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

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.

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

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