A Genome-Wide Association Study Identifies
LIPA
as a Susceptibility Gene for Coronary Artery Disease
Authors: Wild Philipp S. , Zeller Tanja , Schillert Arne , Szymczak Silke , Sinning Christoph R. , Deiseroth Arne , Schnabel Renate B. , Lubos Edith , Keller Till , Eleftheriadis Medea S. , Bickel Christoph , Rupprecht Hans J. , Wilde Sandra , Rossmann Heidi , Diemert Patrick , Cupples L. Adrienne , Perret Claire , Erdmann Jeanette , Stark Klaus , Kleber Marcus E. , Epstein Stephen E. , Voight Benjamin F. , Kuulasmaa Kari , Li Mingyao , Schäfer Arne S. , Klopp Norman , Braund Peter S. , Sager Hendrik B. , Demissie Serkalem , Proust Carole , König Inke R. , Wichmann Heinz-Erich , Reinhard Wibke , Hoffmann Michael M. , Virtamo Jarmo , Burnett Mary Susan , Siscovick David , Wiklund Per Gunnar , Qu Liming , El Mokthari Nour Eddine , Thompson John R. , Peters Annette , Smith Albert V. , Yon Emmanuelle , Baumert Jens , Hengstenberg Christian , März Winfried , Amouyel Philippe , Devaney Joseph , Schwartz Stephen M. , Saarela Olli , Mehta Nehal N. , Rubin Diana , Silander Kaisa , Hall Alistair S. , Ferrieres Jean , Harris Tamara B. , Melander Olle , Kee Frank , Hakonarson Hakon , Schrezenmeir Juergen , Gudnason Vilmundur , Elosua Roberto , Arveiler Dominique , Evans Alun , Rader Daniel J. , Illig Thomas , Schreiber Stefan , Bis Joshua C. , Altshuler David , Kavousi Maryam , Witteman Jaqueline C.M. , Uitterlinden Andre G. , Hofman Albert , Folsom Aaron R. , Barbalic Maja , Boerwinkle Eric , Kathiresan Sekar , Reilly Muredach P. , O'Donnell Christopher J. , Samani Nilesh J. , Schunkert Heribert , Cambien Francois , Lackner Karl J. , Tiret Laurence , Salomaa Veikko , Munzel Thomas , Ziegler Andreas , Blankenberg Stefan 
Published: May 2011

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.