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. 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

doi:10.1161/CIRCGENETICS.110.958728

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^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Universitätsklinikum Hamburg-Eppendorf

134 Zitate (Scopus)

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.

Originalsprache	Englisch
Zeitschrift	Circulation: Cardiovascular Genetics
Jahrgang	4
Ausgabenummer	4
Seiten (von - bis)	403-412
Seitenumfang	10
ISSN	1942-325X
DOIs	https://doi.org/10.1161/CIRCGENETICS.110.958728
Publikationsstatus	Veröffentlicht - 01.08.2011

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10.1161/CIRCGENETICS.110.958728

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Wild, P. S., Zeller, T., Schillert, A., Szymczak, S., Sinning, C. R., Deiseroth, A., Schnabel, R. B., Lubos, E., Keller, T., Eleftheriadis, M. S., Bickel, C., Rupprecht, H. J., Wilde, S., Rossmann, H., Diemert, P., Cupples, L. A., Perret, C., Erdmann, J., Stark, K., ... Blankenberg, S. (2011). A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease. Circulation: Cardiovascular Genetics, 4(4), 403-412. https://doi.org/10.1161/CIRCGENETICS.110.958728

@article{b55e91827ce5450d977e2559e3a42280,

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

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.",

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

year = "2011",

month = aug,

day = "1",

doi = "10.1161/CIRCGENETICS.110.958728",

language = "English",

volume = "4",

pages = "403--412",

journal = "Circulation: Cardiovascular Genetics",

issn = "1942-325X",

number = "4",

}

Wild, PS, Zeller, T, Schillert, A, Szymczak, S, Sinning, CR, Deiseroth, A, Schnabel, RB, Lubos, E, Keller, T, Eleftheriadis, MS, Bickel, C, Rupprecht, HJ, Wilde, S, Rossmann, H, Diemert, P, Cupples, LA, Perret, C, Erdmann, J, Stark, K, Kleber, ME, Epstein, SE, Voight, BF, Kuulasmaa, K, Li, M, Schäfer, AS, Klopp, N, Braund, PS, Sager, HB, Demissie, S, Proust, C, König, IR, Wichmann, HE, Reinhard, W, Hoffmann, MM, Virtamo, J, Burnett, MS, Siscovick, D, Wiklund, PG, Qu, L, El Mokthari, NE, Thompson, JR, Peters, A, Smith, AV, Yon, E, Baumert, J, Hengstenberg, C, März, W, Amouyel, P, Devaney, J, Schwartz, SM, Saarela, O, Mehta, NN, Rubin, D, Silander, K, Hall, AS, Ferrieres, J, Harris, TB, Melander, O, Kee, F, Hakonarson, H, Schrezenmeir, J, Gudnason, V, Elosua, R, Arveiler, D, Evans, A, Rader, DJ, Illig, T, Schreiber, S, Bis, JC, Altshuler, D, Kavousi, M, Witteman, JCM, Uitterlinden, AG, Hofman, A, Folsom, AR, Barbalic, M, Boerwinkle, E, Kathiresan, S, Reilly, MP, O'Donnell, CJ, Samani, NJ, Schunkert, H, Cambien, F, Lackner, KJ, Tiret, L, Salomaa, V, Munzel, T, Ziegler, A & Blankenberg, S 2011, 'A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease', Circulation: Cardiovascular Genetics, Jg. 4, Nr. 4, S. 403-412. https://doi.org/10.1161/CIRCGENETICS.110.958728

TY - JOUR

T1 - A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease

AU - Wild, Philipp S.

AU - Zeller, Tanja

AU - Schillert, Arne

AU - Szymczak, Silke

AU - Sinning, Christoph R.

AU - Deiseroth, Arne

AU - Schnabel, Renate B.

AU - Lubos, Edith

AU - Keller, Till

AU - Eleftheriadis, Medea S.

AU - Bickel, Christoph

AU - Rupprecht, Hans J.

AU - Wilde, Sandra

AU - Rossmann, Heidi

AU - Diemert, Patrick

AU - Cupples, L. Adrienne

AU - Perret, Claire

AU - Erdmann, Jeanette

AU - Stark, Klaus

AU - Kleber, Marcus E.

AU - Epstein, Stephen E.

AU - Voight, Benjamin F.

AU - Kuulasmaa, Kari

AU - Li, Mingyao

AU - Schäfer, Arne S.

AU - Klopp, Norman

AU - Braund, Peter S.

AU - Sager, Hendrik B.

AU - Demissie, Serkalem

AU - Proust, Carole

AU - König, Inke R.

AU - Wichmann, Heinz Erich

AU - Reinhard, Wibke

AU - Hoffmann, Michael M.

AU - Virtamo, Jarmo

AU - Burnett, Mary Susan

AU - Siscovick, David

AU - Wiklund, Per Gunnar

AU - Qu, Liming

AU - El Mokthari, Nour Eddine

AU - Thompson, John R.

AU - Peters, Annette

AU - Smith, Albert V.

AU - Yon, Emmanuelle

AU - Baumert, Jens

AU - Hengstenberg, Christian

AU - März, Winfried

AU - Amouyel, Philippe

AU - Devaney, Joseph

AU - Schwartz, Stephen M.

AU - Saarela, Olli

AU - Mehta, Nehal N.

AU - Rubin, Diana

AU - Silander, Kaisa

AU - Hall, Alistair S.

AU - Ferrieres, Jean

AU - Harris, Tamara B.

AU - Melander, Olle

AU - Kee, Frank

AU - Hakonarson, Hakon

AU - Schrezenmeir, Juergen

AU - Gudnason, Vilmundur

AU - Elosua, Roberto

AU - Arveiler, Dominique

AU - Evans, Alun

AU - Rader, Daniel J.

AU - Illig, Thomas

AU - Schreiber, Stefan

AU - Bis, Joshua C.

AU - Altshuler, David

AU - Kavousi, Maryam

AU - Witteman, Jaqueline C.M.

AU - Uitterlinden, Andre G.

AU - Hofman, Albert

AU - Folsom, Aaron R.

AU - Barbalic, Maja

AU - Boerwinkle, Eric

AU - Kathiresan, Sekar

AU - Reilly, Muredach P.

AU - O'Donnell, Christopher J.

AU - Samani, Nilesh J.

AU - Schunkert, Heribert

AU - Cambien, Francois

AU - Lackner, Karl J.

AU - Tiret, Laurence

AU - Salomaa, Veikko

AU - Munzel, Thomas

AU - Ziegler, Andreas

AU - Blankenberg, Stefan

PY - 2011/8/1

Y1 - 2011/8/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/80052733701

U2 - 10.1161/CIRCGENETICS.110.958728

DO - 10.1161/CIRCGENETICS.110.958728

M3 - Journal articles

C2 - 21606135

AN - SCOPUS:80052733701

SN - 1942-325X

VL - 4

SP - 403

EP - 412

JO - Circulation: Cardiovascular Genetics

JF - Circulation: Cardiovascular Genetics

IS - 4

ER -

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

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