Genome-wide association meta-analysis of spontaneous coronary artery dissection reveals common variants and genes related to artery integrity and tissue-mediated coagulation

Spontaneous coronary artery dissection (SCAD) is an understudied cause of acute myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Through a meta-analysis of genome-wide association studies including 1917 cases and 9292 controls of European ancestry, we identified 17 risk loci, including 12 new, with odds ratios ranging from 2.04 (95%CI 1.77-2.35) on chr21 to 1.25 (95%CI 1.16-1.35) on chr4. A locus on chr1 containing the tissue factor gene ( F3 ), which is involved in blood coagulation cascade, appears to be specific for SCAD risk. Prioritized genes were mainly expressed in vascular smooth muscle cells and fibroblasts of arteries and are implicated predominantly in extracellular matrix biology (e.g. COL4A1/A2, HTRA1 and TIMP3 ). We found that several variants associated with SCAD had diametrically opposite associations with CAD suggesting that shared biological processes contribute to both diseases but through different mechanisms. We also demonstrated an inferred causal role for high blood pressure, but not other CAD risk factors, in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and prevention for this disease. ### Competing Interest Statement Dr Adlam has received in kind support from Astra Zeneca inc. to support gene sequencing in SCAD patients and grant funding for unrelated research, research funding from Abbott vascular to support a clinical research fellow and has undertaken consultancy for General Electric inc. to support research funds. ### Funding Statement This study was supported by the European Research Council grant (ERC-Stg-ROSALIND-716628), The French Society of Cardiology through Fondation Coeur et Recherche, La Federation Francaise de Cardiologie, and the French Coronary Atheroma and Interventional Cardiology Group (GACI), the British Heart Foundation (PG/13/96/30608, SP/16/4/32697), the Leicester NIHR Biomedical Research Centre, BeatSCAD, National Health and Medical Research Council (NHMRC), Cardiac Society of Australia and New Zealand (CSANZ) Cardiovascular Research Innovation Grant Australia (APP1161200), NSW Health Early Mid-Career Cardiovascular Grant (EG), New South Wales Health Senior Scientist Cardiovascular Grant (RG194194), New South Wales Health Senior Clinician Cardiovascular Grant (RMG RG193092), the Bourne Foundation, Agilent, SCAD research Inc., National Institutes of Health (NIH) T32 GM72474, R01HL139672, R35HL161016, R35HL161016, R01HL086694, R01HL148167, R01HL147883, the Genome Consortia, Mayo Clinic Center for Individualized Medicine, Heart and Stroke Foundation of Canada (G-17-0016340), Canadian Institutes of Health Research (grant #136799), and the University of Michigan Frankel Cardiovascular Center, a Canada Research Chair in Precision Cardiovascular Disease Prevention, M-BRISC program, Department of Defense, the A. Alfred Taubman Institute, a Michael Smith Foundation for Health Research Scholar award, FMD Society of America, the American Heart Association (pre-doctoral fellowship 829009), and UCLA Integrative Biology and Physiology Edith Hyde fellowship. Genotyping was supported by the Spanish National Cancer Research Centre, in the Human Genotyping lab, a member of CeGen Biomolecular resources platform (PRB3), to be supported by grant PT17 /0019, of the PE I+D+i 2013-2016, funded by Instituto de Salud Carlos III and a European regional development fund (ERDF), Fondation Alzheimer (Paris, France), The University of Michigan Advanced Genomics Core. The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html. We thank AstraZeneca Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D for funding the sequencing of and providing the bioinformatics support related to subjects in cohort SCAD-UK I. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: - DISCO study was registered under Clinical Trials ID: [NCT02799186][1], and approved by regional committee CPP (comite de protection des personnes) Sud-Est 6 2016 AU-1258 - 3C study protocol was approved by comite consultatif de protection des personnes dans la recherche biomedicale Bicetre Hospital n:99-28 CCPPRB approved 10/06/99, 11/03/2003 and 17/03/2006 - The UK SCAD study ([ISRCTN42661582][2]) was approved by the UK National Research Ethics Service (14/EM/0056) and the UK Health Research Authority - The VCCRI study was approved by the St. Vincent Hospital Human Research Ethics Committee (HREC/16/SVH/338, protocol number SVH 16/245) and conducted in accordance with the Australian National Health and Medical Research Council National Statement on Ethical Conduct in Human Research and the CPMP/ICH Note for Guidance on Good Clinical Practice - The Mayo Clinic study used clinical and genetic research protocols approved by the Mayo Clinic Institutional Review Board ([NCT01429727][3]; [NCT01427179][4]) - CanSCAD/MGI (UBC/MGI) case control study was approved at each site: GenSCAD study was approved by IRB approval: HUM00113268, SCAD Registry, Vancouver Hospital, University of British Columbia Research ethics board approvals were obtained (IRBapproval: HUM00112101), genetic analysis of arterial dysplasia and remodeling (Michigan Genome Initiative /AOS) - The DEFINE study ([NCT01967511][5]) protocol was approved by the Human Research Ethics Committee of the Icahn School of Medicine at Mount Sinai, New York USA. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data in the present study will be available upon request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02799186&atom=%2Fmedrxiv%2Fearly%2F2022%2F07%2F06%2F2022.07.05.22277238.atom [2]: /external-ref?link_type=ISRCTN&access_num=ISRCTN42661582 [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01429727&atom=%2Fmedrxiv%2Fearly%2F2022%2F07%2F06%2F2022.07.05.22277238.atom [4]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01427179&atom=%2Fmedrxiv%2Fearly%2F2022%2F07%2F06%2F2022.07.05.22277238.atom [5]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01967511&atom=%2Fmedrxiv%2Fearly%2F2022%2F07%2F06%2F2022.07.05.22277238.atom