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

Philipp S. Wild, 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. KleberStephen 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

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95 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)403-412
Number of pages10
JournalCirculation: Cardiovascular Genetics
Volume4
Issue number4
DOIs
StatePublished - Aug 2011

Keywords

  • Coronary artery disease
  • Gene expression
  • Genetic variation
  • Genome-wide association studies
  • Genomics
  • LIPA
  • eQTL
  • eSNP

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