Multi-ancestry GWAS deciphers genetic architecture of abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target

Abdominal aortic aneurysm (AAA) is a common disease with significant heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 144 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis was able to explain AAA beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in the pathogenesis of AAA. We further integrated functional data to elucidate expression of genes associated with AAA. These genes also indicate crossover between the development of AAA and other monogenic aortopathies, particularly via TGF-β signaling pathways. Motivated by the strong evidence for the role of lipid levels in AAA by PheWAS, we identified therapeutic opportunities using Mendelian Randomization and, in pre-clinical studies, we demonstrated that PCSK9 inhibition in mice prevented the development of AAA. ### Competing Interest Statement D.G. is employed part-time by Novo Nordisk. A.E.L. is an employee of Regeneron Genetics Center and shareholder of Regeneron Pharmaceuticals. J.B.N. is employed by Regeneron Pharmaceuticals, Inc., unrelated to this work. D.L is an employee of Regeneron Genetics Center and shareholder of Regeneron Pharmaceuticals. J.A.V.H. is a consultant and/ or proctor for Terumo Aortic, Cook medical, Microport, WL Gore and Philips. M.A.F. is an employee of Regeneron Genetics Center and shareholder of Regeneron Pharmaceuticals. A.B. is an employee of Regeneron Genetics Center and shareholder of Regeneron Pharmaceuticals. M.R. is a member of the Scientific Advisory Board for Cipherome. The spouse of C.J.W. is employed by Regeneron Pharmaceuticals. S.M.D. receives research support from RenalytixAI and personal consulting fees from Calico Labs, outside the scope of the current research. ### Funding Statement Please refer to manuscript for information regarding individual studies involved in AAAgen consortium. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Please refer to Supplementary materials for information regarding individual studies involved in AAAgen consortium. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors