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

Regeneron Genetics Center, UK Aneurysm Growth Study, DBDS Genomic Consortium, VA Million Veteran Program, DiscovEHR

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 (US)
Pages (from-to)1831-1842
Number of pages12
JournalNature Genetics
Volume55
Issue number11
DOIs
StatePublished - Nov 2023

Bibliographical note

Publisher Copyright:
© 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

PubMed: MeSH publication types

  • Meta-Analysis
  • Journal Article

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