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Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target. / Roychowdhury, Tanmoy; Klarin, Derek; Levin, Michael G.; Spin, Joshua M.; Rhee, Yae Hyun; Deng, Alicia; Headley, Colwyn A.; Tsao, Noah L.; Gellatly, Corry; Zuber, Verena; Shen, Fred; Hornsby, Whitney E.; Laursen, Ina Holst; Verma, Shefali S.; Locke, Adam E.; Einarsson, Gudmundur; Thorleifsson, Gudmar; Graham, Sarah E.; Dikilitas, Ozan; Pattee, Jack W.; Judy, Renae L.; Pauls-Verges, Ferran; Nielsen, Jonas B.; Wolford, Brooke N.; Brumpton, Ben M.; Dilmé, Jaume; Peypoch, Olga; Juscafresa, Laura Calsina; Edwards, Todd L.; Li, Dadong; Banasik, Karina; Brunak, Søren; Jacobsen, Rikke L.; Garcia-Barrio, Minerva T.; Zhang, Jifeng; Rasmussen, Lars M.; Lee, Regent; Handa, Ashok; Wanhainen, Anders; Mani, Kevin; Lindholt, Jes S.; Obel, Lasse M.; Strauss, Ewa; Oszkinis, Grzegorz; Nelson, Christopher P.; Saxby, Katie L.; van Herwaarden, Joost A.; van der Laan, Sander W.; van Setten, Jessica; Camacho, Mercedes; Davis, Frank M.; Wasikowski, Rachael; Tsoi, Lam C.; Gudjonsson, Johann E.; Eliason, Jonathan L.; Coleman, Dawn M.; Henke, Peter K.; Ganesh, Santhi K.; Chen, Y. Eugene; Guan, Weihua; Pankow, James S.; Pankratz, Nathan; Pedersen, Ole B.; Erikstrup, Christian; Tang, Weihong; Hveem, Kristian; Gudbjartsson, Daniel; Gretarsdottir, Solveig; Thorsteinsdottir, Unnur; Holm, Hilma; Stefansson, Kari; Ferreira, Manuel A.; Baras, Aris; Kullo, Iftikhar J.; Ritchie, Marylyn D.; Christensen, Alex H.; Iversen, Kasper K.; Eldrup, Nikolaj; Sillesen, Henrik; Ostrowski, Sisse R.; Bundgaard, Henning; Ullum, Henrik; Burgess, Stephen; Gill, Dipender; Gallagher, Katherine; Sabater-Lleal, Maria; Dudbridge, Frank; Samani, Nilesh J.; Surakka, Ida; Jones, Gregory T.; Bown, Matthew J.; Tsao, Philip S.; Willer, Cristen J.; Damrauer, Scott M.
In:
Nature Genetics, Vol. 55, 2023, p. 1831–1842.
Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
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, Camacho, M, Davis, FM, Wasikowski, R, Tsoi, LC, Gudjonsson, JE, Eliason, JL, Coleman, DM, Henke, PK, Ganesh, SK, Chen, YE, Guan, W, Pankow, JS, Pankratz, N
, Pedersen, OB, Erikstrup, C, Tang, W, Hveem, K, Gudbjartsson, D, Gretarsdottir, S, Thorsteinsdottir, U, Holm, H, Stefansson, K, Ferreira, MA, Baras, A, Kullo, IJ, Ritchie, MD
, Christensen, AH, Iversen, KK, Eldrup, N, Sillesen, H, Ostrowski, SR, Bundgaard, H, Ullum, H, Burgess, S, Gill, D, Gallagher, K, Sabater-Lleal, M, Dudbridge, F, Samani, NJ, Surakka, I, Jones, GT, Bown, MJ, Tsao, PS, Willer, CJ & Damrauer, SM 2023, '
Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target',
Nature Genetics, vol. 55, pp. 1831–1842.
https://doi.org/10.1038/s41588-023-01510-yAPA
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., Dikilitas, O., ... 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, 1831–1842.
https://doi.org/10.1038/s41588-023-01510-yVancouver
Roychowdhury T, Klarin D, Levin MG, Spin JM, Rhee YH, Deng A et al.
Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target.
Nature Genetics. 2023;55:1831–1842.
https://doi.org/10.1038/s41588-023-01510-yAuthor
Roychowdhury, Tanmoy ; Klarin, Derek ; Levin, Michael G. ; Spin, Joshua M. ; Rhee, Yae Hyun ; Deng, Alicia ; Headley, Colwyn A. ; Tsao, Noah L. ; Gellatly, Corry ; Zuber, Verena ; Shen, Fred ; Hornsby, Whitney E. ; Laursen, Ina Holst ; Verma, Shefali S. ; Locke, Adam E. ; Einarsson, Gudmundur ; Thorleifsson, Gudmar ; Graham, Sarah E. ; Dikilitas, Ozan ; Pattee, Jack W. ; Judy, Renae L. ; Pauls-Verges, Ferran ; Nielsen, Jonas B. ; Wolford, Brooke N. ; Brumpton, Ben M. ; Dilmé, Jaume ; Peypoch, Olga ; Juscafresa, Laura Calsina ; Edwards, Todd L. ; Li, Dadong ; Banasik, Karina ; Brunak, Søren ; Jacobsen, Rikke L. ; Garcia-Barrio, Minerva T. ; Zhang, Jifeng ; Rasmussen, Lars M. ; Lee, Regent ; Handa, Ashok ; Wanhainen, Anders ; Mani, Kevin ; Lindholt, Jes S. ; Obel, Lasse M. ; Strauss, Ewa ; Oszkinis, Grzegorz ; Nelson, Christopher P. ; Saxby, Katie L. ; van Herwaarden, Joost A. ; van der Laan, Sander W. ; van Setten, Jessica ; Camacho, Mercedes ; Davis, Frank M. ; Wasikowski, Rachael ; Tsoi, Lam C. ; Gudjonsson, Johann E. ; Eliason, Jonathan L. ; Coleman, Dawn M. ; Henke, Peter K. ; Ganesh, Santhi K. ; Chen, Y. Eugene ; Guan, Weihua ; Pankow, James S. ; Pankratz, Nathan ; Pedersen, Ole B. ; Erikstrup, Christian ; Tang, Weihong ; Hveem, Kristian ; Gudbjartsson, Daniel ; Gretarsdottir, Solveig ; Thorsteinsdottir, Unnur ; Holm, Hilma ; Stefansson, Kari ; Ferreira, Manuel A. ; Baras, Aris ; Kullo, Iftikhar J. ; Ritchie, Marylyn D. ; Christensen, Alex H. ; Iversen, Kasper K. ; Eldrup, Nikolaj ; Sillesen, Henrik ; Ostrowski, Sisse R. ; Bundgaard, Henning ; Ullum, Henrik ; Burgess, Stephen ; Gill, Dipender ; Gallagher, Katherine ; Sabater-Lleal, Maria ; Dudbridge, Frank ; Samani, Nilesh J. ; Surakka, Ida ; Jones, Gregory T. ; Bown, Matthew J. ; Tsao, Philip S. ; Willer, Cristen J. ; Damrauer, Scott M. / Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target. In: Nature Genetics. 2023 ; Vol. 55. pp. 1831–1842.
Bibtex
@article{03f11edbd62c4aca9876cf81c017e517,
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.",
author = "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 Mercedes Camacho and Davis, {Frank M.} and Rachael Wasikowski and Tsoi, {Lam C.} and Gudjonsson, {Johann E.} and Eliason, {Jonathan L.} and Coleman, {Dawn M.} and Henke, {Peter K.} and Ganesh, {Santhi K.} and Chen, {Y. Eugene} and Weihua Guan and Pankow, {James S.} and Nathan Pankratz and Pedersen, {Ole B.} and Christian Erikstrup and Weihong Tang and Kristian Hveem and Daniel Gudbjartsson and Solveig Gretarsdottir and Unnur Thorsteinsdottir and Hilma Holm and Kari Stefansson and Ferreira, {Manuel A.} and Aris Baras and Kullo, {Iftikhar J.} and Ritchie, {Marylyn D.} and Christensen, {Alex H.} and Iversen, {Kasper K.} and Nikolaj Eldrup and Henrik Sillesen and Ostrowski, {Sisse R.} and Henning Bundgaard and Henrik Ullum and Stephen Burgess and Dipender Gill and Katherine Gallagher and Maria Sabater-Lleal and Frank Dudbridge and Samani, {Nilesh J.} and Ida Surakka and Jones, {Gregory T.} and Bown, {Matthew J.} and Tsao, {Philip S.} and Willer, {Cristen J.} and Damrauer, {Scott M.}",
note = "Publisher Copyright: {\textcopyright} 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",
year = "2023",
doi = "10.1038/s41588-023-01510-y",
language = "English",
volume = "55",
pages = "1831–1842",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "nature publishing group",
}
RIS
TY - JOUR
T1 - Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target
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 - Camacho, Mercedes
AU - Davis, Frank M.
AU - Wasikowski, Rachael
AU - Tsoi, Lam C.
AU - Gudjonsson, Johann E.
AU - Eliason, Jonathan L.
AU - Coleman, Dawn M.
AU - Henke, Peter K.
AU - Ganesh, Santhi K.
AU - Chen, Y. Eugene
AU - Guan, Weihua
AU - Pankow, James S.
AU - Pankratz, Nathan
AU - Pedersen, Ole B.
AU - Erikstrup, Christian
AU - Tang, Weihong
AU - Hveem, Kristian
AU - Gudbjartsson, Daniel
AU - Gretarsdottir, Solveig
AU - Thorsteinsdottir, Unnur
AU - Holm, Hilma
AU - Stefansson, Kari
AU - Ferreira, Manuel A.
AU - Baras, Aris
AU - Kullo, Iftikhar J.
AU - Ritchie, Marylyn D.
AU - Christensen, Alex H.
AU - Iversen, Kasper K.
AU - Eldrup, Nikolaj
AU - Sillesen, Henrik
AU - Ostrowski, Sisse R.
AU - Bundgaard, Henning
AU - Ullum, Henrik
AU - Burgess, Stephen
AU - Gill, Dipender
AU - Gallagher, Katherine
AU - Sabater-Lleal, Maria
AU - Dudbridge, Frank
AU - Samani, Nilesh J.
AU - Surakka, Ida
AU - Jones, Gregory T.
AU - Bown, Matthew J.
AU - Tsao, Philip S.
AU - Willer, Cristen J.
AU - Damrauer, Scott M.
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
Y1 - 2023
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.
U2 - 10.1038/s41588-023-01510-y
DO - 10.1038/s41588-023-01510-y
M3 - Journal article
C2 - 37845353
AN - SCOPUS:85174309497
VL - 55
SP - 1831
EP - 1842
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
ER -
