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Meta-Analysis
. 2011 Aug 1;4(4):403-12.
doi: 10.1161/CIRCGENETICS.110.958728. Epub 2011 May 23.

A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease

Philipp S Wild  1 , Tanja Zeller, Arne Schillert, Silke Szymczak, Christoph R Sinning, Arne Deiseroth, Renate B Schnabel, Edith Lubos, Till Keller, Medea S Eleftheriadis, Christoph Bickel, Hans J Rupprecht, Sandra Wilde, Heidi Rossmann, Patrick Diemert, L Adrienne Cupples, Claire Perret, Jeanette Erdmann, Klaus Stark, Marcus E Kleber, Stephen E Epstein, Benjamin F Voight, Kari Kuulasmaa, Mingyao Li, Arne S Schäfer, Norman Klopp, Peter S Braund, Hendrik B Sager, Serkalem Demissie, Carole Proust, Inke R König, Heinz-Erich Wichmann, Wibke Reinhard, Michael M Hoffmann, Jarmo Virtamo, Mary Susan Burnett, David Siscovick, Per Gunnar Wiklund, Liming Qu, Nour Eddine El Mokthari, John R Thompson, Annette Peters, Albert V Smith, Emmanuelle Yon, Jens Baumert, Christian Hengstenberg, Winfried März, Philippe Amouyel, Joseph Devaney, Stephen M Schwartz, Olli Saarela, Nehal N Mehta, Diana Rubin, Kaisa Silander, Alistair S Hall, Jean Ferrieres, Tamara B Harris, Olle Melander, Frank Kee, Hakon Hakonarson, Juergen Schrezenmeir, Vilmundur Gudnason, Roberto Elosua, Dominique Arveiler, Alun Evans, Daniel J Rader, Thomas Illig, Stefan Schreiber, Joshua C Bis, David Altshuler, Maryam Kavousi, Jaqueline C M Witteman, Andre G Uitterlinden, Albert Hofman, Aaron R Folsom, Maja Barbalic, Eric Boerwinkle, Sekar Kathiresan, Muredach P Reilly, Christopher J O'Donnell, Nilesh J Samani, Heribert Schunkert, Francois Cambien, Karl J Lackner, Laurence Tiret, Veikko Salomaa, Thomas Munzel, Andreas Ziegler, Stefan Blankenberg
Affiliations
Meta-Analysis

A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease

Philipp S Wild et al. Circ Cardiovasc Genet. .

Abstract

Background: eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD).

Methods and results: In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7×10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3×10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10(-3)).

Conclusions: The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.

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Figures

Figure 1
Figure 1
Study Design of the CADomics Study. The study consisted of a discovery GWA stage, followed by two stages of replication (in silico and wet lab) in independent study samples and a final meta-analysis. SNPs with genome-wide significance (P<5×10-8) were further explored for their association with global gene expression (eSNPs, eQTLs) in monocytes and cardiovascular risk factors. Statistical evidence for association was combined across several stages using a final meta-analysis.
Figure 2
Figure 2
Identification of the CAD-related locus LIPA on chromosome 10q23.31. A. Forest Plots for rs2246833 and rs1412444. Meta-analysis of the association of rs2246833 and rs1412444 with coronary artery disease was performed in a case-control design including 14 independent cohorts of European ancestry with n=59,789. Individual studies are plotted against the individual odds ratios (OR). Horizontal lines are the confidence intervals corresponding to the P-value threshold of 5×10–8. The vertical line indicates the value is consistent with no association. If a single-nucleotide polymorphism was not available in a study, there is no data point for that study. The diamond represents the meta-analytic effect size. For reasons of quality control after imputation no data are available for GerMIFS I. B. Association of the eSNPs rs2246833 and rs1412444 with LIPA gene expression. Boxplots are shown for the fold change of LIPA expression in relation to the genotype. Fold change of LIPA expression was calculated relative to median expression of the non-risk allele genotype (C). C. Locus-specific regional association plots for discovery GWA and eQTL analysis results on chromosome 10q23.31 (LIPA). The figure shows from top to bottom: i -log10(P) of the association between SNPs and case and control status (primary GWA), ii -log10(P) of the association between SNPs and LIPA expression (eQTL transcript), and iii recombination fraction based on HapMap and positions of genes. SNP rs2246833, with the smallest eQTL P is represented by a blue diamond. Other SNPs are color coded according to pairwise LD (r2) with this SNP. (see legend in figure). Note that SNP rs1412444 is colored in red (r2 =0.985).
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