This review has been performed to determine Abdominal aortic aneurysm (AAA) is a complex disease affected by both environmental1 and genetic factors,2 and heritability has been estimated to be as high as 70%.3 Genome-wide association studies (GWAS) have revealed only 10 loci reaching genome-wide significance,4–7 leaving a significant portion of AAA heritability unknown. Previously published discovery efforts have been limited by small sample sizes, with the largest previous GWAS analyzing ≈5000 AAA cases.7

Large-scale biobanks combining genetic data with electronic health record (EHR)–derived phenotypes have continued to evolve over the past decade.8,9 The Million Veteran Program (MVP) was established in 2011 to study how genes affect health in the Veterans Health Administration. Recent efforts have demonstrated that a Veterans Health Administration–based biobank provides the ability to aid genetic discovery for understudied vascular diseases with a higher prevalence among US veterans.10,11 Leveraging the MVP resource, we sought to perform a genetic discovery analysis for AAA; explore the spectrum of phenotypic consequences associated with AAA risk variants; examine the genetic relationship between smoking and blood pressure and AAA; test the effects of AAA risk variants on aneurysms in other territories; and develop and evaluate a genome-wide polygenic risk score (PRS) for AAA to identify a subset of the population at higher risk for disease.


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