Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target

Tanmoy Roychowdhury*, Derek Klarin, Michael G. Levin, Joshua M. Spin, Yae Hyun Rhee, Alicia Deng, Colwyn A. Headley, Noah L. Tsao, Corry Gellatly, Verena Zuber, Fred Shen, Whitney E. Hornsby, Ina Holst Laursen, Shefali S. Verma, Adam E. Locke, Gudmundur Einarsson, Gudmar Thorleifsson, Sarah E. Graham, Ozan Dikilitas, Jack W. PatteeRenae L. Judy, Ferran Pauls-Verges, Jonas B. Nielsen, Brooke N. Wolford, Ben M. Brumpton, Jaume Dilmé, Olga Peypoch, Laura Calsina Juscafresa, Todd L. Edwards, Dadong Li, Karina Banasik, Søren Brunak, Rikke L. Jacobsen, Minerva T. Garcia-Barrio, Jifeng Zhang, Lars M. Rasmussen, Regent Lee, Ashok Handa, Anders Wanhainen, Kevin Mani, Jes S. Lindholt, Lasse M. Obel, Ewa Strauss, Grzegorz Oszkinis, Christopher P. Nelson, Katie L. Saxby, Joost A. van Herwaarden, Sander W. van der Laan, Jessica van Setten, Ole B. Pedersen, Regeneron Genetics Center, UK Aneurysm Growth Study, DBDS Genomic Consortium, VA Million Veteran Program, DiscovEHR

*Corresponding author for this work

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Abstract

Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk 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 AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor β signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9 loss of function prevented the development of AAA in a preclinical mouse model.

Original languageEnglish
JournalNature Genetics
Volume55
Issue number11
Pages (from-to)1831-1842
ISSN1061-4036
DOIs
Publication statusPublished - Nov 2023

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