Analyzing ultrarare damaging missense and predicted loss-of-function variants across five major biobanks—totaling more than 10,000 cases and 880,000 controls—a large multi-cohort study identified eight novel candidate genes associated with thoracic aortic disease (TAD): FNDC3B, ROCK1, URM1, SLFN11, ENPP1, CLEC16A, CREM, and VCAN. Discovery in UK Biobank and All of Us was independently replicated across Penn Medicine, Mass General Brigham, and the Million Veteran Program, with associations strongest for aortic dissection and surgically-repaired aneurysms. Cell-type-specific expression in human thoracic aortic tissue further supports biological plausibility.
Thoracic aortic aneurysms are particularly dangerous because they expand without symptoms until catastrophic dissection occurs, and existing genetic panels—covering established HTAD genes like FBN1 and ACTA2—explain only a fraction of cases. These eight new candidates meaningfully broaden the searchable genetic landscape. ROCK1 is especially intriguing given its established role in vascular smooth muscle cytoskeletal signaling, and VCAN encodes versican, a extracellular matrix proteoglycan already implicated in connective tissue pathology. Variable penetrance across sporadic versus familial cases complicates clinical translation, suggesting modifier genes or hemodynamic factors contribute. As a preprint not yet peer-reviewed, these findings require scrutiny of analytical assumptions and phenotype ascertainment across biobanks before clinical gene-panel adoption. Still, the scale and multi-biobank replication strategy marks this as a genuinely significant advance in cardiovascular genomics.
