Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target
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 me...
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| Format: | Article |
| Status: | Published version |
| Publication date: | 2023 |
| Country: | España |
| Institution: | Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau) |
| Repository: | r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau |
| OAI Identifier: | oai:iibsantpau.fundanetsuite.com:p17238 |
| Online Access: | https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=17238 https://www.scopus.com/inward/record.uri?eid=2-s2.0-85174309497&doi=10.1038%2fs41588-023-01510-y&partnerID=40&md5=427e600aeff29bce2b302b6cde8ef7a8 |
| Access Level: | Open access |
| _version_ | 1878742324471660544 |
|---|---|
| author | Roychowdhury T. |
| author2 | 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. Pattee J.W. Judy R.L. Pauls-Verges F. Nielsen J.B. Wolford B.N. Brumpton B.M. Dilmé J. Peypoch O. Juscafresa L.C. Edwards T.L. Li D. Banasik K. Brunak S. Jacobsen R.L. Garcia-Barrio M.T. Zhang J. Rasmussen L.M. Lee R. Handa A. Wanhainen A. Mani K. Lindholt J.S. Obel L.M. Strauss E. Oszkinis G. Nelson C.P. Saxby K.L. van Herwaarden J.A. van der Laan S.W. van Setten J. Camacho M. Davis F.M. Wasikowski R. Tsoi L.C. Gudjonsson J.E. Eliason J.L. Coleman D.M. Henke P.K. Ganesh S.K. Chen Y.E. Guan W. Pankow J.S. Pankratz N. Pedersen O.B. Erikstrup C. Tang W. Hveem K. Gudbjartsson D. Gretarsdottir S. Thorsteinsdottir U. Holm H. Stefansson K. Ferreira M.A. Baras A. Kullo I.J. Ritchie M.D. Christensen A.H. Iversen K.K. Eldrup N. Sillesen H. Ostrowski S.R. Bundgaard H. Ullum H. Burgess S. Gill D. Gallagher K. Sabater-Lleal M. Dudbridge F. Samani N.J. Surakka I. Jones G.T. Bown M.J. Tsao P.S. Willer C.J. Damrauer S.M. |
| author2_role | author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| author_browse | Banasik K. Baras A. Bown M.J. Brumpton B.M. Brunak S. Bundgaard H. Burgess S. Camacho M. Chen Y.E. Christensen A.H. Coleman D.M. Damrauer S.M. Davis F.M. Deng A. Dikilitas O. Dilmé J. Dudbridge F. Edwards T.L. Einarsson G. Eldrup N. Eliason J.L. Erikstrup C. Ferreira M.A. Gallagher K. Ganesh S.K. Garcia-Barrio M.T. Gellatly C. Gill D. Graham S.E. Gretarsdottir S. Guan W. Gudbjartsson D. Gudjonsson J.E. Handa A. Headley C.A. Henke P.K. Holm H. Hornsby W.E. Hveem K. Iversen K.K. Jacobsen R.L. Jones G.T. Judy R.L. Juscafresa L.C. Klarin D. Kullo I.J. Laursen I.H. Lee R. Levin M.G. Li D. Lindholt J.S. Locke A.E. Mani K. Nelson C.P. Nielsen J.B. Obel L.M. Ostrowski S.R. Oszkinis G. Pankow J.S. Pankratz N. Pattee J.W. Pauls-Verges F. Pedersen O.B. Peypoch O. Rasmussen L.M. Rhee Y.H. Ritchie M.D. Roychowdhury T. Sabater-Lleal M. Samani N.J. Saxby K.L. Shen F. Sillesen H. Spin J.M. Stefansson K. Strauss E. Surakka I. Tang W. Thorleifsson G. Thorsteinsdottir U. Tsao N.L. Tsao P.S. Tsoi L.C. Ullum H. Verma S.S. Wanhainen A. Wasikowski R. Willer C.J. Wolford B.N. Zhang J. Zuber V. van Herwaarden J.A. van Setten J. van der Laan S.W. |
| author_facet | 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. Pattee J.W. Judy R.L. Pauls-Verges F. Nielsen J.B. Wolford B.N. Brumpton B.M. Dilmé J. Peypoch O. Juscafresa L.C. Edwards T.L. Li D. Banasik K. Brunak S. Jacobsen R.L. Garcia-Barrio M.T. Zhang J. Rasmussen L.M. Lee R. Handa A. Wanhainen A. Mani K. Lindholt J.S. Obel L.M. Strauss E. Oszkinis G. Nelson C.P. Saxby K.L. van Herwaarden J.A. van der Laan S.W. van Setten J. Camacho M. Davis F.M. Wasikowski R. Tsoi L.C. Gudjonsson J.E. Eliason J.L. Coleman D.M. Henke P.K. Ganesh S.K. Chen Y.E. Guan W. Pankow J.S. Pankratz N. Pedersen O.B. Erikstrup C. Tang W. Hveem K. Gudbjartsson D. Gretarsdottir S. Thorsteinsdottir U. Holm H. Stefansson K. Ferreira M.A. Baras A. Kullo I.J. Ritchie M.D. Christensen A.H. Iversen K.K. Eldrup N. Sillesen H. Ostrowski S.R. Bundgaard H. Ullum H. Burgess S. Gill D. Gallagher K. Sabater-Lleal M. Dudbridge F. Samani N.J. Surakka I. Jones G.T. Bown M.J. Tsao P.S. Willer C.J. Damrauer S.M. |
| author_role | author |
| collection | r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau |
| description | 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. Genome-wide association meta-analysis of AAA identifies 121 independent risk loci and highlights potential therapeutic targets such as proprotein convertase, subtilisin/kexin-type 9 (PCSK9). |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_f3ec50f72fb618d6cbca7bff110295e0 |
| institution | Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau) |
| instname_str | Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau) |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:iibsantpau.fundanetsuite.com:p17238 |
| publishDate | 2023 |
| publishDateSort | 2023 |
| publisher | NATURE PUBLISHING GROUP |
| publisherStr | NATURE PUBLISHING GROUP |
| reponame_str | r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau |
| spelling | Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target 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. Pattee J.W. Judy R.L. Pauls-Verges F. Nielsen J.B. Wolford B.N. Brumpton B.M. Dilmé J. Peypoch O. Juscafresa L.C. Edwards T.L. Li D. Banasik K. Brunak S. Jacobsen R.L. Garcia-Barrio M.T. Zhang J. Rasmussen L.M. Lee R. Handa A. Wanhainen A. Mani K. Lindholt J.S. Obel L.M. Strauss E. Oszkinis G. Nelson C.P. Saxby K.L. van Herwaarden J.A. van der Laan S.W. van Setten J. Camacho M. Davis F.M. Wasikowski R. Tsoi L.C. Gudjonsson J.E. Eliason J.L. Coleman D.M. Henke P.K. Ganesh S.K. Chen Y.E. Guan W. Pankow J.S. Pankratz N. Pedersen O.B. Erikstrup C. Tang W. Hveem K. Gudbjartsson D. Gretarsdottir S. Thorsteinsdottir U. Holm H. Stefansson K. Ferreira M.A. Baras A. Kullo I.J. Ritchie M.D. Christensen A.H. Iversen K.K. Eldrup N. Sillesen H. Ostrowski S.R. Bundgaard H. Ullum H. Burgess S. Gill D. Gallagher K. Sabater-Lleal M. Dudbridge F. Samani N.J. Surakka I. Jones G.T. Bown M.J. Tsao P.S. Willer C.J. Damrauer S.M. 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. Genome-wide association meta-analysis of AAA identifies 121 independent risk loci and highlights potential therapeutic targets such as proprotein convertase, subtilisin/kexin-type 9 (PCSK9). NATURE PUBLISHING GROUP https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=17238 https://www.scopus.com/inward/record.uri?eid=2-s2.0-85174309497&doi=10.1038%2fs41588-023-01510-y&partnerID=40&md5=427e600aeff29bce2b302b6cde8ef7a8 |
| spellingShingle | Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target Roychowdhury T. |
| status_str | publishedVersion |
| title | Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target |
| title_full | Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target |
| title_fullStr | Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target |
| title_full_unstemmed | Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target |
| title_short | Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target |
| title_sort | Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target |
| url | https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=17238 https://www.scopus.com/inward/record.uri?eid=2-s2.0-85174309497&doi=10.1038%2fs41588-023-01510-y&partnerID=40&md5=427e600aeff29bce2b302b6cde8ef7a8 |