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. Pattee; Renae L. Judy; Ferran Pauls-Verges; Jonas B. Nielsen; Brooke N. Wolford; Ben M. Brumpton; Jaume Dilme; Olga Peypoch; Laura Calsina Juscafresa; Todd L. Edwards; Dadong Li; Karina Banasik; Soren 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; Mercedes Camacho; Frank M. Davis; Rachael Wasikowski; Lam C. Tsoi; Johann E. Gudjonsson; Jonathan L. Eliason; Dawn M. Coleman; Peter K. Henke; Santhi K. Ganesh; Y. Eugene Chen; Weihua Guan; James S. Pankow; Nathan Pankratz; Ole B. Pedersen; Christian Erikstrup; Weihong Tang; Kristian Hveem; Daniel Gudbjartsson; Solveig Gretarsdottir; Unnur Thorsteinsdottir; Hilma Holm; Kari Stefansson; Manuel A. Ferreira; Aris Baras; Iftikhar J. Kullo; Marylyn D. Ritchie; Alex H. Christensen; Kasper K. Iversen; Nikolaj Eldrup; Henrik Sillesen; Sisse R. Ostrowski; Henning Bundgaard; Henrik Ullum; Stephen Burgess; Dipender Gill; Katherine Gallagher; Maria Sabater-Lleal; Ida Surakka; Gregory T. Jones; Matthew J. Bown; Philip S. Tsao; Cristen J. Willer; Scott M. Damrauer; VA Million Veteran Program

doi:10.1038/s41588-023-01510-y

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

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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, …

Nature genetics, Vol.55(11), p.1831

01/11/2023

DOI: https://doi.org/10.1038/s41588-023-01510-y

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https://hdl.handle.net/10523/16733

Abstract

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

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 beta 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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Record Identifier: 9926495496201891
Title: Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target
Creators: 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. Pattee
Renae L. Judy
Ferran Pauls-Verges
Jonas B. Nielsen
Brooke N. Wolford
Ben M. Brumpton
Jaume Dilme
Olga Peypoch
Laura Calsina Juscafresa
Todd L. Edwards
Dadong Li
Karina Banasik
Soren 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
Mercedes Camacho
Frank M. Davis
Rachael Wasikowski
Lam C. Tsoi
Johann E. Gudjonsson
Jonathan L. Eliason
Dawn M. Coleman
Peter K. Henke
Santhi K. Ganesh
Y. Eugene Chen
Weihua Guan
James S. Pankow
Nathan Pankratz
Ole B. Pedersen
Christian Erikstrup
Weihong Tang
Kristian Hveem
Daniel Gudbjartsson
Solveig Gretarsdottir
Unnur Thorsteinsdottir
Hilma Holm
Kari Stefansson
Manuel A. Ferreira
Aris Baras
Iftikhar J. Kullo
Marylyn D. Ritchie
Alex H. Christensen
Kasper K. Iversen
Nikolaj Eldrup
Henrik Sillesen
Sisse R. Ostrowski
Henning Bundgaard
Henrik Ullum
Stephen Burgess
Dipender Gill
Katherine Gallagher
Maria Sabater-Lleal
Ida Surakka
Gregory T. Jones
Matthew J. Bown
Philip S. Tsao
Cristen J. Willer
Scott M. Damrauer
VA Million Veteran Program
Publication Details: Nature genetics, Vol.55(11), p.1831
Academic Unit: Surgery and Critical Care (DSM)
Publisher: NATURE PORTFOLIO
Grant note: RE/18/4/34215 / British Heart Foundation Center of Research Excellence R35-HL135824-03; R01-HL142023-02; R01-HL166991 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania R01-HL109946 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Leducq Foundation - Wellcome Trust 23SCEFIA1153369 / American Heart Association MC_UU_00002/7 / United Kingdom Research and Innovation Medical Research Council 0134-00363B / Independent Research Fund Denmark; Det Frie Forskningsrad (DFF) European Social Fund; European Social Fund (ESF) IK2BX005759-01 / Department of Veterans Affairs; US Department of Veterans Affairs 848146 / EU; European Union (EU) CS/14/2/30841; RG/18/10/33842 / British Heart Foundation US Department of Veterans Affairs Clinical Science Research and Development Service T32HL007843 / NIH/NHLBI National Research Service Award postdoctoral fellowship CS/14/2/30841; RG/18/10/33842 / Propel Postdoctoral Scholars Program of the Stanford University School of Medicine - British Heart Foundation 222959/Z/21/Z. / Wellcome Trust Doctoral Training Program; Wellcome Trust 14/155; 17/402; 20/144 / Health Research Council of New Zealand CVON 2011/B019; CVON 2017-20; 01KL1802 / Netherlands CardioVascular Research Initiative of the Netherlands Heart Foundation T31IR1845; HG06379; HG11710 / Tobacco-Related Disease Research Program; University of California System Mayo Clinic Clinician Investigator training program NHLBI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) BRC1215-20014 / National Institute for Health Research Cambridge Biomedical Research Center; National Institutes of Health Research (NIHR) T32HL098049 / NIH/National Heart, Lung and Blood Institute (NHLBI) Institutional Training Grant Stanford University School of Medicine NNF17OC0027594; NNF14CC0001 / Novo Nordisk Foundation; Novocure Limited 204623/Z/16/Z / Royal Society CP17/00142 / Miguel Servet contract from the ISCIII Spanish Health Institute IK2-CX001780 / Department of Defense; United States Department of Defense K24HL137010 / National Human Genome Research Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) I01-BX003362 / Veterans Administration Office of Research and Development
Date published ; e-published: 01/11/2023
Language: English
Resource Type ; Subtype: Journal article