TY - JOUR
T1 - Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target
AU - Regeneron Genetics Center
AU - UK Aneurysm Growth Study
AU - DBDS Genomic Consortium
AU - VA Million Veteran Program
AU - DiscovEHR
AU - Roychowdhury, Tanmoy
AU - Klarin, Derek
AU - Levin, Michael G.
AU - Spin, Joshua M.
AU - Rhee, Yae Hyun
AU - Deng, Alicia
AU - Headley, Colwyn A.
AU - Tsao, Noah L.
AU - Gellatly, Corry
AU - Zuber, Verena
AU - Shen, Fred
AU - Hornsby, Whitney E.
AU - Laursen, Ina Holst
AU - Verma, Shefali S.
AU - Locke, Adam E.
AU - Einarsson, Gudmundur
AU - Thorleifsson, Gudmar
AU - Graham, Sarah E.
AU - Dikilitas, Ozan
AU - Pattee, Jack W.
AU - Judy, Renae L.
AU - Pauls-Verges, Ferran
AU - Nielsen, Jonas B.
AU - Wolford, Brooke N.
AU - Brumpton, Ben M.
AU - Dilmé, Jaume
AU - Peypoch, Olga
AU - Juscafresa, Laura Calsina
AU - Edwards, Todd L.
AU - Li, Dadong
AU - Banasik, Karina
AU - Brunak, Søren
AU - Jacobsen, Rikke L.
AU - Garcia-Barrio, Minerva T.
AU - Zhang, Jifeng
AU - Rasmussen, Lars M.
AU - Lee, Regent
AU - Handa, Ashok
AU - Wanhainen, Anders
AU - Mani, Kevin
AU - Lindholt, Jes S.
AU - Obel, Lasse M.
AU - Strauss, Ewa
AU - Oszkinis, Grzegorz
AU - Nelson, Christopher P.
AU - Saxby, Katie L.
AU - van Herwaarden, Joost A.
AU - van der Laan, Sander W.
AU - van Setten, Jessica
AU - Kullo, Iftikhar J.
N1 - Publisher Copyright:
© 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2023/11
Y1 - 2023/11
N2 - 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.
AB - 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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U2 - 10.1038/s41588-023-01510-y
DO - 10.1038/s41588-023-01510-y
M3 - Article
C2 - 37845353
AN - SCOPUS:85174309497
SN - 1061-4036
VL - 55
SP - 1831
EP - 1842
JO - Nature Genetics
JF - Nature Genetics
IS - 11
ER -