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

Research output: Contribution to journalArticlepeer-review

65 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 languageEnglish (US)
Pages (from-to)341-353
Number of pages13
JournalCirculation research
Volume120
Issue number2
DOIs
StatePublished - Jan 20 2017

Bibliographical note

Funding Information:
The Welcome Trust Case Control Consortium project was funded by the Wellcome Trust (awards 076113 and 085475). The New Zealand project was funded by the Health Research Council of New Zealand (0875, 14155). Recruitment of abdominal aortic aneurysm patients and controls in Belgium, Canada, and Pittsburgh, USA, was funded in part by the National Heart, Lung, and Blood Institute, National Institutes of Health (HL064310 and HL044682). The Geisinger sample collection was funded in part by the Pennsylvania Commonwealth Universal Research Enhancement program, the Geisinger Clinical Research Fund, the American Heart Association, and the Ben Franklin Technology Development Fund of Pennsylvania. The Barts and the Leicester Cardiovascular Biomedical Research Units are funded by the National Institute for Health Research. The eMERGE (electronic Medical Records and Genomics) Network is funded by the National Human Genome Research Institute, with additional funding from the National Institute of General Medical Sciences through the following grants: U01HG004438 to Johns Hopkins University; U01HG004424 to The Broad Institute; U01HG004438 to CIDR; U01HG004610 and U01HG006375 to Group Health Cooperative; U01HG004608 to Marshfield Clinic; U01HG006389 to Essentia Institute of Rural Health; U01HG04599 and U01HG006379 to Mayo Clinic; U01HG004609 and U01HG006388 to Northwestern University; U01HG04603 and U01HG006378 to Vanderbilt University; U01HG006385 to the Coordinating Center; U01HG006382 to Geisinger Health System; U01HG006380 to Icahn School of Medicine Mount Sinai. The generation and management of genome-wide association study (GWAS) data for the Rotterdam Study (control samples for the Dutch GWAS) is supported by the Netherlands Organization of Scientific Research (NWO) Investments (175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative/NWO project nr. 050-060-810. The Italian sample collection were funded by grants from Ente Cassa di Risparmio di Firenze to Fiorgen Foundation, Florence, Italy, and from the Italian Ministry of Health. Sample collections from Poland were funded in part by the National Science Centre in Poland (6P05A03921, NN403250440). The Mayo Vascular Disease Biorepository was funded by a Marriot Award for Individualized Medicine and an Award from the Mayo Center of Individualized Medicine. The Vanderbilt data set(s) were obtained from Vanderbilt University Medical Centers BioVU supported by institutional funding and by the National Center for Research Resources (UL1 RR024975-01, which is now at the National Center for Advancing Translational Sciences, UL1 TR000445-06). The ASAP study (Advanced Study of Aortic Pathology) was supported by the Swedish Research Council, the Swedish Heart-Lung Foundation, the Leducq Foundation (MIBAVA), and a donation by Fredrik Lundberg. S.E. Humphries holds a Chair funded by the British Heart Foundation, and is supported by the British Heart Foundation (BHF; PG08/008) and by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The Cardiogenics project was supported by the European Union 6th Framework Programme (LSHM-CT-2006037593). S.C. Harrison was funded by a BHF clinical training fellowship (FS/11/16/28696). The Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task biobank and the generation of the RNASeq data set was funded by Astra-Zeneca Translational Science Centre-Karolinska Institutet, the University of Tartu (SP1GVARENG), the Estonian Research Council (ETF 8853), the Torsten and Ragnar Sderberg Foundation, the Knut and Alice Wallenberg Foundation, the American Heart Association (A14SFRN20840000) and by the National Institute of Health (R01HL71207).

Keywords

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

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