrenska Academy at University of Goth- enburg, Sweden; Stroke Theme (V.T.), Florey Institute of Neuroscience and Mental Health, University of Melbourne; Department of Neurology (V.T.), Austin Health, Heidelberg, Victoria, Australia; Department of Neurology (J.H.V.), University Medical Center Utrecht Brain Center, Utrecht University, the Netherlands; Department of Neurology and Re- habilitation Medicine (D.W.), University of Cincinnati College of Medicine, OH; Departments of Neurology and Public Health Sciences (B.B.W.), University of Virginia School of Medicine, Charlottesville; Section of Neurology (A.G.L.), Skåne University Hospital, Lund, Sweden; Program in Medical and Population Genetics (C.D.A.), Broad Institute of MIT and Harvard, Cambridge, MA; Institute for Stroke and Dementia Research (ISD) (R.M., M.D.), University Hospital, LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (M.D.); German Center for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany; Geriatric Research and Education Clinical Center (B.D.M., S.J.K.), Veterans Administration Medical Center, Baltimore, MD. Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. *These authors contributed equally to this work as co-first authors. †These authors contributed equally to this work as co-senior authors. The Article Processing Charge was funded by the authors. Coinvestigators are listed at links.lww.com/WNL/C316 Neurology.org/N Neurology | Volume 99, Number 16 | October 18, 2022 e1739 interaction = 0.001 and 0.005, respectively. Using PRSs, we observed that greater genetic risk for VTE, another prothrombotic condition, was more strongly associated with EOS compared with LOS (p = 0.008). Discussion The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS. Substantial advances have been made in recent years toward Barcelona and BASICMAR), controls from each study were of identifying common genetic variation associated with risk of the same age or older than cases. Analysis groups were assigned ischemic stroke.1,2 This progress has been largely based on meta- as previously described to combine cases and controls of similar analyses of genome-wide association study (GWAS) results genetic ancestry groups and genotyped on arrays of similar derived from predominantly late-onset cases. Given that a higher density.16 Clinical characteristics of stroke cases are shown in heritability of early-onset ischemic stroke is observed in multiple eTable 2. Genotypes for all studies except Helsinki were im- studies,3-6 there is a strong need for genetic studies focusing on puted using the TOPMed reference panel on the University of early-onset stroke (EOS). A pressing question is whether the Michigan Imputation Server.17 The Helsinki Study imputed genetic contribution to EOS includes novel or specific mecha- genotypes using a Finnish population–specific reference panel nisms that may have translational importance across the whole and the BEAGLE software. All genotype data were based on age spectrum, as has been found from studies of early-onset cases genome build hg38. Genotyping platforms and cohort-specific in other complex diseases.7-9 quality control and analysis parameters are provided in eTable 3. Because atherosclerosis is a less common cause of stroke in GWAS of stroke cases and controls were conducted within sites young adults, we hypothesized that nonatherosclerotic, pro- or within groupings of sites and then meta-analyzed. Before thrombotic mechanisms may be more important and dis- analysis, we removed cases if there were fewer than 40 in the cernible in studies of EOS.10,11 This concept is supported by analysis strata, if they could not be assigned to a genetic an- associations reported between EOS and multiple pro- cestry group, or if there was an inadequate number of controls. thrombotic candidate genes.10-14 In this report, we present Filtering on these criteria left 16,730 (of 16,880) EOS cases for findings from the Genetics of Early Onset Ischemic Stroke analysis. The overall analytic design is depicted in Figure 1. Our Consortium, contrast the effect sizes of known stroke loci in primary analysis was a transethnic meta-analysis. In parallel, we early-onset vs late-onset stroke (LOS), and evaluate differing performed a European-only meta-analysis. Logistic regression contributions of prothrombotic loci to EOS and LOS. was performed to test for association between stroke occur- rence and single variants. Covariates included sex and up to 10 principal components to adjust for population stratification, unless otherwise specified. Power calculations indicated that Methods our study provided 80% power to detect odds ratios (ORs) tThe Early Onset Stroke Consortium (EOSC) is a collaboration ranging from 1.09 to 1.20 for common genetic variants with of 48 different studies across North America, Europe, Japan, minor allele frequencies (MAFs) > 5% at the genome-wide Pakistan, and Australia for a GWAS meta-analysis of early-onset threshold for significance, that is, 5 × 10−8. For comparison, the ischemic stroke in cases aged 18–59 years. Collectively, these previously detected ORs for ischemic stroke from MEGA- studies contributed 16,880 cases (16,730 cases included for STROKE GWAS (67,162 cases) ranged from 1.05 to 1.09.1 We analysis) and 601,413 nonstroke controls (599,237 included for also performed TOAST-defined stroke subtype analyses for analysis) (eMethods and eTable 1, links.lww.com/WNL/ sites providing subtype classification. C245). All patients had brain imaging to exclude diagnoses other than ischemic stroke. Additional screening was performed in We compared effect sizes between EOS and LOS cases of Eu- most studies to exclude cases believed to be due to a known ropean ancestry at 40 loci previously associated with stroke in monogenic cause (e.g., sickle cell disease) or nongenetic cause MEGASTROKE,1 MEGASTROKE and UK Biobank com- (e.g., drug use, complications of procedures). Ischemic stroke bined,2 or in a previously published meta-analysis of small vessel subtyping was performed using the Trial of Org 10 172 in Acute stroke.18 We created an LOS case cohort (age onset ≥60 years) Stroke Treatment (TOAST) criteria15 by most sites. from the SiGN Consortium consisting of 9,272 LOS cases and 25,124 controls of European ancestry for this comparison. Effect The EOSC includes cases from 2 different sources: EOS cases sizes between EOS and LOS were compared using a Wald test. who previously participated in the Stroke Genetics Network (SiGN)16 (n = 7,619) and EOS cases from additional non- To explore associations of serologically defined ABO blood groups SiGN study sites (n = 9,598). eTable 1 (links.lww.com/WNL/ (i.e., A, B, AB, and O) with stroke, we compared the distribution of C245) lists the 48 sites contributing EOS cases and sources of blood groups among EOS, LOS, and controls. We assigned ABO controls. With 1 exception (Group 7 including cases from blood groups using genotypes at 2 single-nucleotide polymorphisms e1740 Neurology | Volume 99, Number 16 | October 18, 2022 Neurology.org/N Figure 1 Overview of the Study Design (SNPs; rs8176719 and rs8176746), as described by Groot et al.19 PRS score with stroke in the European ancestry sample using (see eMethods, links.lww.com/WNL/C245). logistic regression with 10 principal components for ancestry and sex included as covariates. Effect sizes between EOS and ABO blood groups can be further subdivided into 5 different LOS stroke were compared using a Wald test (see eMethods). haplotypes, or subgroups, each of which can be tagged by a single SNP20 (see eMethods, links.lww.com/WNL/C245). We identified several disorders and plasma biomarkers (LOS, The 5 ABO subgroups are A1 (the ancestral subgroup, tagged VTE, and plasma levels of von Willebrand factor [VWF] and by rs2519093-T), O1 (tagged by a frameshift deletion, factor VIII) for which associations at the ABO locus have pre- rs8176719-delG), A2 (tagged by rs1053878-A), B (tagged by viously been reported and then used the coloc software25 to assess rs8176743-T), and O2 (tagged by rs41302905-T).20 A evidence that the same causal SNPs associated with EOS also study20 has recently shown that relative to subgroup O1, the drove associations with the second trait. In brief, coloc uses a genetically defined subgroups A1 and B are strongly associ- Bayesian approach and summary-level association results for 2 ated with venous thrombosis risk, and subgroup A2 is asso- traits to calculate the posterior probabilities of 5 competing hy- ciated with a modest increase in risk. potheses (H0–H4) that assess whether the associations are due to the same (corresponding to H4) or a different (corresponding to We hypothesized that the strong association of EOS with the H3) causal variant (see eMethods, links.lww.com/WNL/C245). ABO locus was related to the prothrombotic properties of the ABO blood group. We evaluated this hypothesis first by Standard Protocol Approvals, Registrations, testing whether the 2 lead ABO variants were associated with and Patient Consents venous thromboembolism (VTE), another prothrombotic All participating sites obtained IRB or Ethics Board approval, condition, in the UKB and whether the association was more and informed consent was obtained from all participants or prominent in early-onset compared with later-onset VTE. their legally authorized representative. Using summary-level association results (VTE results from the INVENT Consortium21), we estimated pairwise genetic Data Availability correlations among EOS, LOS, and VTE using LD Score Summary results will be made available on application to the Regression analysis (LDSC).22 We then tested whether ge- contact authors and consortium approval of the request. netic predisposition to VTE, as measured by a polygenic risk Individual-level data from a subset of sites will be made avail- score (PRS), was more prominently associated with EOS able on the database of Genotypes and Phenotypes (dbGaP). compared with LOS. For this purpose, we generated a VTE PRS for individuals from the EOSC and LOS subset from SiGN based on a large prior GWAS of VTE23 using PRSice Results software.24 The VTE PRS included 255 SNPs using a GWAS Genome-wide Analysis Results p-value threshold of 1 × 10−5 (see eMethods, links.lww.com/ The transethnic meta-analysis included a total of 16,730 EOS WNL/C245). We tested the association between the VTE cases, representing 990 of African, 11,114 of European, 189 of Neurology.org/N Neurology | Volume 99, Number 16 | October 18, 2022 e1741 Figure 2 Genome-wide Association Analysis of EOS Manhattan plot of EOS meta-analysis in the EOSC, random effects model, in TRANS ancestry (A) and European Ancestry (B). EOS = early-onset stroke; EOSC = Early Onset Stroke Consortium. Hispanic, 230 of Afro-Caribbean, and 4,207 of pan-Asian an- difference in effect sizes of either ABO rs529565 or rs635634 cestry. There was little evidence for inflation of p-values across between men and women. sites, as indicated by genomic control ranging from 0.86 to 1.14 (eTable 3, links.lww.com/WNL/C245). We identified 2 sep- We performed a joint analysis of ABO SNPs rs529565 and arate loci associated with EOS at genome-wide significance, rs635634 to assess their independent associations with EOS. both mapping to the ABO gene (Figure 2A and eTable 4). The The frequencies of the rs529565 T and rs635634 T alleles in lead variants at these loci tag ABO subgroups O1 and A1, European ancestry populations are 0.63 and 0.19, respectively. respectively (see below). The OR for rs975381715, the O1- There was a moderate correlation between these 2 SNPs (r2 = tagging variant (MAF = 0.37 in Europeans and 0.43 in African 0.39), although the rs635634 T allele seems exclusively on the Americans), was 0.88 (95% confidence interval [95% CI]: background of the rs529565 C allele, resulting in a D9 of 1 0.85–0.92; p = 3.72 × 10−10). The A1-tagging variant, (eFigure 1, links.lww.com/WNL/C245). We therefore used a rs8176685 (MAF = 0.19 in Europeans and 0.07 in African stratified approach to assess the contribution of rs529565 to Americans), marks a 12 base-pair insertion/deletion poly- stroke risk in the absence of the rs635634 T allele. In this morphism and had an OR of 1.16 (95% CI: 1.10–1.21; p = 2.06 analysis, restricted to strata for whom we had individual-level × 10−9). This deletion variant has previously associated with data, rs529565 remained associated with all EOS and at ap- ischemic stroke1,26 and is in near-perfect linkage disequilibrium proximately the same effect size (OR = 0.90, 95% CI: (LD) with rs635634, the lead ABO SNP associated with all 0.85–0.96; p = 0.003), implying an association of this SNP ischemic stroke in MEGASTROKE.1 that was independent of rs635634. The European ancestry-only meta-analysis, based on 11,114 In addition to the 2 genome-wide significant loci, we observed EOS cases, also identified genome-wide associations marking 1 additional SNP meeting genome-wide significance the O1 and A1 blood groups the ABO gene, albeit with 2 (rs118091666 in SHKBP1), although this SNP was rare different tagging SNPs (Figure 2B and eTable 5, links.lww. (MAF = 0.018 in Europeans and monomorphic in non- com/WNL/C245). In this analysis, the lead O1-tagging SNP Europeans). We observed 19 “suggestive” loci with sub- was rs529565 (previously rs912805253) and had an OR = threshold levels of significance (i.e., p < 1 × 10−6) in the 0.88 (95% CI: 0.85–0.91; p = 4.31 × 10−14), and the lead A1- transethnic analysis (eTable 4, links.lww.com/WNL/C245) tagging SNP was rs635634 and had an OR = 1.16 (95% CI: and 14 loci in the European-only analysis (eTable 5). 1.11–1.21; p = 6.54 × 10−13). Stratified analyses revealed no Among these loci were MC4R (melanocortin-4 receptor), e1742 Neurology | Volume 99, Number 16 | October 18, 2022 Neurology.org/N an obesity-associated gene, and TEK (TEK receptor tyrosine SNP encoding blood subgroup A1 and in near-perfect LD kinase, rs78411354), which plays a role in embryonic vascular with rs635634 [r2 = 0.99]) in the UKB as a quasireplication, development. Three of the 29 unique loci associated with EOS in “quasi” because EOS UKB cases were included as part of the either the transethnic or European-only analysis at subgenome primary EOSC analyses, but LOS cases were not. The analysis thresholds (i.e., p < 1 × 10−6) were nominally associated with was limited to ischemic stroke cases and based on ICD codes, LOS at p < 0.05 (eTables 4 and 5), and one of these, as described in the eMethods (links.lww.com/WNL/C245). rs115133729 in MAPKAPK5, was strongly associated with LOS Similar to our analysis in EOSC and SiGN, we observed (p = 1.30 × 10−7) and has previously been associated with all stronger associations of both SNPs in EOS than in LOS. ischemic stroke in MEGASTROKE Europeans (Cerebrovascular The ORs for ABO rs529565 (O1-defining) were 0.93 (95% Disease Knowledge Portal, accessed April 16, 2022). CI: 0.86–0.99; p = 0.02) for EOS and 0.95 (95% CI: 0.90–0.99; p = 0.02) for LOS and for ABO rs2519093 (A1- Analysis of stroke subtypes, available in 69.5% of all stroke cases, defining) were 1.10 (95% CI: 1.01–1.19; p = 0.03) for EOS revealed 11 SNPs associated with various stroke subtypes at and 1.05 (95% CI: 1.00–1.02; p = 0.07) for LOS. genome-wide thresholds of significance (eTable 6, links.lww.com/ WNL/C245), although the sample sizes were relatively small for Association of ABO Serologic Blood Group With each subtype (ranging from 886 to 5,149 for transethnic analysis EOS and LOS and 376 to 1,502 for European-only analysis) and the frequencies We initially compared the distribution of A, B, AB, and O of the associated SNPs were low (8 SNPs with European ancestry blood groups between EOS cases, LOS cases, and nonstroke (EUR) MAF <0.02 and MAF of the 3 SNPs <0.09). controls. As indicated in Table 1, EOS cases were more likely to have blood group A and less likely to have blood group There was no evidence for replication of the HABP2 O compared with LOS cases and controls (p < 0.001 for each rs11196288 variant, which was previously associated with comparison). EOS and LOS cases were also more likely to EOS in our earlier phase 1 transethnic meta-analysis from the have blood group B compared with controls (p = 0.004 and EOSC,12 although its MAF is low (;3% in gnomAD Euro- p = 0.012, respectively). pean ancestry populations). In the expanded meta-analysis presented in this report (16,927 currently vs 4,505 cases Associations of Genetically Defined ABO Blood previously), there was no evidence for association of this SNP Subgroup With EOS and LOS with EOS in any of the new sites, including those of non- We further compared associations of all 5 ABO blood sub- European ancestry (eFigure 2, links.lww.com/WNL/C245). groups between EOS and LOS cases of European ancestry. The top ABO SNPs identified in our GWAS, rs529565 and Associations of Index ABO Variants With All rs635634, are in high LD with the tagging SNPs for blood Stroke and Stroke Subtypes in EOS and LOS subgroups O1 and A1, which were not included in our data set As indicated above, the rs529565 T and rs635634 T alleles at (Table 2). We also used rs1137827 as a high LD tag for the ABO locus tag blood subgroups O1 and AO1, respectively. rs8176743 (blood subgroup B). As previously described and The associations we observed for these SNPs with EOS are consistent with the VTE analysis of another study,20 we found substantially higher than the peak associations previously blood subgroup O1 (rs529565) to be protective against EOS reported at the ABO locus in predominantly older stroke (OR = 0.88, 95% CI: 0.85–0.91; p = 4.31 × 10−14) and blood populations (e.g., OR = 1.08; 95% CI: 1.05–1.11 in MEGA- subgroup A1 (rs635634) to be strongly associated with EOS STROKE1). Both SNPs also had significantly larger effect sizes (OR = 1.16, 95% CI: 1.11–1.21; p = 6.54 × 10−13) (Table 2). for all stroke in EOS compared with LOS (ABO rs529565: Unlike for VTE, blood subgroup B (rs1137827) showed little OR = 0.88 [95% CI: 0.85–0.91] vs 0.96 [95% CI: 0.91–1.00] evidence for association with EOS (OR = 1.05, 95% CI: and ABO rs635634: OR = 1.16 [95% CI: 1.11–1.21] vs 1.05 0.93–1.16; p = 0.324). These trends were also evident for [95% CI: 1.00–1.10], p-values for interaction = 0.0004 and LOS, although the strengths of association were markedly 0.001, respectively) (eFigure 3, links.lww.com/WNL/C245). reduced, that is, blood subgroup A1 (OR = 1.05, 95% CI: 1.00–1.10, p = 0.044), and blood subgroup O1 (OR = 0.96, In stroke subtype–specific analyses, the O1-defining allele at 95% CI: 0.92–1.00, p = 0.036). rs529565 had higher effect sizes (i.e., was more protective) in EOS than in LOS for large artery stroke, cardioembolic stroke, Based on an allele frequency of 0.20 and OR of 1.16, we and undetermined stroke (p-values for homogeneity = 0.026, estimated that 6% of all EOS cases in Europeans can be at- 0.007 and 0.0004, respectively). Similarly, the effect sizes of tributed to rs635634, compared with ;2% of LOS cases (see the A1-defining SNP rs635634 were significantly higher in Supplement, eMethods, links.lww.com/WNL/C245). EOS than in LOS for cardioembolic stroke (p = 0.018) and for undetermined stroke p = 0.001) (eFigure 3, links.lww.com/ To evaluate whether rs529565 and rs635634 accounted for all WNL/C245). of the genetic effects at the ABO locus, we performed a conditional analysis in Europeans to test for association of all We assessed the associations of ABO SNPs rs529565 SNPs at this locus (±50 kb from ABO) with EOS after in- (encoding blood subgroup O1) and rs2519093 (the defining cluding rs529565 and rs635634 in the model as covariates. Neurology.org/N Neurology | Volume 99, Number 16 | October 18, 2022 e1743 Table 1 Distribution of ABO Blood Types in EOS Cases, LOS Cases, and in Nonstroke Controlsa p Values for omnibus test for p Values for pairwise test for difference in distribution of blood difference in distribution of blood EOS cases LOS cases Controls groups (3 df) groups (1 df) Blood Early vs Early vs Late vs Early vs Early vs Late vs group n Proportion n Proportion n Proportion late controls controls late controls controls A 2,817 0.484 4,187 0.452 13,023 0.444 0.0001 <0.00001 0.0009 0.0001 <0.00001 0.20 AB 282 0.048 439 0.047 1,270 0.043 0.77 0.10 0.08 B 661 0.113 1,021 0.110 2,964 0.101 0.53 0.004 0.012 O 2,065 0.355 3,622 0.391 12,063 0.411 <0.00001 <0.00001 0.0004 Total 5,825 9,269 29,320 a European ancestry subjects only. These analyses revealed 7 SNPs, falling within 4 LD groups, to rs146390073 and TM4SF4 rs7610618, although the MAFs be associated with all stroke at a p-value < 0.01. Of these, were relatively rare for both SNPs and there were no statis- rs5598407 (MAF = 0.045) was the most strongly associated tically significant differences between EOS and LOS. with stroke (OR = 1.21, p = 3.13 × 10−4). This SNP was in LD with all of the blood group–defining SNPs (r2 < 0.03 but D’ = Genetically Defined ABO and Risk of Early- 1 for all) and with rs176694 (r2 = 0.347), which is strongly Onset and Late-Onset VTE associated with E-selectin levels (p < 10−406) in the GWAS Because the ABO locus has been previously associated with catalog.27 None of the tag SNPs for the 3 other blood sub- VTE and other prothrombotic states,28 we assessed whether groups (rs1053878-A2, rs1137827-B, and rs41302905-O2) there was a similar graded age-at-onset association between showed evidence for association after conditioning on ABO SNPs rs529565 (O1-defining) and rs2519093 (A1- rs529565 (O1) and rs635634 (A1); p > 0.40 for all. defining) and VTE in the UKB. The ABO rs529565-O1 allele was more strongly associated with early-onset VTE (OR = Associations of Other Established Stroke Loci 0.66, 95% CI: 0.62–0.69; p = 2.95 × 10−58) than with late- With EOS onset VTE (OR = 0.77, 95% CI: 0.74–0.81; p = 6.63 × 10−28); We compared the effect sizes of 40 loci previously found to p-value for homogeneity of OR = 2.15 × 10−6). Similarly, the associate with ischemic stroke1,2,16 between EOS (age at first ABO rs2519093-A1 allele was more strongly associated with stroke: younger than 60 years) and LOS (60 years or older). early-onset VTE (younger than 60 years; n = 3,514 cases) As indicated in eTable 7 (links.lww.com/WNL/C245), the (OR = 1.64, 95% CI: 1.54–1.74; p = 1.42 × 10−54) than with ORs associated with EOS were generally consistent with late-onset VTE (60 years or older; n = 5,043 cases) (OR = those estimated for LOS with 2 exceptions, RGS7 1.34, 95% CI: 1.27–1.41; p = 2.89 × 10−29); p-value for Table 2 Association of the ABO Blood Group–Defining SNPs With EOS and LOS, EUR Only Frequency of EOS LOS Blood blood p Value for Blood group–determining group–determining p p interaction SNP group Alleles allele allelea OR Value OR Value (early vs late) rs635634 High LD proxy for rs2519093 A1c T/C T 0.19 1.16 6.54E- 1.05 0.032 0.005 (r2 = 0.99, D’ = 0.99b) 13 rs529565 High LD proxy for rs8176719 O1 T/C T 0.64 0.88 4.31E- 0.96 0.036 0.001 (r2 = 0.94, D’ = 0.98b) 14 rs1053878 A2d G/A A 0.08 1.00 0.908 1.00 0.977 0.96 rs1137827 High LD proxy for rs8176743 Bc C/T T 0.09 1.05 0.324 1.02 0.591 0.76 (r2 = 1.00, D’ = 1.00b) rs41302905 O2 C/T T 0.02 0.94 0.346 0.90 0.111 0.58 Abbreviations: EOS = early-onset stroke; EUR = European ancestry; LD = linkage disequilibrium; LOS = late-onset stroke; SNP = single-nucleotide poly- morphism; VTE = venous thromboembolism. a Frequency values obtained from gnomAD genomes European samples. b LD values based on 1,000 genome CEU population (i.e., Northern Europeans from Utah). c Blood group–associated allele associated with high VTE risk. d Blood group–associated allele associated with moderate VTE risk. e1744 Neurology | Volume 99, Number 16 | October 18, 2022 Neurology.org/N Figure 3 Associations of SNPs at the ABO Locus With Multiple Traits Association plots showing SNPs associated with EOS at the ABO locus (±50 kb) and the corresponding associations of these SNPs with LOS (A), VTE (B), plasma levels of VWF (C), and plasma levels of factor VIII (D). EOS = early-onset stroke; LOS = late-onset stroke; SNP = single-nucleotide polymorphism; VWF = von Willebrand factor. homogeneity of ORs = 4.01 × 10−7 (details in eMethods, EOS and 0.032 ± 0.198, p = 0.87, between VTE and LOS. The links.lww.com/WNL/C245). genetic correlation between EOS and LOS was 0.455 ± 0.128 (p = 0.0004). Genetic Risk of VTE on Risk of EOS and LOS We used 2 approaches to evaluate whether genetic risk of Second, we measured genetic risk of VTE using a 255- VTE confers risk for stroke and especially for earlier-onset SNP–based PRS,23 as described in the eMethods (links.lww. stroke. First, using LDSC analysis on our current GWAS and com/WNL/C245). A 1-SD unit increase in VTE PRS was the GWAS of VTE from INVENT, we estimated genetic associated with a 1.13-fold increase in risk of EOS (95% CI: correlations of 0.376 ± 0.153, p = 0.014, between VTE and 1.10–1.16, p < 5.21 × 10−16) and a 1.04-fold increase in risk of Neurology.org/N Neurology | Volume 99, Number 16 | October 18, 2022 e1745 LOS (95% CI: 1.01–1.08, p = 0.010; p-value for homogeneity producing A and B antigens. These carbohydrate structures of OR = 0.0002). These results were essentially unchanged are expressed on red blood cells and on other cell types of when the analysis was repeated after removing 7 SNPs at the importance for hemostasis, such as platelets and endothelial ABO locus from the PRS. cells.34 These carbohydrates are also present on circulating solubilized glycoproteins, including VWF.34 It is well known Colocation of Associations at the ABO Locus that non-O blood groups have increased plasma levels of Between EOS and Other Thrombotic-Related VWF and coagulation factor VIII,20,34-36 with the A1 subtype Disorders and Biomarkers having the highest levels of both.37 The ABO locus has also Figure 3 provides a visualization of the SNPs most strongly been shown to associate with circulating levels of other associated with EOS and their corresponding associations glycoproteins such as tumor necrosis factor, soluble with VTE and 2 prothrombotic biomarkers. Each panel shows E-selection, P-selectin, intracellular adhesion molecule 1, the zoom plot depicting the association of SNPs at the ABO and thrombomodulin.38,39 locus (±50 kb) with EOS. The heat map in each panel and the color coding of the variants depict the association with LOS Because the ABO locus is so pleiotropic, several mechanisms may (panel 3A), VTE (panel 3B), plasma levels of VWF (panel contribute to our finding of an association to EOS. However, 3C), and plasma levels of factor VIII (F8, panel 3D). The taken together, our results clearly support an increased role of SNPs most strongly associated with EOS tended also to be the prothrombotic mechanisms in EOS compared with LOS. First, ones most strongly associated with VTE, VWF, and F8. This we have shown that the ABO rs529565-O1 SNP is not only trend was less apparent for LOS. Consistent with these ob- associated with EOS but also more strongly associated with early- servations, there was strong evidence to support the hy- onset compared with late-onset VTE. Second, our results show pothesis of colocalization of at least 1 shared causal SNP that genetic risk of VTE, a well-recognized prothrombotic- between EOS and VTE, EOS and VWF, and EOS and FVIII related disorder, is also more strongly associated with EOS (posterior probability supporting H4 > 99% for all pairs). compared with LOS. Consistent with these observations, we Consistent with the weak and dispersed set of associations further found that the EOS-associated haplotype colocalizes with with LOS at this locus, there was insufficient evidence to deep venous thrombosis and with increased levels of VWF and strongly support either colocalization or absence of colocali- FVIII, which are well-recognized prothrombotic factors. zation of shared causal SNPs between EOS and LOS (pos- terior probability supporting H4 = 39%; posterior probability Although our study had limited power to examine stroke supporting H3 = 61%). subtypes, it is notable that the ABO O1 and A1-defining SNPs were also significantly associated with large artery athero- sclerosis, cardioembolic, and undetermined stroke subtypes. Discussion This leads to the question, what are the clinical implications Our analyses revealed 2 variants at the ABO locus that were of an enrichment of prothrombotic mechanisms in EOS? highly associated with EOS. These variants tag 2 of the ABO Clinical translation will require a better understanding of the blood subgroups, O1 and A1, showing a strong deleterious prothrombotic mechanisms in EOS and, likely, a personalized and protective association with ischemic stroke, respectively. secondary prevention strategy. The effect sizes of the stroke- Non-O blood groups have been associated previously with associated common variants at the ABO locus are too small risk of ischemic stroke,29-31 but the novel contributions of our per se to have immediate clinical implications, but gene-gene analysis are in showing a significantly stronger association of and gene-environment interaction deserve future study.40 these blood groups with EOS compared with LOS and in One path to translation would be to identify gene-drug in- linking risk predominantly to the blood subgroup A1. In teractions (e.g., oral contraceptives and genetic risk for particular, our analyses suggest that the ABO blood subgroups thrombosis) and determine whether the joint effect has im- A1-tagging and O1-tagging variants (rs529565 and rs635634) plications for primary prevention. Additional research im- are sufficient for capturing nearly all of the ABO-mediated plications are that rare variant studies should target genetic association with early-onset (and perhaps late) stroke. prothrombotic and related pathways, which could identify Stratified analyses indicate that both SNPs are independently variants of larger effect size. associated with stroke, and further association analyses at the ABO locus that condition on the effects of these 2 SNPs reveal In addition to ABO, we detected genome-wide evidence for only modest additional signal at this locus. association of EOS with SHKBP1 rs118091666. Given that the MAF of this SNP is very low and this locus has not Non-O blood groups have been associated with a variety of previously been associated with stroke to our knowledge, diseases and phenotypes, including arterial and venous further follow-up is warranted of this observation. thrombosis.1,20,23,30,32,33 The ABO blood groups are de- termined by the ABO gene, and the A and B allele encodes Our study is not without limitations. First, further fine- glycosyltransferase A and B, respectively, whereas the O al- mapping and detailed functional experiments will be needed lele encodes a nonactive enzyme. The glycosyltransferases to identify the causal variants and detailed biological pathways add specific monosaccharides to the precursor H antigen, that link ABO to increased risk of EOS. Second, although 35% e1746 Neurology | Volume 99, Number 16 | October 18, 2022 Neurology.org/N of participants in the EOSC are of non-European ancestry, the Tuladhar is a junior staff member of the Dutch Heart diversity of the current EOSC cohort is still somewhat limited, Foundation (grant number 2016T044) and received a grant reducing power to detect variants whose frequencies might be from the Netherlands CardioVascular Research Initiative: high in non-European populations yet low in Europeans. A the Dutch Heart Foundation (CVON 2018-28 & 2012-06 third limitation is that the sample size even for all stroke is still Heart Brain Connection). F.E. de Leeuw received a grant small by GWAS standards; power to detect subtype-specific from the Dutch Heart Foundation (grant 2014 T060 to variants is even more limited. FE.d.L) and Bike4Brains. A.G. Lindgren reports personal fees from Bayer, Astra Zeneca, BMS Pfizer, and Portola. C.D. In summary, our genome-wide analysis indicates a stronger Anderson receives sponsored research support from the association of ABO risk variants tagging blood groups O1 and NIH of the United States (R01NS103924, U01NS069763), A1 with EOS compared with LOS and stronger associations the American Heart Association, the Bugher Foundation, of the same ABO variants with early-onset compared with Massachusetts General Hospital, and Bayer AG and has late-onset VTE, another prothrombotic condition. Similarly, consulted for ApoPharma and Invitae. The other authors we observed genetic risk for VTE to be more strongly cor- report no relevant disclosures. Go to Neurology.org/N for related with EOS compared with LOS. Our findings are full disclosures. consistent with an increased role for prothrombotic mecha- nisms in EOS compared with LOS. Publication History Previously published in medRxiv (doi.org/10.1101/2021.11.06.21265795). Acknowledgment Received by Neurology October 5, 2021. Accepted in final form Please see eAppendix 1 (links.lww.com/WNL/C245) for the June 9, 2022. Submitted and externally peer reviewed. The handling funding and acknowledgements for each contributing study. editor was José Merino, MD, MPhil, FAAN. Study Funding This study was supported by the NIH grants R01 NS105150, R01 NS100178, and R01NS114045 and Department of Vet- Appendix 1 Authors erans Affairs grant BX004672-01A1. The project utilized the Name Location Contribution resources and facilities at the VA Maryland Health Care System, Thomas Division of Endocrinology, Drafting/revision of the Baltimore, MD. The contents do not represent the views of the Jaworek, MS Diabetes and Nutrition, manuscript for content, U.S. Department of Veterans Affairs or the United States University of Maryland including medical writing Government. Tom Jaworek was supported by a T32 AG000262 School of Medicine, for content; analysis or Baltimore interpretation of data Epidemiology of Aging grant. Huichun Xu was supported by AHA Career Development Award (19CDA34760258). Please Huichun Xu, MD, Division of Endocrinology, Drafting/revision of the PhD Diabetes and Nutrition, manuscript for content, see eAppendix 1 (links.lww.com/WNL/C245) for the funding University of Maryland including medical writing and acknowledgements for each contributing study. School of Medicine, for content; study concept Baltimore or design; analysis or interpretation of data Brady J. Gaynor, Division of Endocrinology, Drafting/revision of the Disclosure MS Diabetes and Nutrition, manuscript for content, A. Butterworth reports grants outside of this work from University of Maryland including medical writing School of Medicine, for content; analysis or AstraZeneca, Biogen, BioMarin, Bioverativ, Merck, Novartis, Baltimore interpretation of data Pfizer, and Sanofi and personal fees from Novartis. J. Cárcel- John W. Cole, VA Maryland Health Care Drafting/revision of the Márquez is supported by an AGAUR Contract (agència de MD, MS System; Department of manuscript for content, gestió d’ajuts universitaris i de recerca; FI_DGR 2019, grant Neurology, University of including medical writing Maryland School of for content; major role in number 2019_FI_B 00853) co-financed with Fons Social Medicine, Baltimore the acquisition of data; Europeu (FSE). J. Danesh reports grants, personal fees and analysis or interpretation nonfinancial support from Merck Sharp & Dohme (MSD), of data grants, personal fees and nonfinancial support from Novar- Kristiina Centre for Medical Drafting/revision of the tis, grants from Pfizer and grants from AstraZeneca outside Rannikmae, MD, Informatics, Usher manuscript for content, PhD Institute, University of including medical writing the submitted work. J. Danesh sits on the International Edinburgh, United for content Cardiovascular and Metabolic Advisory Board for Novartis Kingdom (since 2010); the Steering Committee of UK Biobank (since Tara M. Stanne, Institute of Biomedicine, Drafting/revision of the 2011); the MRC International Advisory Group (ING) PhD Department of Laboratory manuscript for content, Medicine, Sahlgrenska including medical writing member, London (since 2013); the MRC High Throughput Academy, University of for content; analysis or Science ‘Omics Panel Member, London (since 2013); the Gothenburg, Sweden interpretation of data Scientific Advisory Committee for Sanofi (since 2013); the Liisa Tomppo, Department of Neurology, Drafting/revision of the International Cardiovascular and Metabolism Research and MD, PhD Helsinki University manuscript for content, Hospital and University of including medical writing Development Portfolio Committee for Novartis; and the Helsinki, Finland for content Astra Zeneca Genomics Advisory Board (2018). A.M. Continued Neurology.org/N Neurology | Volume 99, Number 16 | October 18, 2022 e1747 Appendix 1 (continued) Appendix 1 (continued) Name Location Contribution Name Location Contribution Vida Abedi, PhD Department of Molecular Drafting/revision of the Michael Chong, DBCVS Research Institute, Drafting/revision of the and Functional Genomics, manuscript for content, PhD, MSc Population Health manuscript for content, Geisinger Health System, including medical writing Research Institute, including medical writing Danville, PA for content Department of Pathology for content and Molecular Medicine, Philippe LabEx DISTALZ-U1167, Drafting/revision of the McMaster University; Amouyel, MD, RID-AGE-Risk Factors and manuscript for content, Thrombosis & PhD Molecular Determinants including medical writing Atherosclerosis Research of Aging-Related Diseases, for content Institute (TaARI), Hamilton, University of Lille; Inserm ON, Canada U1167, Lille, France; Centre Hospitalier Carlos Cruchaga, Department of Psychiatry, Drafting/revision of the Universitaire Lille; Institut PhD Washington University manuscript for content, Pasteur de Lille, France School of Medicine, St. including medical writing Louis, MO for content Nicole D. Department of Drafting/revision of the Armstrong, MS, Epidemiology, University manuscript for content, Mary Cushman, Department of Medicine, Drafting/revision of the PhD of Alabama at including medical writing MD, MSc University of Vermont manuscript for content, Birmingham for content Larner College of including medical writing Medicine, Burlington for content John Attia, MD, School of Medicine and Drafting/revision of the PhD Public Health, University of manuscript for content, John Danesh, British Heart Foundation Drafting/revision of the Newcastle and Hunter including medical writing FMedSci, DPhil Cardiovascular manuscript for content, Medical Research for content Epidemiology Unit, including medical writing Institute, Newcastle, Department of Public for content Australia Health and Primary Care, University of Cambridge; Steven Bell, PhD Stroke Research Group, Drafting/revision of the British Heart Foundation Department of Clinical manuscript for content, Centre of Research Neurosciences, University including medical writing Excellence, University of of Cambridge, United for content Cambridge; National Kingdom Institute for Health Research Blood and Oscar R. Department of Neurology, Drafting/revision of the Transplant Research Unit Benavente, MD University of British manuscript for content, in Donor Health and Columbia, Vancouver, including medical writing Genomics, University of Canada for content Cambridge; Health Data Research UK Cambridge, Giorgio B. Department of Drafting/revision of the Wellcome Genome Boncoraglio, MD Cerebrovascular Diseases, manuscript for content, Campus and University of Fondazione IRCCS Istituto including medical writing Cambridge; Department Neurologico “Carlo Besta,” for content; major role in of Human Genetics, Milan, Italy the acquisition of data Wellcome Sanger Institute, Hinxton, United Kingdom Adam British Heart Foundation Drafting/revision of the Butterworth, Cardiovascular manuscript for content, Stéphanie INSERM U1219 Bordeaux Drafting/revision of the PhD Epidemiology Unit, including medical writing Debette, MD, Population Health manuscript for content, Department of Public Health for content PhD Research Center, including medical writing and Primary Care, University University of Bordeaux; for content; major role in of Cambridge; British Heart Department of Neurology, the acquisition of data Foundation Centre of Institute for Research Excellence, Neurodegenerative University of Cambridge; Disease, Bordeaux National Institute for Health University Hospital, Research Blood and France Transplant Research Unit in Donor Health and Genomics, University of David J. Duggan, Quantitative Medicine and Drafting/revision of the Cambridge; Health Data PhD Systems Biology Division, manuscript for content, Research UK Cambridge, Translational Genomics including medical writing Wellcome Genome Campus Research Institute, An for content and University of Affiliate of City of Hope, Cambridge, United Kingdom Phoenix, AZ Jara Carcel- Stroke Drafting/revision of the Jon Peter Durda, Laboratory for Clinical Drafting/revision of the Marquez, MSc Pharmacogenomics and manuscript for content, PhD Biochemistry Research, manuscript for content, Genetics group, including medical writing Department of Pathology including medical writing Biomedical Research for content and Laboratory Medicine, for content Institute Sant Pau (IIB Sant University of Vermont Pau), Barcelona, Spain Larner College of Medicine, Burlington Zhengming MRC Population Health Drafting/revision of the Chen, DPhil Research Unit, Nuffield manuscript for content, Gunnar Department of Clinical Drafting/revision of the Department of Population including medical writing Engstrom, MD, Sciences, Malmö, Lund manuscript for content, Health, University of for content; major role in PhD University, Sweden including medical writing Oxford, United Kingdom the acquisition of data for content e1748 Neurology | Volume 99, Number 16 | October 18, 2022 Neurology.org/N Appendix 1 (continued) Appendix 1 (continued) Name Location Contribution Name Location Contribution Chris Enzinger, Department of Neurology, Drafting/revision of the Marc C. Division of Rheumatology Drafting/revision of the MD Medical University Graz, manuscript for content, Hochberg, MD and Clinical Immunology, manuscript for content, Austria including medical writing Department of Medicine, including medical writing for content University of Maryland for content School of Medicine; Jessica D. Faul, Survey Research Center, Drafting/revision of the Department of PhD, MPH Institute for Social manuscript for content, Epidemiology and Public Research, University of including medical writing Health, University of Michigan, Ann Arbor for content Maryland School of Medicine, Baltimore Natalie S. Department of Neurology, Drafting/revision of the Fecteau, MPH University of Maryland manuscript for content, Elizabeth Department of Drafting/revision of the School of Medicine, including medical writing Holliday, BSc, Epidemiology, University manuscript for content, Baltimore for content; additional MSc, PhD of Alabama at including medical writing contributions: Birmingham for content coordinating the consortium. Jie Hu, MD, PhD Division of Women’s Drafting/revision of the Health, Brigham and manuscript for content, Israel Stroke Drafting/revision of the Women’s Hospital, including medical writing Fernandez- Pharmacogenomics and manuscript for content, Harvard Medical School; for content Cadenas, MD, Genetics group, including medical writing Department of PhD Biomedical Research for content; major role in Epidemiology, Harvard Institute Sant Pau (IIB Sant the acquisition of data T.H. Chan School of Public Pau), Barcelona; Stroke Health, Boston, MA Pharmacogenomics and Genetics, Fundacio Andreea Ilinca, Department of Clinical Drafting/revision of the Docència i Recerca MD, PhD Sciences Lund, Neurology, manuscript for content, MutuaTerrassa Lund University; including medical writing Department of Neurology for content Christian Gieger, Institute of Epidemiology, Drafting/revision of the and Rehabilitation PhD Helmholtz Zentrum manuscript for content, Medicine, Skane München German including medical writing University Hospital, Lund, Research Center for for content Sweden Environmental Health; Research Unit of Marguerite R. Department of Drafting/revision of the Molecular Epidemiology, Irvin, PhD Epidemiology, University manuscript for content, Institute of Epidemiology, of Alabama at including medical writing Helmholtz Zentrum Birmingham for content; major role in München German the acquisition of data Research Center for Environmental Health, Rebecca D. Division of Endocrinology, Drafting/revision of the Neuherberg, Germany Jackson, MD Diabetes and Metabolism, manuscript for content, Department of Internal including medical writing Anne-Katrin Klinik und Poliklinik für Drafting/revision of the Medicine and the Center for content; major role in Giese, MD Neurologie, Kopf- und manuscript for content, for Clinical and the acquisition of data Neurozentrum, including medical writing Translational Science, The Universitätsklinikum for content Ohio State University, Hamburg-Eppendorf, Columbus Germany Mina A. Jacob, Department of Neurology, Drafting/revision of the Raji P. Grewal, Neuroscience Institute, Drafting/revision of the MD Radboud University manuscript for content, MD Saint Francis Medical manuscript for content, Medical Center, Donders including medical writing Center, Trenton, NJ including medical Medical Center for for content writing for content; Neuroscience, Nijmegen, major role in the the Netherlands acquisition of data Raquel Rabionet, Department of Genetics, Drafting/revision of the Ulrike Grittner, Department for Drafting/revision of the PhD Microbiology and manuscript for content, PhD Biostatistics and Clinical manuscript for content, Statistics, Institute of including medical writing Epidemiology, Charité- including medical writing Biomedicine (IBUB), for content; major role in University Medical Centre, for content University of Barcelona, the acquisition of data Berlin, Germany Barcelona, Spain; Institut de Recerca Sant Joan de Aki S. Havulinna, National Institute for Drafting/revision of the Déu, Esplugues de DSc Health and Welfare, manuscript for content, Llobregat, Spain; Centro Helsinki, Finland including medical de investigación writing for content; biomédica en red major role in the (CIBERER), Spain acquisition of data Jordi Jimenez- Neurovascular Research Drafting/revision of the Laura Heitsch, Departments of Drafting/revision of the Conde, MD, PhD Group (NEUVAS), manuscript for content, MD Emergency Medicine and manuscript for content, Neurology Department, including medical writing Neurology, Washington including medical writing Institut Hospital del Mar for content; major role in University School of for content d’Investigacio Medica, the acquisition of data Medicine, St. Louis, Universitat Autonoma de MO Barcelona, Spain Continued Neurology.org/N Neurology | Volume 99, Number 16 | October 18, 2022 e1749 Appendix 1 (continued) Appendix 1 (continued) Name Location Contribution Name Location Contribution Julie A. Johnson, Department of Drafting/revision of the Haley Lopez, BS Department of Neurology, Drafting/revision of the PharmD Pharmacotherapy and manuscript for content, University of Maryland manuscript for content, Translational Research including medical writing School of Medicine, including medical writing and Center for for content; major role in Baltimore, MD for content Pharmacogenomics, the acquisition of data University of Florida, Sothear Luke, Department of Neurology, Drafting/revision of the College of Pharmacy; MPH Mayo Clinic, Jacksonville, manuscript for content, Division of Cardiovascular FL including medical writing Medicine, College of for content Medicine, University of Florida, FL Jane Maguire, Faculty of Health, School Drafting/revision of the PhD of Nursing and Midwifery, manuscript for content, Yoichiro Laboratory of Complex Drafting/revision of the University of Technology including medical writing Kamatani, MD, Trait Genomics, Graduate manuscript for content, Sydney, NSW, Australia for content PhD School of Frontier including medical Sciences, The University of writing for content; Patrick F. Division of Endocrinology, Drafting/revision of the Tokyo, Japan major role in the McArdle, PhD Diabetes and Nutrition, manuscript for content, acquisition of data University of Maryland including medical writing School of Medicine, for content; analysis or Sharon L.R. Department of Drafting/revision of the Baltimore interpretation of data Kardia, PhD Epidemiology, School of manuscript for content, Public Health, University of including medical writing Caitrin W. Department of Drafting/revision of the Michigan, Ann Arbor for content McDonough, Pharmacotherapy and manuscript for content, PhD Translational Research including medical writing Masaru Koido, Department of Cancer Drafting/revision of the and Center for for content PhD Biology, Institute of manuscript for content, Pharmacogenomics, Medical Science, The including medical writing University of Florida, College University of Tokyo, Japan for content of Pharmacy, Gainesville Leslie Lange, Department of Medicine, Drafting/revision of the James F. Department of Neurology, Drafting/revision of the PhD University of Colorado manuscript for content, Meschia, MD Mayo Clinic, Jacksonville, manuscript for content, Denver, Anschutz Medical including medical writing FL including medical writing Campus, Aurora for content for content; major role in the acquisition of data Jin-Moo Lee, MD, Department of Neurology, Drafting/revision of the PhD Washington University manuscript for content, Tiina Metso, MD, Department of Neurology, Drafting/revision of the School of Medicine, St. including medical writing PhD Helsinki University Central manuscript for content, Louis, MO for content; major role in Hospital, Finland including medical writing the acquisition of data for content Robin Lemmens, Department of Drafting/revision of the Martina Müller- Institute of Genetic Drafting/revision of the MD, PhD Neurosciences, manuscript for content, Nurasyid, PhD Epidemiology, Helmholtz manuscript for content, Experimental Neurology, including medical writing Zentrum including medical writing VIB Center, For Brain & for content; major role in München–German for content Disease Research, KU the acquisition of data Research Center for Leuven–University of Environmental Health, Leuven, Belgium; Neuherberg; IBE, Faculty Department of Neurology, of Medicine, LMU Munich; University Hospitals Institute of Medical Leuven, Belgium Biostatistics, Epidemiology and Informatics (IMBEI), Christopher R. John Hunter Hospital, Drafting/revision of the University Medical Center, Levi, MD, PhD Hunter Medical Research manuscript for content, Johannes Gutenberg Institute and University of including medical writing University Mainz, Newcastle and Priority for content; major role in Germany Research Centre for the acquisition of data Stroke & Brain Injury, Timothy D. Division of Drafting/revision of the University of Newcastle, O’Connor, PhD Endocrinology, Diabetes manuscript for content, Australia and Nutrition, University including medical writing of Maryland School of for content; analysis or Jiang Li, PhD Department of Molecular Drafting/revision of the Medicine; Institute for interpretation of data and Functional Genomics, manuscript for content, Genome Sciences, Geisinger Health System, including medical writing University of Maryland Danville, PA for content School of Medicine, Baltimore Liming Li, MPH Peking University Health Drafting/revision of the Science Center, manuscript for content, Martin Health Research Board Drafting/revision of the Department of including medical writing O’Donnell, PhD Clinical Research Facility, manuscript for content, Epidemiology and for content Geata an Eolais, National including medical writing Biostatistics, Peking University of Ireland, for content University, Beijing, China Galway Kuang Lin, PhD MRC Population Health Drafting/revision of the Leema R. Neuroscience Institute, Drafting/revision of the Research Unit, University manuscript for content, Peddareddygari, Saint Francis Medical manuscript for content, of Oxford, United including medical writing MBBS, MD Center, Trenton, NJ including medical writing for Kingdom for content content e1750 Neurology | Volume 99, Number 16 | October 18, 2022 Neurology.org/N Appendix 1 (continued) Appendix 1 (continued) Name Location Contribution Name Location Contribution Joanna Pera, MD, Department of Neurology, Drafting/revision of the Tatjana Rundek, Department of Drafting/revision of the PhD Jagiellonian University, manuscript for content, MD, PhD Neurology and Evelin F. manuscript for content, Krakow, Poland including medical writing McKnight Brain Institute, including medical writing for content Miller School of for content; major role in Medicine, University of the acquisition of data James A. Perry, Division of Endocrinology, Drafting/revision of the Miami, FL PhD Diabetes and Nutrition, manuscript for content, University of Maryland including medical writing Kathleen A. Division of Endocrinology, Drafting/revision of the School of Medicine, for content Ryan, MPH Diabetes and Nutrition, manuscript for content, Baltimore University of Maryland including medical writing School of Medicine, for content; analysis or Annette Peters, Institute of Epidemiology, Drafting/revision of the Baltimore interpretation of data PhD Helmholtz Zentrum manuscript for content, München German Research including medical writing Ralph L. Sacco, Department of Neurology Drafting/revision of the Center for Environmental for content MD, MS and Evelin F. McKnight manuscript for content, Health, Neuherberg, Brain Institute, Miller including medical writing Germany; Institute for School of Medicine, for content; major role in Medical Information University of Miami, FL the acquisition of data Sciences, Biometry and Epidemiology, Ludwig- Veikko Salomaa, National Institute for Drafting/revision of the Maximilians-University, MD, PhD Health and Welfare, manuscript for content, Munich, Germany Helsinki, Finland including medical writing for content Jukka Putaala, Department of Neurology, Drafting/revision of the MD, PhD Helsinki University manuscript for content, Cristina Psychiatric Genetics Unit, Drafting/revision of the Hospital and University including medical writing Sanchez-Mora, Group of Psychiatry, manuscript for content, of Helsinki, Helsinki, for content BSc, PhD Mental Health and including medical writing Finland Addiction, Vall d’Hebron for content Research Institute (VHIR), Debashree Ray, Department of Drafting/revision of the Universitat Autònoma de BSc, MStat, PhD Epidemiology, Bloomberg manuscript for content, Barcelona; Department of School of Public Health, including medical writing Psychiatry, Hospital Johns Hopkins University, for content Universitari Vall d’Hebron, Baltimore, MD Barcelona, Spain Kathryn Division of Women’s Drafting/revision of the Reinhold Department of Neurology, Drafting/revision of the Rexrode, MD, Health, Department of manuscript for content, Schmidt, MD Medical University Graz, manuscript for content, MPH Medicine, Brigham and including medical writing Austria including medical writing Women’s Hospital, for content; major role in for content; major role in Boston, MA the acquisition of data the acquisition of data Marta Ribases, Psychiatric Genetics Unit, Drafting/revision of the Pankaj Sharma, Institute of Cardiovascular Drafting/revision of the BSc, PhD Group of Psychiatry, Mental manuscript for content, MD, PhD, FRCP Research, Royal Holloway manuscript for content, Health and Addiction, Vall including medical writing University of London, including medical writing d’Hebron Research Institute for content; major role in London, and Ashford and for content; major role in (VHIR), Universitat the acquisition of data St. Peters Hospital, Surrey, the acquisition of data Autònoma de Barcelona, United Kingdom Barcelona, Spain; Department of Psychiatry, Agnieszka Department of Neurology, Drafting/revision of the Hospital Universitari Vall Slowik, MD, PhD Jagiellonian University, manuscript for content, d’Hebron; Biomedical Krakow, Poland including medical writing Network Research Centre on for content; major role in Mental Health (CIBERSAM), the acquisition of data Instituto de Salud Carlos III, Madrid, Spain; Department Jennifer A. Department of Clinical Drafting/revision of the of Genetics, Microbiology, Smith, PhD, MPH Sciences, Malmö, Lund manuscript for content, and Statistics, Faculty of University, Sweden including medical writing Biology, Universitat de for content Barcelona, Spain Nicholas L. Group Health Research Drafting/revision of the Jonathan McCance Center for Brain Drafting/revision of the Smith, PhD, MPH Institute, Group Health manuscript for content, Rosand, MD, MSc Health, Massachusetts manuscript for content, Cooperative; Department including medical writing General Hospital, Boston, including medical writing of Epidemiology, for content MA; Center for Genomic for content; major role in University of Washington; Medicine, MGH; the acquisition of data Seattle Epidemiologic Department of Neurology, Research and Information MGH, Boston; Program in Center, VA Office of Medical and Population Research and Genetics, Broad Institute, Development, WA Cambridge, MA Sylvia Department of Drafting/revision of the Peter M. Nuffield Department of Drafting/revision of the Wassertheil- Epidemiology and manuscript for content, Rothwell, MD, Clinical Neurosciences, manuscript for content, Smoller, PhD Population Health, Albert including medical PhD, FMedSci University of Oxford, including medical writing Einstein College of writing for content; United Kingdom for content; major role in Medicine, New York major role in the the acquisition of data acquisition of data Continued Neurology.org/N Neurology | Volume 99, Number 16 | October 18, 2022 e1751 Appendix 1 (continued) Appendix 1 (continued) Name Location Contribution Name Location Contribution Martin Department of Clinical Drafting/revision of the Jan H. Veldink, Department of Neurology, Drafting/revision of the Söderholm, MD, Sciences, Malmö, Lund manuscript for content, MD, PhD University Medical Center, manuscript for content, PhD University; Department of including medical writing Utrecht Brain Center, including medical Clinical Sciences Lund, for content Utrecht University, the writing for content; Neurology, Lund Netherlands major role in the University, Sweden acquisition of data O. Colin Stine, Department of Drafting/revision of the Robin G. Walters, MRC Population Health Drafting/revision of the PhD Epidemiology and Public manuscript for content, PhD Research Unit, Nuffield manuscript for content, Health, University of including medical writing Department of Population including medical writing Maryland School of for content; analysis or Health, University of for content Medicine, Baltimore interpretation of data Oxford, United Kingdom Daniel Strbian, Department of Neurology, Drafting/revision of the David R. Weir, Department of Clinical Drafting/revision of the MD, PhD, MSc Helsinki University manuscript for content, PhD Sciences, Malmö, Lund manuscript for content, (Stroke Med) Hospital and University of including medical writing University, Sweden including medical Helsinki, Finland for content writing for content; major role in the Cathie L.M. Centre for Medical Drafting/revision of the acquisition of data Sudlow, DPhil, Informatics, Usher manuscript for content, FRCP(E) Institute, University of including medical writing Daniel Woo, MD Department of Neurology Drafting/revision of the Edinburgh; BHF Data for content; major role in and Rehabilitation manuscript for content, Science Centre, Health the acquisition of data Medicine, University of including medical Data Research UK, Cincinnati College of writing for content; London, United Kingdom Medicine, OH major role in the acquisition of data Turgut Department of Neurology, Drafting/revision of the Tatlisumak, MD, Helsinki University manuscript for content, Bradford B. Departments of Drafting/revision of the PhD Hospital and University of including medical writing Worrall, MD, MSc Neurology and Public manuscript for content, Helsinki, Finland; for content Health Sciences, including medical writing Department of Neurology, University of Virginia for content; major role in Sahlgrenska University School of Medicine, the acquisition of data Hospital; Department of Charlottesville Clinical Neuroscience, Institute of Neurosciences Charles C. Hong, Department of Medicine, Drafting/revision of the and Physiology, MD, PhD University of Maryland manuscript for content, Sahlgrenska Academy at School of Medicine, including medical writing University of Gothenburg, Baltimore for content Sweden Owen A. Ross, Department of Neurology, Drafting/revision of the Chikashi Terao, RIKEN Center for Drafting/revision of the PhD Mayo Clinic, Jacksonville, manuscript for content, MD, PhD Integrative Medical manuscript for content, FL including medical writing Sciences, Yokohama, including medical writing for content Japan for content Ramin Zand, MD, Department of Molecular Drafting/revision of the Vincent Thijs, Stroke Theme, Florey Drafting/revision of the MPH and Functional Genomics, manuscript for content, MD, PhD Institute of Neuroscience manuscript for content, Geisinger Health System, including medical writing and Mental Health, including medical writing Danville, PA for content; major role in University of Melbourne; for content the acquisition of data Department of Neurology, Austin Health, Heidelberg, Frank-Erik de Department of Neurology, Drafting/revision of the VIC, Australia Leeuw, MD, PhD Radboud University manuscript for content, Medical Center, Donders including medical writing Nuria P. Torres- Stroke Drafting/revision of the Medical Center for for content; major role in Aguila, PhD Pharmacogenomics and manuscript for content, Neuroscience, Nijmegen, the acquisition of data Genetics group, including medical writing the Netherlands Biomedical Research for content Institute Sant Pau (IIB Sant Arne G. Department of Clinical Drafting/revision of the Pau), Barcelona, Spain Lindgren, MD, Sciences Lund, Neurology, manuscript for content, PhD Lund University; Section of including medical writing David-Alexandre University of Bordeaux, Drafting/revision of the Neurology, Skåne University for content; major role in Trégouët PhD Inserm, Bordeaux manuscript for content, Hospital, Lund, Sweden the acquisition of data Population Health including medical writing Research Center, UMR for content Guillaume Pare, DBCVS Research Institute, Drafting/revision of the 1219, France MD, MSc Population Health Research manuscript for content, Institute, Department of including medical writing Anil M. Tuladhar, Department of Neurology, Drafting/revision of the Pathology and Molecular for content; major role in MD Radboud University manuscript for content, Medicine, McMaster the acquisition of data Medical Center, Donders including medical writing University; Thrombosis & Medical Center for for content Atherosclerosis Research Neuroscience, Nijmegen, Institute (TaARI), Hamilton, the Netherlands ON, Canada e1752 Neurology | Volume 99, Number 16 | October 18, 2022 Neurology.org/N References Appendix 1 (continued) 1. Malik R, Chauhan G, Traylor M, et al, AFGen Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology CHARGE Consortium, International Name Location Contribution Genomics of Blood Pressure iGEN-BP Consortium, INVENT Consortium, STAR- NET, BioBank Japan Cooperative Hospital Group, COMPASS Consortium, EPIC- CVD Consortium, EPIC-InterAct Consortium, International Stroke Genetics Con- Christopher D. 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