The ROSALIND project provided major advances in deciphering the genetic basis of FMD and SCAD using genomic analyses, mainly genome-wide association (GWAS) methodology. We showed that both diseases present high polygenic heritability, are genetically close to hypertension, migraine, cervical artery dissection, and intracranial aneurysm, supporting shared genetic risk factors. We also provided support for an opposite direction of genetic link between SCAD and atherosclerotic form of coronary artery disease at a number of risk loci and at the genomic level (Adlam et la., Nature genetics 2023). We examined the functional properties using genomic annotations in silico and in vitro and provided evidence for genetic variants at play in FMD and SCAD risk are mostly relevant to the regulation of genes related to smooth muscle cells and fibroblasts biology (Georges et al., Nat Com 2021, and Adlam et al., Nat Genetics 2023). Most genes prioritized were mainly in link with calcium exchange involved in cell contraction, extracellular matrix secretion and organization and prostacyclin signaling through the study of rare variations. Interestingly, we identified a novel biological mechanism in SCAD related to tissue factor coagulation through the identification of a genetic risk locus specific to the risk of SCAD.
ROSALIND has allowed the generation of an unprecedented wealth of genetic and genomic data related to FMD and SCAD and beyond, as we found novel biological mechanisms also related to a large spectrum of arterial diseases. Our findings set the stage for an ambitious follow-up with aim to translate those genetic and genomic findings into specific preventive and therapeutic strategies to cardiovascular diseases predominantly affecting women.
