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 F. 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

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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 languageEnglish
Pages (from-to)341-353
Number of pages13
JournalCirculation Research
Volume120
Issue number2
DOIs
Publication statusPublished - 20 Jan 2017
Externally publishedYes

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