Genetic Association Studies Of Fibromuscular Dysplasia Identify New Risk Loci And Shared Genetic Basis With More Common Vascular Diseases

Fibromuscular dysplasia (FMD) is an arteriopathy that presents clinically by hypertension and stroke, mostly in early middle-aged women. We report results from the first genome-wide association meta-analysis of FMD including 1962 FMD cases and 7100 controls. We confirmed PHACTR1 and identified three new loci ( LRP1, ATP2B1 , and LIMA1) associated with FMD. Transcriptome-wide association analysis in arteries identified one additional locus ( SLC24A3) . FMD associated variants were located in arterial-specific enhancers active in vascular smooth muscle cells and fibroblasts. Target genes are broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. Cross-trait linkage disequilibrium analyses identified positive genetic correlations with blood pressure, migraine and intracranial aneurysm, and an inverse correlation with coronary artery disease, independent from the genetics of blood pressure. ### Competing Interest Statement HLG, SKG, JO, and JCS are non-compensated members of the Medical Advisory Board of the FMD Society of America (FMDSA). SKG is a non-compensated member of the Scientific Advisory Board of SCAD Alliance. Both are non-profit organizations. ### Funding Statement This study was supported by the European Research Council grant (ERC-Stg-ROSALIND-716628) to NB-N and National Institute of Health grant (R01 HL139672) to SKG. The ARCADIA study was sponsored by the Assistance Publique-Hopitaux de Paris and funded by a grant from the French Ministry of Health (Programme Hospitalier de Recherche Clinique 2009, AOM 08192) and the Fondation de Recherche sur hypertension Arterielle. Genotyping of the French study was supported by the French research agency (ANR-13-JSV1-0002) to NB-N. The genotyping of controls from the Three-City Study (3C) was supported by the non-profit organization Fondation Alzheimer (Paris, France) to PA. ARCADIA-Pol study was supported by grant no 2.40/III/19 of Institute of Cardiology, Poland. The WOBASZ II Project was financed from the resources at the disposal of the Polish Minister of Health within the framework of the National Program of Equalization and Accessibility to Cardiovascular Disease Prevention and Treatment for 2010-2012. MV benefited from Fonds de la Recherche Scientifique - FNRS Grant T.0247.19, Belgium. The Spanish National Cancer Research Centre (CNIO), in the Human Genotyping lab, a member of CeGen Biomolecular resources platform (PRB3), is 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). DEFINE-FMD is supported by NIH grant 1R01HL148167-01A1 to JCK. BAS is supported by the Mayo Clinic Clinician-Investigator Training Program. IJK is additionally supported by NIH grant K24HL137010. The UM study is supported by NHLBI/NIH (R01 HL139672, R01 HL122684), the University of Michigan Taubman Institute, Frankel Cardiovascular Center. S.K.G. is supported by R01HL139672, R01HL122684, and R01HL086694. The Michigan Genomics Initiative was supported by the University of Michigan Precision Health Initiative. The Cleveland Clinic Biorepository was supported by CTSA 1UL1RR024989. The Cleveland Clinic FMD Biorepository has been supported in part by the National Institutes of Health, National Center for Research Resources, CTSA 1UL1RR024989, Cleveland, Ohio. YR received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No. 852173). The intracranial aneurysm working group acknowledges the support from the Netherlands Cardiovascular Research Initiative: an initiative with the support of the Dutch Heart Foundation, CVON2015-08 ERASE. ### 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: the Comite de Protection des Personnes (CPP) Ile-de-France II- ID RCB: 2009-A00288-49 Comite consultatif de protection des personnes dans la recherche biomedicale Bicetre Hopital Bicetre #99-28 CCPPRB approved 10/06/99, 11/03/2003 and 17/03/2006 Local Ethics Committee, Institute of Cardiology, IK-NPIA-0021017/1482/17 Field Bioethics Committee of the Institute of Cardiology in Warsaw (IK-NP-0021-69/1344/12 Mount Sinai Health System Study ID: HSM# 13-00575 / GCO# 13-1118 Mayo Clinic IRB #08-008355 University of Michigan IRB #HUM00044507, #HUM00112101 and Cleveland Clinic IRB approval #10-318 All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. 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 Data will be fully and freely available after publication acceptance.