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Meta-Analysis
. 2017 Jan 20;120(2):341-353.
doi: 10.1161/CIRCRESAHA.116.308765. Epub 2016 Nov 29.

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

Gregory T Jones  1 , Gerard Tromp  2 , Helena Kuivaniemi  2 , Solveig Gretarsdottir  2 , Annette F Baas  2 , Betti Giusti  2 , Ewa Strauss  2 , Femke N G Van't Hof  2 , Thomas R Webb  2 , Robert Erdman  2 , Marylyn D Ritchie  2 , James R Elmore  2 , Anurag Verma  2 , Sarah Pendergrass  2 , Iftikhar J Kullo  2 , Zi Ye  2 , Peggy L Peissig  2 , Omri Gottesman  2 , Shefali S Verma  2 , Jennifer Malinowski  2 , Laura J Rasmussen-Torvik  2 , Kenneth M Borthwick  2 , Diane T Smelser  2 , David R Crosslin  2 , Mariza de Andrade  2 , Evan J Ryer  2 , Catherine A McCarty  2 , Erwin P Böttinger  2 , Jennifer A Pacheco  2 , Dana C Crawford  2 , David S Carrell  2 , Glenn S Gerhard  2 , David P Franklin  2 , David J Carey  2 , Victoria L Phillips  2 , Michael J A Williams  2 , Wenhua Wei  2 , Ross Blair  2 , Andrew A Hill  2 , Thodor M Vasudevan  2 , David R Lewis  2 , Ian A Thomson  2 , Jo Krysa  2 , Geraldine B Hill  2 , Justin Roake  2 , Tony R Merriman  2 , Grzegorz Oszkinis  2 , Silvia Galora  2 , Claudia Saracini  2 , Rosanna Abbate  2 , Raffaele Pulli  2 , Carlo Pratesi  2 , Athanasios Saratzis  2 , Ana R Verissimo  2 , Suzannah Bumpstead  2 , Stephen A Badger  2 , Rachel E Clough  2 , Gillian Cockerill  2 , Hany Hafez  2 , D Julian A Scott  2 , T Simon Futers  2 , Simon P R Romaine  2 , Katherine Bridge  2 , Kathryn J Griffin  2 , Marc A Bailey  2 , Alberto Smith  2 , Matthew M Thompson  2 , Frank M van Bockxmeer  2 , Stefan E Matthiasson  2 , Gudmar Thorleifsson  2 , Unnur Thorsteinsdottir  2 , Jan D Blankensteijn  2 , Joep A W Teijink  2 , Cisca Wijmenga  2 , Jacqueline de Graaf  2 , Lambertus A Kiemeney  2 , Jes S Lindholt  2 , Anne Hughes  2 , Declan T Bradley  2 , Kathleen Stirrups  2 , Jonathan Golledge  2 , Paul E Norman  2 , Janet T Powell  2 , Steve E Humphries  2 , Stephen E Hamby  2 , Alison H Goodall  2 , Christopher P Nelson  2 , Natzi Sakalihasan  2 , Audrey Courtois  2 , Robert E Ferrell  2 , Per Eriksson  2 , Lasse Folkersen  2 , Anders Franco-Cereceda  2 , John D Eicher  2 , Andrew D Johnson  2 , Christer Betsholtz  2 , Arno Ruusalepp  2 , Oscar Franzén  2 , Eric E Schadt  2 , Johan L M Björkegren  2 , Leonard Lipovich  2 , Anne M Drolet  2 , Eric L Verhoeven  2 , Clark J Zeebregts  2 , Robert H Geelkerken  2 , Marc R van Sambeek  2 , Steven M van Sterkenburg  2 , Jean-Paul de Vries  2 , Kari Stefansson  2 , John R Thompson  2 , Paul I W de Bakker  2 , Panos Deloukas  2 , Robert D Sayers  2 , Seamus C Harrison  2 , Andre M van Rij  2 , Nilesh J Samani  2 , Matthew J Bown  1
Affiliations
Meta-Analysis

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

Gregory T Jones et al. Circ Res. .

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.

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Figures

Figure 1.
Figure 1.
Whole-genome association plot for the primary meta-analysis of genome-wide association studies of abdominal aortic aneurysm (AAA). Data represent a meta-analysis of 4972 AAA cases and 99 858 controls. The horizontal line indicates the P value threshold of 5×10−6 used to select loci for validation studies. The 9 subsequently validated AAA loci are indicated along with the previously identified LRP1 locus, which fell to P=6.4×10–7 in the combined discovery/ validation analysis (Online Tables III and IV).
Figure 2.
Figure 2.
Regional association plots for 4 new abdominal aortic aneurysm (AAA) genome-wide significant loci at 1q32.3, 13q12.11, 20q13.12, and 21q22.2. New AAA genome-wide significant loci at 1q32.3 (near SMYD2), 13q12.11 (LINC00540), 20q13.12 (near MMP9/ZNF335), and 21q22.2 (ERG). −log10 (Pfixed) values for single nucleotide polymorphisms (SNPs) from the AAA discovery meta-analysis of 4972 cases and 99 858 controls were plotted against their genomic positions using LocusZoom (1000Genomes, EUR, November 2014). The peak SNP in each region is labeled (purple diamond), whereas the color indicates LD (r2) with the peak.
Figure 3.
Figure 3.
Association between the lead single nucleotide polymorphisms (SNP) at the abdominal aortic aneurysm risk loci and association P values for other cardiovascular risk factors/traits (Online Table IX). CAD indicates coronary artery disease; DBP, diastolic blood pressure; DM, diabetes mellitus; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SBP, systolic blood pressure; and TG, triglyceride.
Figure 4.
Figure 4.
Circle plot showing the lead single nucleotide polymorphism (SNP) distal interaction regions based on the 9 replicated abdominal aortic aneurysm genome-wide association study SNPs. Top variants with highest regulatory signals and distal interaction regions are shown on the outer circle (significant regulatory variants are labeled with I). The inner circle shows genes and genomic loci, whereas the distal interactive signals are shown with red lines (width corresponds to intensity of interaction). Note the long-range interactions, such as that between variants associated with IL6R (rs4845620, 1q21.3) and TYW1B (7q11.23).
See this image and copyright information in PMC

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References

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