Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases
FEIRI investigators; International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group; MEGASTROKE
(2021) Nature Communications, volume 12, issue 1, pp. 1 - 16
(Article)
Abstract
Fibromuscular dysplasia (FMD) is an arteriopathy associated with hypertension, stroke and myocardial infarction, affecting mostly women. We report results from the first genome-wide association meta-analysis of six studies including 1556 FMD cases and 7100 controls. We find an estimate of SNP-based heritability compatible with FMD having a polygenic basis, and
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report four robustly associated loci (PHACTR1, LRP1, ATP2B1, and LIMA1). Transcriptome-wide association analysis in arteries identifies one additional locus (SLC24A3). We characterize open chromatin in arterial primary cells and find that FMD associated variants are located in arterial-specific regulatory elements. Target genes are broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. We find significant genetic overlap between FMD and more common cardiovascular diseases and traits including blood pressure, migraine, intracranial aneurysm, and coronary artery disease.
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Keywords: General Chemistry, General Biochemistry,Genetics and Molecular Biology, General Physics and Astronomy
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: We thank all patients who participated in these studies. We thank Dr. Antoine Chédid for collecting and managing clinical data of patients in ARCADIA protocol. We thank Patrick Bruneval for his scientific input and exchanges about arterial pathology in FMD. This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001. This work has benefited from the facilities and expertise of the high throughput sequencing core facility of I2BC (Centre de Recherche de Gif – http://www.i2bc.paris-saclay.fr/). ARCADIA-Pol investigators thank Ewa Rudolf, Elzbieta Pazio and Małgorzata Lewan-dowska, who were responsible for all administrative work. The Steering Committee of the WOBASZ study expresses special thanks for participating in the implementation of the study to: all their co-workers from research teams at six academic centres, to nurses, doctors, and analysts from field research centres located in 16 voivodeships. We acknowledge the Spanish National Cancer Research Centre (CNIO), in the Human Genotyping lab, a member of CeGen where genotyping was performed for part of the cohorts studied. We thank the participants of the study and the Fibromuscular Dysplasia Society of America for facilitating the enrolment of subjects at their annual meetings. We thank the Frankel Cardiovascular Center and M-BRISC programme for their support and the UM Advanced Genomics Core where genotyping of UM-MGI/CCF samples was performed. The authors acknowledge the University of Michigan Precision Health Initiative and Medical School Central Biorepository for providing biospecimen storage, management, processing and distribution services and the Center for Statistical Genetics in the Department of Biostatistics at the School of Public Health for genotype data management in support of this research. This study was supported by the European Research Council grant (ERC-Stg-ROSALIND-716628) to NB-N and National Institute of Health grant (R01HL139672) to S.K.G. The ARCADIA study was sponsored by the Assistance Publique-Hôpitaux 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 l’Hypertension Artérielle. Genotyping of French study was supported by the French research agency (ANR-13-JSV1-0002) to N.B.-N. The geno-typing of controls from the Three-City Study (3C) was supported by the non-profit organization Fondation Alzheimer (Paris, France) to P.A. ARCADIA-Pol study was supported by the 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”. M.V. 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 J.C.K. BAS is supported by the Mayo Clinic Clinician-Investigator Training Program. I.J.K. is additionally supported by NIH grant K24HL137010. The UM-MGI/CCF study is supported by NHLBI/NIH (R01HL139672, R01 HL122684), the University of Michigan Taubman Institute, and Frankel Cardiovascular Center. S.K.G. is supported by R01HL139672, R01HL122684, and R01HL086694. The Michigan Genomics Initiative (MGI) 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. Y.R. received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 852173). Intracranial aneurysm working group acknowledges the support from the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation, CVON2015-08 ERASE. Publisher Copyright: © 2021, The Author(s).
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