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

DiscovEHR; 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 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; Scott M Damrauer

doi:10.1038/s41588-023-01510-y

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

DiscovEHR
, 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 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, Scott M Damrauer^*

^*Corresponding author af dette arbejde

Klinisk Immunologisk Afdeling

Publikation: Bidrag til tidsskrift › Artikel › Forskning › peer review

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.

Originalsprog	Engelsk
Sider (fra-til)	1831-1842
Antal sider	12
Tidsskrift	Nature Genetics
Vol/bind	55
Udgave nummer	11
DOI	https://doi.org/10.1038/s41588-023-01510-y
Status	Udgivet - nov. 2023

Finansiering

Bevillingsgivere	Bevillingsgivernummer
Health Research Council of New Zealand	14/155, 17/402, 20/144
British Heart Foundation	CS/14/2/30841, RG/18/10/33842
Department of Veterans Affairs	I01-BX003362
University of California at Los Angeles	T31IR1845, HG06379, HG11710
National Institutes of Health	R35-HL135824-03, R01-HL142023-02, R01-HL166991
Danmarks Frie Forskningsfond	0134-00363B
Novo Nordisk Foundation	NNF17OC0027594, NNF14CC0001
National Institutes of Health	T32HL098049
Stanford Medicine	CS/14/2/30841, RG/18/10/33842
British Heart Foundation	RE/18/4/34215
Department of Veterans Affairs	IK2BX005759-01
American Heart Association	23SCEFIA1153369
National Human Genome Research Institute	K24HL137010
National Heart, Lung, and Blood Institute
Wellcome Trust	222959/Z/21/Z.
Instituto de Salud Carlos III	CP17/00142
European Social Fund Plus
University of Pennsylvania
National Institutes of Health	T32HL007843
Mayo Clinic College of Medicine and Science
European Union	848146
Netherlands Heart Institute	CVON 2011/B019, CVON 2017-20, 01KL1802
Leducq Foundation
Royal Society of Medicine	204623/Z/16/Z
Medical Research Council	MC_UU_00002/7
NIHR Cambridge Biomedical Research Centre	BRC1215-20014
National Institutes of Health	R01-HL109946
United States Department of Defense	IK2-CX001780
Department of Veterans Affairs
Stanford Medicine
National Heart, Lung, and Blood Institute	R35HL161016
Medical Research Council	MR/S019669/1, MR/W029790/1
Wellcome Trust	222959/Z/21/Z
American Heart Association	23SCEFIA1153369

Adgang til dokumentet

10.1038/s41588-023-01510-y

Citationsformater

DiscovEHR, Roychowdhury, T., Klarin, D., Levin, M. G., Spin, J. M., Rhee, Y. H., Deng, A., Headley, C. A., Tsao, N. L., Gellatly, C., Zuber, V., Shen, F., Hornsby, W. E., Laursen, I. H., Verma, S. S., Locke, A. E., Einarsson, G., Thorleifsson, G., Graham, S. E., ... Damrauer, S. M. (2023). Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target. Nature Genetics, 55(11), 1831-1842. https://doi.org/10.1038/s41588-023-01510-y

@article{8d01459816364d57b35fcb5e8c15a2f1,

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

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.",

keywords = "Humans, Animals, Mice, Genome-Wide Association Study, Proprotein Convertase 9/genetics, Subtilisin, Proprotein Convertases, Aortic Aneurysm, Abdominal/genetics, Enrichment, Set, Lipids, Triglycerides, Cholesterol, Guidelines, Variant, Mouse model, Society, Gene-expression",

author = "DiscovEHR and Tanmoy Roychowdhury and Derek Klarin and Levin, \{Michael G\} and Spin, \{Joshua M\} and Rhee, \{Yae Hyun\} and Alicia Deng and Headley, \{Colwyn A\} and Tsao, \{Noah L\} and Corry Gellatly and Verena Zuber and Fred Shen and Hornsby, \{Whitney E\} and Laursen, \{Ina Holst\} and Verma, \{Shefali S\} and Locke, \{Adam E\} and Gudmundur Einarsson and Gudmar Thorleifsson and Graham, \{Sarah E\} and Ozan Dikilitas and Pattee, \{Jack W\} and Judy, \{Renae L\} and Ferran Pauls-Verges and Nielsen, \{Jonas B\} and Wolford, \{Brooke N\} and Brumpton, \{Ben M\} and Jaume Dilm{\'e} and Olga Peypoch and Juscafresa, \{Laura Calsina\} and Edwards, \{Todd L\} and Dadong Li and Karina Banasik and S{\o}ren Brunak and Jacobsen, \{Rikke L\} and Garcia-Barrio, \{Minerva T\} and Jifeng Zhang and Rasmussen, \{Lars M\} and Regent Lee and Ashok Handa and Anders Wanhainen and Kevin Mani and Lindholt, \{Jes S\} and Obel, \{Lasse M\} and Ewa Strauss and Grzegorz Oszkinis and Nelson, \{Christopher P\} and Saxby, \{Katie L\} and \{van Herwaarden\}, \{Joost A\} and \{van der Laan\}, \{Sander W\} and \{van Setten\}, Jessica and Pedersen, \{Ole B\} and Damrauer, \{Scott M\}",

note = "{\textcopyright} 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

year = "2023",

month = nov,

doi = "10.1038/s41588-023-01510-y",

language = "English",

volume = "55",

pages = "1831--1842",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "11",

}

DiscovEHR, Roychowdhury, T, Klarin, D, Levin, MG, Spin, JM, Rhee, YH, Deng, A, Headley, CA, Tsao, NL, Gellatly, C, Zuber, V, Shen, F, Hornsby, WE, Laursen, IH, Verma, SS, Locke, AE, Einarsson, G, Thorleifsson, G, Graham, SE, Dikilitas, O, Pattee, JW, Judy, RL, Pauls-Verges, F, Nielsen, JB, Wolford, BN, Brumpton, BM, Dilmé, J, Peypoch, O, Juscafresa, LC, Edwards, TL, Li, D, Banasik, K, Brunak, S, Jacobsen, RL, Garcia-Barrio, MT, Zhang, J, Rasmussen, LM, Lee, R, Handa, A, Wanhainen, A, Mani, K, Lindholt, JS, Obel, LM, Strauss, E, Oszkinis, G, Nelson, CP, Saxby, KL, van Herwaarden, JA, van der Laan, SW, van Setten, J, Pedersen, OB & Damrauer, SM 2023, 'Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target', Nature Genetics, bind 55, nr. 11, s. 1831-1842. https://doi.org/10.1038/s41588-023-01510-y

TY - JOUR

T1 - Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target

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 - Pedersen, Ole B

AU - Damrauer, Scott M

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.

KW - Humans

KW - Animals

KW - Mice

KW - Genome-Wide Association Study

KW - Proprotein Convertase 9/genetics

KW - Subtilisin

KW - Proprotein Convertases

KW - Aortic Aneurysm, Abdominal/genetics

KW - Enrichment

KW - Set

KW - Lipids

KW - Triglycerides

KW - Cholesterol

KW - Guidelines

KW - Variant

KW - Mouse model

KW - Society

KW - Gene-expression

U2 - 10.1038/s41588-023-01510-y

DO - 10.1038/s41588-023-01510-y

M3 - Article

C2 - 37845353

SN - 1061-4036

VL - 55

SP - 1831

EP - 1842

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

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

Abstract

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