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 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.
Highlights
Fibromuscular dysplasia (FMD) is an arteriopathy associated with hypertension, stroke and myocardial infarction, affecting mostly women
We report four loci (PHACTR1, LDL receptor protein 1 (LRP1), ATP2B1, and LIM domain and acting binding 1 (LIMA1)) that are associated with FMD, in addition to SLC24A3 identified through transcriptome-wide association studies of arterial transcriptomes from the GTEx database
Using linkage disequilibrium score regression, we report an estimate of single nucleotide polymorphism (SNP)-based heritability compatible with FMD having a polygenic basis, and an important genetic overlap with blood pressure, migraine, intracranial aneurysm, and coronary artery disease (CAD)
Summary
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. Only PHACTR1, a pleiotropic locus involved in the genetic risk of several cardiovascular and neurovascular diseases, has been reported to associate with FMD3. We find that risk genes for FMD are consistently expressed in smooth muscle cells, fibroblasts, and arterial tissues These genes are involved in regulatory mechanisms related to actin cytoskeleton and intracellular calcium homoeostasis, a mechanism central to vascular contraction. Using linkage disequilibrium score regression, we report an estimate of single nucleotide polymorphism (SNP)-based heritability compatible with FMD having a polygenic basis, and an important genetic overlap with blood pressure, migraine, intracranial aneurysm, and coronary artery disease (CAD)
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