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

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.

Genetic risk score for intracranial aneurysms to predict aneurysmal subarachnoid hemorrhage and identify associations with patient characteristics

“…2 These 24 traits included: 1. established risk factors for IA and/or ASAH, being diastolic and systolic blood pressure (SBP), smoking (cigarettes per day), and alcohol consumption (drinks per week); 4, 5, 15-19 2. suggestive risk factors including those related to female hormones (age at menarche, age at menopause and number of births), 20-23 and cardiovascular disease risk (diabetes type II, body-mass index, waist-to-hip ratio, low- and high density lipoprotein levels, total cholesterol, and triglyceride levels), 15, 24-29 migraine, 30-32 epilepsy (focal and generalized), 2, 33 and years of education 34, 35 and 3. diseases genetically correlated with IA, being intracerebral hemorrhage, ischemic stroke, abdominal aortic aneurysms, and fibromuscular dysplasia (multifocal and any type). 36-39 Only data of European-ancestry individuals were used while UK Biobank participants were excluded. Data pre-processing steps are described in the Supplementary Data.…”

“…Summary statistics of large GWASs of IA and 24 traits (potentially) associated with IA were obtained (Supplementary [20][21][22][23] and cardiovascular disease risk (diabetes type II, body-mass index, waist-to-hip ratio, low-and high density lipoprotein levels, total cholesterol, and triglyceride levels), 15,[24][25][26][27][28][29] migraine, [30][31][32] epilepsy (focal and generalized), 2,33 and years of education 34,35 and 3. diseases genetically correlated with IA, being intracerebral hemorrhage, ischemic stroke, abdominal aortic aneurysms, and fibromuscular dysplasia (multifocal and any type). [36][37][38][39] Only data of European-ancestry individuals were used while UK Biobank participants were excluded.…”