Gene-Based Rare Variant Burden Analyses Across Biobanks Identify Novel High-Risk Genes for Thoracic Aortic Disease

The study examined rare genetic variants associated with thoracic aortic disease, a serious condition characterized by aortic enlargement and risk of fatal aortic dissection. Researchers analyzed data from five large biobanks including UK Biobank and All of Us, containing more than 10,000 cases and 880,000 controls. They identified 80 genes significantly associated with aortic disease, including eight completely novel candidate genes: FNDC3B, ROCK1, URM1, SLFN11, ENPP1, CLEC16A, CREM, and VCAN. The study confirmed six previously known genes and two putative genes. The identified associations were strongest for aortic dissection and aortic aneurysms requiring surgical repair. The results expand understanding of the genetic basis of thoracic aortic disease and demonstrate the utility of rare variant analysis in large biobanks for gene discovery.