bioRxiv2021
BackgroundThoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) are known to have a strong genetic component. Methods and ResultsIn a genome-wide association study (GWAS) using the UK Biobank, we analyzed the genomes of 1,363 individuals with AAA compared to 27,260 age, ancestry, and sex-matched controls (1:20 case:control study design). A similar analysis was repeated for 435 individuals with TAA compared to 8,700 controls. Polymorphism with minor allele frequency (MAF) >0.5% were evaluated. We identified novel loci near LINC01021, ATOH8 and JAK2 genes that achieved genome-wide significance for AAA (p-value <5x10-8), in addition to three known loci. For TAA, three novel loci in CTNNA3, FRMD6 and MBP achieved genome-wide significance. There was no overlap in the genes associated with AAAs and TAAs. Additionally, we identified a linkage group of high-frequency variants (MAFs [~]10%) encompassing FBN1, the causal gene for Marfan syndrome, which was associated with TAA. In Finngen PheWeb, this FBN1 haplotype was associated with aortic dissection. Finally, we found that baseline bradycardia was associated with TAA, but not AAA. ConclusionsOur GWAS found that AAA and TAA were associated with distinct sets of genes, suggesting distinct underlying genetic architecture. We also found association between baseline bradycardia and TAA. These findings, including JAK2 association, offer plausible mechanistic and therapeutic insights. We also found a common FBN1 linkage group that is associated with TAA and aortic dissection in patients who do not have Marfan syndrome. These FBN1 variants suggest shared pathophysiology between Marfan disease and sporadic TAA. Condensed AbstractIn genome-wide association study (GWAS) of thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) using UK Biobank database, we found 3 novel loci associated with TAA, and 3 novel loci associated AAA. We also found significant association between baseline bradycardia and TAA. These findings, including JAK2 association, offer plausible mechanistic and therapeutic insights. Additionally, we identified a common FBN1 linkage group associated with TAA in patients who do not have Marfan syndrome. In the FinnGen cohort, this haplotype is associated with aortic dissection. These results suggest a shared pathophysiology between Marfan disease and sporadic TAA. Study LimitationsAs with any GWAS study, the discovery of novel loci associated with aortopathies does not prove functional causality, and the findings described herein needs to be validated by analysis of other databases, ideally in a patient population of more diverse genetic origins than the UK Biobank. The use of the ICD10 codes to classify disease carriers and noncarriers in a population cohort may not be the most accurate assessment of prevalence of aortopathies. The association between baseline bradycardia and TAA does not take into account the concurrent use of medications that may impact heart rate. HighlightsO_LIIdentification of 3 novel AAA-associated loci near LINC01021, ATOH8 and JAK2 genes. C_LIO_LIIdentification of 3 novel TAA-associated loci near CTNNA3, FRMD6 and MBP genes. C_LIO_LIIdentification of a linkage group of common FBN1 variants associated with non-syndromic TAA in the UK Biobank and with aortic dissection in the FinnGen cohort, strengthening the evidence for a shared pathophysiology between Marfan disease and nonsyndromic aortopathy. C_LIO_LIAssociation between baseline bradycardia and TAA but not AAA. C_LI