A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease

PS Wild; T Zeller; A Schillert; S Szymczak; CR Sinning; A Deiseroth; RB Schnabel; E Lubos; T Keller; MS Eleftheriadis; C Bickel; HJ Rupprecht; S Wilde; H Rossmann; P Diemert; LA Cupples; C Perret; J Erdmann; K Stark; ME Kleber; SE Epstein; BF Voight; K Kuulasmaa; MY Li; AS Schafer; N Klopp; PS Braund; H Sager; S Demissie; C Proust; IR Konig; HE Wichmann; W Reinhard; MM Hoffmann; J Virtamo; MS Burnett; D Siscovick; PG Wiklund; LM Qu; NE El Mokthari; JR Thompson; A Peters; AV Smith; E Yon; J Baumert; C Hengstenberg; W Marz; P Amouyel; J Devaney; S Schwartz; O Saarela; NN Mehta; D Rubin; K Silander; AS Hall; J Ferriers; TB Harris; O Melander; F Kee; H Hakonarson; J Schrezenmeir; V Gudnason; R Elosua; D Arveiler; A Evans; DJ Rader; T Illig; S Schreiber; JC Bis; D Altshuler; Maryam Kavousi; JCM Witteman; André Uitterlinden; Bert Hofman; AR Folsom; M Barbalic; E Boerwinkle; S Kathiresan; MP Reilly; CJ O'Donnell; NJ Samani; H Schunkert; F Cambien; KJ Lackner; L Tiret; V Salomaa; T Munzel; A Ziegler; S Blankenberg

A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease

PS Wild, T Zeller, A Schillert, S Szymczak, CR Sinning, A Deiseroth, RB Schnabel, E Lubos, T Keller, MS Eleftheriadis, C Bickel, HJ Rupprecht, S Wilde, H Rossmann, P Diemert, LA Cupples, C Perret, J Erdmann, K Stark, ME KleberSE Epstein, BF Voight, K Kuulasmaa, MY Li, AS Schafer, N Klopp, PS Braund, H Sager, S Demissie, C Proust, IR Konig, HE Wichmann, W Reinhard, MM Hoffmann, J Virtamo, MS Burnett, D Siscovick, PG Wiklund, LM Qu, NE El Mokthari, JR Thompson, A Peters, AV Smith, E Yon, J Baumert, C Hengstenberg, W Marz, P Amouyel, J Devaney, S Schwartz, O Saarela, NN Mehta, D Rubin, K Silander, AS Hall, J Ferriers, TB Harris, O Melander, F Kee, H Hakonarson, J Schrezenmeir, V Gudnason, R Elosua, D Arveiler, A Evans, DJ Rader, T Illig, S Schreiber, JC Bis, D Altshuler, Maryam Kavousi, JCM Witteman, André Uitterlinden, Bert Hofman, AR Folsom, M Barbalic, E Boerwinkle, S Kathiresan, MP Reilly, CJ O'Donnell, NJ Samani, H Schunkert, F Cambien, KJ Lackner, L Tiret, V Salomaa, T Munzel, A Ziegler, S Blankenberg

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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 x 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 x 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 x 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. (Circ Cardiovasc Genet. 2011;4:403-412.)

Original language	Undefined/Unknown
Pages (from-to)	403-U203
Journal	Circulation-cardiovascular genetics
Volume	4
Issue number	4
Publication status	Published - 2011

Research programs

EMC MM-01-25-01
EMC MM-01-39-09-A
EMC NIHES-01-64-01

Cite this

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., ... Blankenberg, S. (2011). A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease. Circulation-cardiovascular genetics, 4(4), 403-U203.

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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 x 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 x 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 x 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. (Circ Cardiovasc Genet. 2011;4:403-412.)",

author = "PS Wild and T Zeller and A Schillert and S Szymczak and CR Sinning and A Deiseroth and RB Schnabel and E Lubos and T Keller and MS Eleftheriadis and C Bickel and HJ Rupprecht and S Wilde and H Rossmann and P Diemert and LA Cupples and C Perret and J Erdmann and K Stark and ME Kleber and SE Epstein and BF Voight and K Kuulasmaa and MY Li and AS Schafer and N Klopp and PS Braund and H Sager and S Demissie and C Proust and IR Konig and HE Wichmann and W Reinhard and MM Hoffmann and J Virtamo and MS Burnett and D Siscovick and PG Wiklund and LM Qu and {El Mokthari}, NE and JR Thompson and A Peters and AV Smith and E Yon and J Baumert and C Hengstenberg and W Marz and P Amouyel and J Devaney and S Schwartz and O Saarela and NN Mehta and D Rubin and K Silander and AS Hall and J Ferriers and TB Harris and O Melander and F Kee and H Hakonarson and J Schrezenmeir and V Gudnason and R Elosua and D Arveiler and A Evans and DJ Rader and T Illig and S Schreiber and JC Bis and D Altshuler and Maryam Kavousi and JCM Witteman and Andr{\'e} Uitterlinden and Bert Hofman and AR Folsom and M Barbalic and E Boerwinkle and S Kathiresan and MP Reilly and CJ O'Donnell and NJ Samani and H Schunkert and F Cambien and KJ Lackner and L Tiret and V Salomaa and T Munzel and A Ziegler and S Blankenberg",

year = "2011",

language = "Undefined/Unknown",

volume = "4",

pages = "403--U203",

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, MY, Schafer, AS, Klopp, N, Braund, PS, Sager, H, Demissie, S, Proust, C, Konig, IR, Wichmann, HE, Reinhard, W, Hoffmann, MM, Virtamo, J, Burnett, MS, Siscovick, D, Wiklund, PG, Qu, LM, El Mokthari, NE, Thompson, JR, Peters, A, Smith, AV, Yon, E, Baumert, J, Hengstenberg, C, Marz, W, Amouyel, P, Devaney, J, Schwartz, S, Saarela, O, Mehta, NN, Rubin, D, Silander, K, Hall, AS, Ferriers, 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, A , Hofman, B, 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, vol. 4, no. 4, pp. 403-U203.

TY - JOUR

T1 - A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease

AU - Wild, PS

AU - Zeller, T

AU - Schillert, A

AU - Szymczak, S

AU - Sinning, CR

AU - Deiseroth, A

AU - Schnabel, RB

AU - Lubos, E

AU - Keller, T

AU - Eleftheriadis, MS

AU - Bickel, C

AU - Rupprecht, HJ

AU - Wilde, S

AU - Rossmann, H

AU - Diemert, P

AU - Cupples, LA

AU - Perret, C

AU - Erdmann, J

AU - Stark, K

AU - Kleber, ME

AU - Epstein, SE

AU - Voight, BF

AU - Kuulasmaa, K

AU - Li, MY

AU - Schafer, AS

AU - Klopp, N

AU - Braund, PS

AU - Sager, H

AU - Demissie, S

AU - Proust, C

AU - Konig, IR

AU - Wichmann, HE

AU - Reinhard, W

AU - Hoffmann, MM

AU - Virtamo, J

AU - Burnett, MS

AU - Siscovick, D

AU - Wiklund, PG

AU - Qu, LM

AU - El Mokthari, NE

AU - Thompson, JR

AU - Peters, A

AU - Smith, AV

AU - Yon, E

AU - Baumert, J

AU - Hengstenberg, C

AU - Marz, W

AU - Amouyel, P

AU - Devaney, J

AU - Schwartz, S

AU - Saarela, O

AU - Mehta, NN

AU - Rubin, D

AU - Silander, K

AU - Hall, AS

AU - Ferriers, J

AU - Harris, TB

AU - Melander, O

AU - Kee, F

AU - Hakonarson, H

AU - Schrezenmeir, J

AU - Gudnason, V

AU - Elosua, R

AU - Arveiler, D

AU - Evans, A

AU - Rader, DJ

AU - Illig, T

AU - Schreiber, S

AU - Bis, JC

AU - Altshuler, D

AU - Kavousi, Maryam

AU - Witteman, JCM

AU - Uitterlinden, André

AU - Hofman, Bert

AU - Folsom, AR

AU - Barbalic, M

AU - Boerwinkle, E

AU - Kathiresan, S

AU - Reilly, MP

AU - O'Donnell, CJ

AU - Samani, NJ

AU - Schunkert, H

AU - Cambien, F

AU - Lackner, KJ

AU - Tiret, L

AU - Salomaa, V

AU - Munzel, T

AU - Ziegler, A

AU - Blankenberg, S

PY - 2011

Y1 - 2011

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 x 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 x 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 x 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. (Circ Cardiovasc Genet. 2011;4:403-412.)

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 x 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 x 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 x 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. (Circ Cardiovasc Genet. 2011;4:403-412.)

M3 - Article

SN - 1942-325X

VL - 4

SP - 403-U203

JO - Circulation-cardiovascular genetics

JF - Circulation-cardiovascular genetics

IS - 4

ER -