Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

Gregory T. Jones; Gerard Tromp; Helena Kuivaniemi; Solveig Gretarsdottir; Annette F. Baas; Betti Giusti; Ewa Strauss; Femke N.G. Van'T Hof; Thomas R. Webb; Robert Erdman; Marylyn D. Ritchie; James R. Elmore; Anurag Verma; Sarah Pendergrass; Iftikhar J. Kullo; Zi Ye; Peggy L. Peissig; Omri Gottesman; Shefali S. Verma; Jennifer Malinowski; Laura J. Rasmussen-Torvik; Kenneth M. Borthwick; DIane T. Smelser; David R. Crosslin; Mariza De Andrade; Evan J. Ryer; Catherine A. McCarty; Erwin P. Böttinger; Jennifer A. Pacheco; Dana C. Crawford; David S. Carrell; Glenn S. Gerhard; David P. Franklin; David J. Carey; Victoria L. Phillips; Michael J.A. Williams; Wenhua Wei; Ross Blair; Andrew A. Hill; Thodor M. Vasudevan; David R. Lewis; Ian A. Thomson; Jo Krysa; Geraldine B. Hill; Justin Roake; Tony R. Merriman; Grzegorz Oszkinis; Silvia Galora; Claudia Saracini; Rosanna Abbate; Raffaele Pulli; Carlo Pratesi; Athanasios Saratzis; Ana R. Verissimo; Suzannah Bumpstead; Stephen A. Badger; Rachel E. Clough; Gillian Cockerill; Hany Hafez; D. Julian A. Scott; T. Simon Futers; Simon P.R. Romaine; Katherine Bridge; Kathryn J. Griffin; Marc A. Bailey; Alberto Smith; Matthew M. Thompson; Frank M. Van Bockxmeer; Stefan E. Matthiasson; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Jan D. Blankensteijn; Joep A.W. Teijink; Cisca Wijmenga; Jacqueline De Graaf; Lambertus A. Kiemeney; Jes S. Lindholt; Anne Hughes; Declan T. Bradley; Kathleen Stirrups; Jonathan Golledge; Paul E. Norman; Janet T. Powell; Steve E. Humphries; Stephen E. Hamby; Alison H. Goodall; Christopher P. Nelson; Natzi Sakalihasan; Audrey Courtois; Robert E. Ferrell; Per Eriksson; Lasse Folkersen; Anders Franco-Cereceda; John D. Eicher; Andrew D. Johnson; Christer Betsholtz; Arno Ruusalepp; Oscar Franzén; Eric E. Schadt; Johan L.M. Björkegren; Leonard Lipovich; Anne M. Drolet; Eric L. Verhoeven; Clark J. Zeebregts; Robert H. Geelkerken; Marc R. Van Sambeek; Steven M. Van Sterkenburg; Jean Paul De Vries; Kari Stefansson; John R. Thompson; Paul I.W. De Bakker; Panos Deloukas; Robert D. Sayers; Seamus C. Harrison; Andre M. Van Rij; Nilesh J. Samani; Matthew J. Bown

doi:10.1161/CIRCRESAHA.116.308765

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

Gregory T. Jones, Gerard Tromp, Helena Kuivaniemi, Solveig Gretarsdottir, Annette F. Baas, Betti Giusti, Ewa Strauss, Femke N.G. Van'T Hof, Thomas R. Webb, Robert Erdman, Marylyn D. Ritchie, James R. Elmore, Anurag Verma, Sarah Pendergrass, Iftikhar J. Kullo, Zi Ye, Peggy L. Peissig, Omri Gottesman, Shefali S. Verma, Jennifer MalinowskiLaura J. Rasmussen-Torvik, Kenneth M. Borthwick, DIane T. Smelser, David R. Crosslin, Mariza De Andrade, Evan J. Ryer, Catherine A. McCarty, Erwin P. Böttinger, Jennifer A. Pacheco, Dana C. Crawford, David S. Carrell, Glenn S. Gerhard, David P. Franklin, David J. Carey, Victoria L. Phillips, Michael J.A. Williams, Wenhua Wei, Ross Blair, Andrew A. Hill, Thodor M. Vasudevan, David R. Lewis, Ian A. Thomson, Jo Krysa, Geraldine B. Hill, Justin Roake, Tony R. Merriman, Grzegorz Oszkinis, Silvia Galora, Claudia Saracini, Rosanna Abbate, Raffaele Pulli, Carlo Pratesi, Athanasios Saratzis, Ana R. Verissimo, Suzannah Bumpstead, Stephen A. Badger, Rachel E. Clough, Gillian Cockerill, Hany Hafez, D. Julian A. Scott, T. Simon Futers, Simon P.R. Romaine, Katherine Bridge, Kathryn J. Griffin, Marc A. Bailey, Alberto Smith, Matthew M. Thompson, Frank M. Van Bockxmeer, Stefan E. Matthiasson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Jan D. Blankensteijn, Joep A.W. Teijink, Cisca Wijmenga, Jacqueline De Graaf, Lambertus A. Kiemeney, Jes S. Lindholt, Anne Hughes, Declan T. Bradley, Kathleen Stirrups, Jonathan Golledge, Paul E. Norman, Janet T. Powell, Steve E. Humphries, Stephen E. Hamby, Alison H. Goodall, Christopher P. Nelson, Natzi Sakalihasan, Audrey Courtois, Robert E. Ferrell, Per Eriksson, Lasse Folkersen, Anders Franco-Cereceda, John D. Eicher, Andrew D. Johnson, Christer Betsholtz, Arno Ruusalepp, Oscar Franzén, Eric E. Schadt, Johan L.M. Björkegren, Leonard Lipovich, Anne M. Drolet, Eric L. Verhoeven, Clark J. Zeebregts, Robert H. Geelkerken, Marc R. Van Sambeek, Steven M. Van Sterkenburg, Jean Paul De Vries, Kari Stefansson, John R. Thompson, Paul I.W. De Bakker, Panos Deloukas, Robert D. Sayers, Seamus C. Harrison, Andre M. Van Rij, Nilesh J. Samani, Matthew J. Bown

Epidemiology

Research output: Contribution to journal › Article › peer-review

138 Scopus citations

Abstract

Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective: To identify additional AAA risk loci using data from all available genome-wide association studies. Methods and Results: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.

Original language	English (US)
Pages (from-to)	341-353
Number of pages	13
Journal	Circulation research
Volume	120
Issue number	2
DOIs	https://doi.org/10.1161/CIRCRESAHA.116.308765
State	Published - Jan 20 2017

Bibliographical note

Publisher Copyright:
© 2016 The Authors.

Keywords

aortic aneurysm abdominal
computational biology
genetics
genome-wide association study
matrix metalloproteinases
meta-analysis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1161/CIRCRESAHA.116.308765

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253231

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Jones, G. T., Tromp, G., Kuivaniemi, H., Gretarsdottir, S., Baas, A. F., Giusti, B., Strauss, E., Van'T Hof, F. N. G., Webb, T. R., Erdman, R., Ritchie, M. D., Elmore, J. R., Verma, A., Pendergrass, S., Kullo, I. J., Ye, Z., Peissig, P. L., Gottesman, O., Verma, S. S., ... Bown, M. J. (2017). Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci. Circulation research, 120(2), 341-353. https://doi.org/10.1161/CIRCRESAHA.116.308765

Jones, GT, Tromp, G, Kuivaniemi, H, Gretarsdottir, S, Baas, AF, Giusti, B, Strauss, E, Van'T Hof, FNG, Webb, TR, Erdman, R, Ritchie, MD, Elmore, JR, Verma, A, Pendergrass, S, Kullo, IJ, Ye, Z, Peissig, PL, Gottesman, O, Verma, SS, Malinowski, J, Rasmussen-Torvik, LJ, Borthwick, KM, Smelser, DIT, Crosslin, DR, De Andrade, M, Ryer, EJ, McCarty, CA, Böttinger, EP, Pacheco, JA, Crawford, DC, Carrell, DS, Gerhard, GS, Franklin, DP, Carey, DJ, Phillips, VL, Williams, MJA, Wei, W, Blair, R, Hill, AA, Vasudevan, TM, Lewis, DR, Thomson, IA, Krysa, J, Hill, GB, Roake, J, Merriman, TR, Oszkinis, G, Galora, S, Saracini, C, Abbate, R, Pulli, R, Pratesi, C, Saratzis, A, Verissimo, AR, Bumpstead, S, Badger, SA, Clough, RE, Cockerill, G, Hafez, H, Scott, DJA, Futers, TS, Romaine, SPR, Bridge, K, Griffin, KJ, Bailey, MA, Smith, A, Thompson, MM, Van Bockxmeer, FM, Matthiasson, SE, Thorleifsson, G, Thorsteinsdottir, U, Blankensteijn, JD, Teijink, JAW, Wijmenga, C, De Graaf, J, Kiemeney, LA, Lindholt, JS, Hughes, A, Bradley, DT, Stirrups, K, Golledge, J, Norman, PE, Powell, JT, Humphries, SE, Hamby, SE, Goodall, AH, Nelson, CP, Sakalihasan, N, Courtois, A, Ferrell, RE, Eriksson, P, Folkersen, L, Franco-Cereceda, A, Eicher, JD, Johnson, AD, Betsholtz, C, Ruusalepp, A, Franzén, O, Schadt, EE, Björkegren, JLM, Lipovich, L, Drolet, AM, Verhoeven, EL, Zeebregts, CJ, Geelkerken, RH, Van Sambeek, MR, Van Sterkenburg, SM, De Vries, JP, Stefansson, K, Thompson, JR, De Bakker, PIW, Deloukas, P, Sayers, RD, Harrison, SC, Van Rij, AM, Samani, NJ & Bown, MJ 2017, 'Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci', Circulation research, vol. 120, no. 2, pp. 341-353. https://doi.org/10.1161/CIRCRESAHA.116.308765

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title = "Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci",

abstract = "Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective: To identify additional AAA risk loci using data from all available genome-wide association studies. Methods and Results: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.",

keywords = "aortic aneurysm abdominal, computational biology, genetics, genome-wide association study, matrix metalloproteinases, meta-analysis",

author = "Jones, {Gregory T.} and Gerard Tromp and Helena Kuivaniemi and Solveig Gretarsdottir and Baas, {Annette F.} and Betti Giusti and Ewa Strauss and {Van'T Hof}, {Femke N.G.} and Webb, {Thomas R.} and Robert Erdman and Ritchie, {Marylyn D.} and Elmore, {James R.} and Anurag Verma and Sarah Pendergrass and Kullo, {Iftikhar J.} and Zi Ye and Peissig, {Peggy L.} and Omri Gottesman and Verma, {Shefali S.} and Jennifer Malinowski and Rasmussen-Torvik, {Laura J.} and Borthwick, {Kenneth M.} and Smelser, {DIane T.} and Crosslin, {David R.} and {De Andrade}, Mariza and Ryer, {Evan J.} and McCarty, {Catherine A.} and B{\"o}ttinger, {Erwin P.} and Pacheco, {Jennifer A.} and Crawford, {Dana C.} and Carrell, {David S.} and Gerhard, {Glenn S.} and Franklin, {David P.} and Carey, {David J.} and Phillips, {Victoria L.} and Williams, {Michael J.A.} and Wenhua Wei and Ross Blair and Hill, {Andrew A.} and Vasudevan, {Thodor M.} and Lewis, {David R.} and Thomson, {Ian A.} and Jo Krysa and Hill, {Geraldine B.} and Justin Roake and Merriman, {Tony R.} and Grzegorz Oszkinis and Silvia Galora and Claudia Saracini and Rosanna Abbate and Raffaele Pulli and Carlo Pratesi and Athanasios Saratzis and Verissimo, {Ana R.} and Suzannah Bumpstead and Badger, {Stephen A.} and Clough, {Rachel E.} and Gillian Cockerill and Hany Hafez and Scott, {D. Julian A.} and Futers, {T. Simon} and Romaine, {Simon P.R.} and Katherine Bridge and Griffin, {Kathryn J.} and Bailey, {Marc A.} and Alberto Smith and Thompson, {Matthew M.} and {Van Bockxmeer}, {Frank M.} and Matthiasson, {Stefan E.} and Gudmar Thorleifsson and Unnur Thorsteinsdottir and Blankensteijn, {Jan D.} and Teijink, {Joep A.W.} and Cisca Wijmenga and {De Graaf}, Jacqueline and Kiemeney, {Lambertus A.} and Lindholt, {Jes S.} and Anne Hughes and Bradley, {Declan T.} and Kathleen Stirrups and Jonathan Golledge and Norman, {Paul E.} and Powell, {Janet T.} and Humphries, {Steve E.} and Hamby, {Stephen E.} and Goodall, {Alison H.} and Nelson, {Christopher P.} and Natzi Sakalihasan and Audrey Courtois and Ferrell, {Robert E.} and Per Eriksson and Lasse Folkersen and Anders Franco-Cereceda and Eicher, {John D.} and Johnson, {Andrew D.} and Christer Betsholtz and Arno Ruusalepp and Oscar Franz{\'e}n and Schadt, {Eric E.} and Bj{\"o}rkegren, {Johan L.M.} and Leonard Lipovich and Drolet, {Anne M.} and Verhoeven, {Eric L.} and Zeebregts, {Clark J.} and Geelkerken, {Robert H.} and {Van Sambeek}, {Marc R.} and {Van Sterkenburg}, {Steven M.} and {De Vries}, {Jean Paul} and Kari Stefansson and Thompson, {John R.} and {De Bakker}, {Paul I.W.} and Panos Deloukas and Sayers, {Robert D.} and Harrison, {Seamus C.} and {Van Rij}, {Andre M.} and Samani, {Nilesh J.} and Bown, {Matthew J.}",

note = "Publisher Copyright: {\textcopyright} 2016 The Authors.",

year = "2017",

month = jan,

day = "20",

doi = "10.1161/CIRCRESAHA.116.308765",

language = "English (US)",

volume = "120",

pages = "341--353",

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TY - JOUR

T1 - Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

AU - Jones, Gregory T.

AU - Tromp, Gerard

AU - Kuivaniemi, Helena

AU - Gretarsdottir, Solveig

AU - Baas, Annette F.

AU - Giusti, Betti

AU - Strauss, Ewa

AU - Van'T Hof, Femke N.G.

AU - Webb, Thomas R.

AU - Erdman, Robert

AU - Ritchie, Marylyn D.

AU - Elmore, James R.

AU - Verma, Anurag

AU - Pendergrass, Sarah

AU - Kullo, Iftikhar J.

AU - Ye, Zi

AU - Peissig, Peggy L.

AU - Gottesman, Omri

AU - Verma, Shefali S.

AU - Malinowski, Jennifer

AU - Rasmussen-Torvik, Laura J.

AU - Borthwick, Kenneth M.

AU - Smelser, DIane T.

AU - Crosslin, David R.

AU - De Andrade, Mariza

AU - Ryer, Evan J.

AU - McCarty, Catherine A.

AU - Böttinger, Erwin P.

AU - Pacheco, Jennifer A.

AU - Crawford, Dana C.

AU - Carrell, David S.

AU - Gerhard, Glenn S.

AU - Franklin, David P.

AU - Carey, David J.

AU - Phillips, Victoria L.

AU - Williams, Michael J.A.

AU - Wei, Wenhua

AU - Blair, Ross

AU - Hill, Andrew A.

AU - Vasudevan, Thodor M.

AU - Lewis, David R.

AU - Thomson, Ian A.

AU - Krysa, Jo

AU - Hill, Geraldine B.

AU - Roake, Justin

AU - Merriman, Tony R.

AU - Oszkinis, Grzegorz

AU - Galora, Silvia

AU - Saracini, Claudia

AU - Abbate, Rosanna

AU - Pulli, Raffaele

AU - Pratesi, Carlo

AU - Saratzis, Athanasios

AU - Verissimo, Ana R.

AU - Bumpstead, Suzannah

AU - Badger, Stephen A.

AU - Clough, Rachel E.

AU - Cockerill, Gillian

AU - Hafez, Hany

AU - Scott, D. Julian A.

AU - Futers, T. Simon

AU - Romaine, Simon P.R.

AU - Bridge, Katherine

AU - Griffin, Kathryn J.

AU - Bailey, Marc A.

AU - Smith, Alberto

AU - Thompson, Matthew M.

AU - Van Bockxmeer, Frank M.

AU - Matthiasson, Stefan E.

AU - Thorleifsson, Gudmar

AU - Thorsteinsdottir, Unnur

AU - Blankensteijn, Jan D.

AU - Teijink, Joep A.W.

AU - Wijmenga, Cisca

AU - De Graaf, Jacqueline

AU - Kiemeney, Lambertus A.

AU - Lindholt, Jes S.

AU - Hughes, Anne

AU - Bradley, Declan T.

AU - Stirrups, Kathleen

AU - Golledge, Jonathan

AU - Norman, Paul E.

AU - Powell, Janet T.

AU - Humphries, Steve E.

AU - Hamby, Stephen E.

AU - Goodall, Alison H.

AU - Nelson, Christopher P.

AU - Sakalihasan, Natzi

AU - Courtois, Audrey

AU - Ferrell, Robert E.

AU - Eriksson, Per

AU - Folkersen, Lasse

AU - Franco-Cereceda, Anders

AU - Eicher, John D.

AU - Johnson, Andrew D.

AU - Betsholtz, Christer

AU - Ruusalepp, Arno

AU - Franzén, Oscar

AU - Schadt, Eric E.

AU - Björkegren, Johan L.M.

AU - Lipovich, Leonard

AU - Drolet, Anne M.

AU - Verhoeven, Eric L.

AU - Zeebregts, Clark J.

AU - Geelkerken, Robert H.

AU - Van Sambeek, Marc R.

AU - Van Sterkenburg, Steven M.

AU - De Vries, Jean Paul

AU - Stefansson, Kari

AU - Thompson, John R.

AU - De Bakker, Paul I.W.

AU - Deloukas, Panos

AU - Sayers, Robert D.

AU - Harrison, Seamus C.

AU - Van Rij, Andre M.

AU - Samani, Nilesh J.

AU - Bown, Matthew J.

PY - 2017/1/20

Y1 - 2017/1/20

N2 - Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective: To identify additional AAA risk loci using data from all available genome-wide association studies. Methods and Results: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.

AB - Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective: To identify additional AAA risk loci using data from all available genome-wide association studies. Methods and Results: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.

KW - aortic aneurysm abdominal

KW - computational biology

KW - genetics

KW - genome-wide association study

KW - matrix metalloproteinases

KW - meta-analysis

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UR - http://www.scopus.com/inward/citedby.url?scp=85002194690&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.116.308765

DO - 10.1161/CIRCRESAHA.116.308765

M3 - Article

C2 - 27899403

AN - SCOPUS:85002194690

SN - 0009-7330

VL - 120

SP - 341

EP - 353

JO - Circulation research

JF - Circulation research

IS - 2

ER -

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

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Keywords

UN SDGs

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