Genetic association studies of fibromuscular dysplasia identify new risk loci and shared genetic basis with more common vascular diseases

Adrien B. Georges; Min‐Lee Yang; Takiy-Eddine Berrandou; Mark K. Bakker; Ozan Dikilitas; Soto Romuald Kiando; Lijiang Ma; Benjamin A. Satterfield; Sebanti Sengupta; Mengyao Yu; Jean‐François Deleuze; Délia Dupré; Kristina L. Hunker; Sergiy Kyryachenko; Lu Liu; Laurence Amar; Chad M. Brummett; Dawn M. Coleman; Valentina d’Escamard; Peter W. de Leeuw; Natalia Fendrikova-Mahlay; Daniella L. Kadian‐Dodov; Jun Z. Li; Aurélien Lorthioir; Marco Pappaccogli; Aleksander Prejbisz; Witold Śmigielski; James C. Stanley; Matthew Zawistowski; Xiang Zhou

doi:10.1101/2020.09.16.20195701

Genetic & Genomic MedicinemedRxivSep 16, 2020

Preprint

Genetic association studies of fibromuscular dysplasia identify new risk loci and shared genetic basis with more common vascular diseases

Adrien B. Georges iD, Min‐Lee Yang iD, Takiy-Eddine Berrandou iD, Mark K. Bakker iD, Ozan Dikilitas iD, Soto Romuald Kiando iD, Lijiang Ma iD, Benjamin A. Satterfield iD, Sebanti Sengupta, Mengyao Yu iD, Jean‐François Deleuze iD, Délia Dupré, Kristina L. Hunker iD, Sergiy Kyryachenko iD, Lu Liu iD, Laurence Amar iD, Chad M. Brummett iD, Dawn M. Coleman iD, Valentina d’Escamard, Peter W. de Leeuw iD, Natalia Fendrikova-Mahlay iD, Daniella L. Kadian‐Dodov iD, Jun Z. Li iD, Aurélien Lorthioir iD, Marco Pappaccogli iD, , Nabila Bouatia‐Naji iD

Abstract

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.

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