TY - JOUR
T1 - Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases
AU - FEIRI investigators
AU - International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group
AU - MEGASTROKE
AU - Georges, Adrien
AU - Yang, Min Lee
AU - Berrandou, Takiy Eddine
AU - Bakker, Mark K.
AU - Dikilitas, Ozan
AU - Kiando, Soto Romuald
AU - Ma, Lijiang
AU - Satterfield, Benjamin A.
AU - Sengupta, Sebanti
AU - Yu, Mengyao
AU - Deleuze, Jean François
AU - Dupré, Delia
AU - Hunker, Kristina L.
AU - Kyryachenko, Sergiy
AU - Liu, Lu
AU - Sayoud-Sadeg, Ines
AU - Amar, Laurence
AU - Brummett, Chad M.
AU - Coleman, Dawn M.
AU - d’Escamard, Valentina
AU - de Leeuw, Peter
AU - Fendrikova-Mahlay, Natalia
AU - Kadian-Dodov, Daniella
AU - Li, Jun Z.
AU - Lorthioir, Aurélien
AU - Pappaccogli, Marco
AU - Prejbisz, Aleksander
AU - Smigielski, Witold
AU - Stanley, James C.
AU - Zawistowski, Matthew
AU - Zhou, Xiang
AU - Zöllner, Sebastian
AU - de Leeuw, Peter
AU - Amouyel, Philippe
AU - De Buyzere, Marc L.
AU - Debette, Stéphanie
AU - Dobrowolski, Piotr
AU - Drygas, Wojciech
AU - Gornik, Heather L.
AU - Olin, Jeffrey W.
AU - Piwonski, Jerzy
AU - Rietzschel, Ernst R.
AU - Ruigrok, Ynte M.
AU - Vikkula, Miikka
AU - Warchol Celinska, Ewa
AU - Januszewicz, Andrzej
AU - Kullo, Iftikhar J.
AU - Azizi, Michel
AU - Jeunemaitre, Xavier
AU - Persu, Alexandre
AU - Kovacic, Jason C.
AU - Ganesh, Santhi K.
AU - Bouatia-Naji, Nabila
N1 - 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).
PY - 2021/12
Y1 - 2021/12
N2 - 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 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.
AB - 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 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.
UR - http://www.scopus.com/inward/record.url?scp=85119089555&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-26174-2
DO - 10.1038/s41467-021-26174-2
M3 - Article
C2 - 34654805
AN - SCOPUS:85119089555
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6031
ER -