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

Tanmoy Roychowdhury(University of Michigan), Derek Klarin(VA Palo Alto Health Care System), Michael G. Levin(University of Pennsylvania), Joshua M. Spin(VA Palo Alto Health Care System), Yae Hyun Rhee(VA Palo Alto Health Care System), Alicia Deng(VA Palo Alto Health Care System), Colwyn A. Headley(VA Palo Alto Health Care System), Noah L. Tsao(University of Pennsylvania), Corry Gellatly(University of Leicester), Verena Zuber(UK Dementia Research Institute), Fred Shen(University of Michigan), Whitney Hornsby(University of Michigan), Ina Holst Laursen(Copenhagen University Hospital), Shefali S. Verma, Adam E. Locke(Regeneron (United States)), Guðmundur Einarsson(deCODE Genetics (Iceland)), Guðmar Þorleifsson(deCODE Genetics (Iceland)), Sarah E. Graham(University of Michigan), Ozan Dikilitas(Mayo Clinic), Jack Pattee(University of Minnesota), Renae Judy(University of Pennsylvania), Ferran Paüls-Vergés(Hospital de Sant Pau), Jonas B. Nielsen(Norwegian University of Science and Technology), Brooke N. Wolford(Norwegian University of Science and Technology), Ben Brumpton(Norwegian University of Science and Technology), Jaume Dilmé(Universitat Autònoma de Barcelona), Olga Peypoch(Universitat Autònoma de Barcelona), Laura Calsina Juscafresa(Parc de Salut), Todd L. Edwards(Vanderbilt University Medical Center), Dadong Li(Regeneron (United States)), Karina Banasik(University of Copenhagen), Søren Brunak(University of Copenhagen), Rikke Louise Jacobsen(Copenhagen University Hospital), Minerva T. Garcia-Barrio(University of Michigan), Jifeng Zhang(University of Michigan), Lars Melholt Rasmussen(Odense University Hospital), Regent Lee(University of Oxford), Ashok Handa(University of Oxford), Anders Wanhainen(Uppsala University), Kevin Mani(Uppsala University), Jes S. Lindholt(Odense University Hospital), Lasse M. Obel(Odense University Hospital), Ewa Strauss(Poznan University of Medical Sciences), Grzegorz Oszkinis(Poznan University of Medical Sciences), Christopher P. Nelson(University of Leicester), Katie Saxby(University of Leicester), Joost A. van Herwaarden(Utrecht University), Sander W. van der Laan(Utrecht University), Jessica van Setten(Utrecht University), Mercedes Camacho(Hospital de Sant Pau), Frank M. Davis(University of Michigan), Rachael Wasikowski(University of Michigan), Lam C. Tsoi(University of Michigan), Jóhann E. Guðjónsson(University of Michigan), Jonathan L. Eliason(University of Michigan), Dawn M. Coleman(University of Michigan), Peter K. Henke(University of Michigan), Santhi K. Ganesh(University of Michigan), Y. Eugene Chen(University of Michigan), Weihua Guan(University of Minnesota), James S. Pankow(University of Minnesota), Nathan Pankratz(University of Minnesota), Ole Birger Pedersen(University of Copenhagen), Christian Erikstrup(Aarhus University Hospital), Weihong Tang(University of Minnesota), Kristian Hveem(Norwegian University of Science and Technology), Daníel F. Guðbjartsson(deCODE Genetics (Iceland)), Sólveig Grétarsdóttir(deCODE Genetics (Iceland)), Unnur Þorsteinsdóttir(deCODE Genetics (Iceland)), Hilma Hólm(deCODE Genetics (Iceland)), Kāri Stefánsson(deCODE Genetics (Iceland)), Manuel A. R. Ferreira(Regeneron (United States)), Aris Baras(Regeneron (United States)), Iftikhar J. Kullo(Mayo Clinic), Marylyn D. Ritchie(University of Pennsylvania), Alex Hørby Christensen(University of Copenhagen), Kasper Iversen(University of Copenhagen), Nikolaj Eldrup(University of Copenhagen), Henrik Sillesen(University of Copenhagen), Sisse Rye Ostrowski(University of Copenhagen), Henning Bundgaard(University of Copenhagen), Henrik Ullum(Statens Serum Institut), Stephen Burgess(University of Cambridge), Dipender Gill(Novo Nordisk (Denmark)), Katherine Gallagher(University of Michigan), Maria Sabater‐Lleal(Hospital de Sant Pau), DiscovEHR(University of Leicester), UK Aneurysm Growth Study(University of Leicester), Frank Dudbridge(University of Leicester), Nilesh J. Samani(University of Leicester), VA Million Veteran Program(University of Leicester), Ida Surakka(VA Palo Alto Health Care System), Gregory T. Jones(University of Michigan), Matthew J. Bown(University of Leicester), Philip S. Tsao(VA Palo Alto Health Care System), Cristen J. Willer(University of Michigan), Scott M. Damrauer(Philadelphia VA Medical Center)
Nature Genetics
October 16, 2023
10.1038/s41588-023-01510-y
Cited by 91Open Access
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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.

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