Abstract Body (Do not enter title and authors here): Introduction: Thoracic aortic aneurysm and dissection (TAAD) is a morbid cardiovascular disease with 21 known common-variant genomic risk loci. Aneurysm represents an extreme of diameter, so we sought to jointly analyze TAAD and aortic diameter to enhance discovery power.
Methods: Genome-wide association studies (GWAS) were performed for UK Biobank MRI-derived aortic diameter measured at the aortic root (N=62,919), ascending aorta (N=61,156), and descending aorta (N=62,412). Separately, TAAD GWAS summary statistics from UKB (1,076 cases, 416,263 controls), FinnGen (3,880 cases, 381,977 controls), and the Million Veteran Program (8,626 cases, 453,043 controls) were meta-analyzed. Genetic correlation was assessed with ldsc. Multi-trait analysis was then performed for the aortic measurements and TAAD with MTAG. A 1.1-million-variant polygenic risk score (PRS) was produced and tested in the All of Us biobank.
Results: The genetic correlation between ascending aortic diameter and TAAD was 0.83 (P=6.6E-129). The TAAD meta-analysis had an effective sample size of 53,516, augmented to 147,377 after multi-trait analysis. We identified 59 risk loci for TAAD (189 in the multi-trait analysis). These loci included one on the X-chromosome near MIR222HG, previously reported to be regulated by angiopoietin-2; others were near TGF-β-superfamily members (FBN1, FBN2,GDF6, GDF7, LTBP4, TGFB2, SMAD3); genes involved in vasoconstriction (ADRA1D, ADRB1, ANGPT1, EDN1, EDN2, EDNRA, PDE3A); and cell cycle regulators (CCND2, CCNE1, CDC27, CDK6, CDKN1A, CDKN1B, CENPW, DSCC1, MAD2L1, TP53). 307 distinct loci were significantly associated with at least one of the four traits; all but 7 TAAD loci were genome-wide significant for one of the three aortic measurements, and all loci had at least sub-significant signal in those traits. Gene-set analyses highlighted contributions from fibroblasts, pericytes, and vascular smooth muscle cells. In All of Us, a one standard deviation (SD) greater PRS was associated with a hazard ratio (HR) of 1.88 for TAAD (P=1.2E-78) and 1.62 for thoracic aortic dissection (P=5.7E-05). Individuals in the top 5% for the PRS had HR 3.77 for TAAD (P=2.7E-48) and HR 2.87 for thoracic aortic dissection (P=3.3E-03).
Discussion: The multi-trait analysis yielded an eight-fold expansion of loci for TAAD risk. The findings underscore that sporadic TAAD is a complex, common disease—intricately linked with the processes associated with normal variation in aortic diameter.