Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

CARDIoGRAMplusC4D; Joanna M M Howson; Wei Zhao; Daniel R Barnes; Weang-Kee Ho; Robin Young; Dirk S Paul; Lindsay L Waite; Daniel F Freitag; Eric B Fauman; Elias L Salfati; Benjamin B Sun; John D Eicher; Andrew D Johnson; Wayne H H Sheu; Sune F Nielsen; Wei-Yu Lin; Praveen Surendran; Anders Malarstig; Jemma B Wilk; Anne Tybjærg-Hansen; Katrine L Rasmussen; Pia R Kamstrup; Panos Deloukas; Jeanette Erdmann; Sekar Kathiresan; Nilesh J Samani; Heribert Schunkert; Hugh Watkins; Ron Do; Daniel J Rader; Julie A Johnson; Stanley L Hazen; Arshed A Quyyumi; John A Spertus; Carl J Pepine; Nora Franceschini; Anne Justice; Alex P Reiner; Steven Buyske; Lucia A Hindorff; Cara L Carty; Kari E North; Charles Kooperberg; Eric Boerwinkle; Kristin Young; Mariaelisa Graff; Ulrike Peters; Devin Absher; Chao A Hsiung; Wen-Jane Lee

doi:10.1038/ng.3874

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

CARDIoGRAMplusC4D, Joanna M M Howson, Wei Zhao, Daniel R Barnes, Weang-Kee Ho, Robin Young, Dirk S Paul, Lindsay L Waite, Daniel F Freitag, Eric B Fauman, Elias L Salfati, Benjamin B Sun, John D Eicher, Andrew D Johnson, Wayne H H Sheu, Sune F Nielsen, Wei-Yu Lin, Praveen Surendran, Anders Malarstig, Jemma B WilkAnne Tybjærg-Hansen, Katrine L Rasmussen, Pia R Kamstrup, Panos Deloukas, Jeanette Erdmann, Sekar Kathiresan, Nilesh J Samani, Heribert Schunkert, Hugh Watkins, Ron Do, Daniel J Rader, Julie A Johnson, Stanley L Hazen, Arshed A Quyyumi, John A Spertus, Carl J Pepine, Nora Franceschini, Anne Justice, Alex P Reiner, Steven Buyske, Lucia A Hindorff, Cara L Carty, Kari E North, Charles Kooperberg, Eric Boerwinkle, Kristin Young, Mariaelisa Graff, Ulrike Peters, Devin Absher, Chao A Hsiung, Wen-Jane Lee

Abstract

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10-8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

Original language	English
Journal	Nature Genetics
Volume	49
Issue number	7
Pages (from-to)	1113-1119
Number of pages	7
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.3874
Publication status	Published - 07.2017

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CARDIoGRAMplusC4D, Howson, J. M. M., Zhao, W., Barnes, D. R., Ho, W-K., Young, R., Paul, D. S., Waite, L. L., Freitag, D. F., Fauman, E. B., Salfati, E. L., Sun, B. B., Eicher, J. D., Johnson, A. D., Sheu, W. H. H., Nielsen, S. F., Lin, W-Y., Surendran, P., Malarstig, A., ... Lee, W-J. (2017). Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms. Nature Genetics, 49(7), 1113-1119. https://doi.org/10.1038/ng.3874

@article{ea2b2a64647c4bae8b34d5201c9e8694,

title = "Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms",

abstract = "Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10-8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.",

author = "CARDIoGRAMplusC4D and Howson, {Joanna M M} and Wei Zhao and Barnes, {Daniel R} and Weang-Kee Ho and Robin Young and Paul, {Dirk S} and Waite, {Lindsay L} and Freitag, {Daniel F} and Fauman, {Eric B} and Salfati, {Elias L} and Sun, {Benjamin B} and Eicher, {John D} and Johnson, {Andrew D} and Sheu, {Wayne H H} and Nielsen, {Sune F} and Wei-Yu Lin and Praveen Surendran and Anders Malarstig and Wilk, {Jemma B} and Anne Tybj{\ae}rg-Hansen and Rasmussen, {Katrine L} and Kamstrup, {Pia R} and Panos Deloukas and Jeanette Erdmann and Sekar Kathiresan and Samani, {Nilesh J} and Heribert Schunkert and Hugh Watkins and Ron Do and Rader, {Daniel J} and Johnson, {Julie A} and Hazen, {Stanley L} and Quyyumi, {Arshed A} and Spertus, {John A} and Pepine, {Carl J} and Nora Franceschini and Anne Justice and Reiner, {Alex P} and Steven Buyske and Hindorff, {Lucia A} and Carty, {Cara L} and North, {Kari E} and Charles Kooperberg and Eric Boerwinkle and Kristin Young and Mariaelisa Graff and Ulrike Peters and Devin Absher and Hsiung, {Chao A} and Wen-Jane Lee",

year = "2017",

month = jul,

doi = "10.1038/ng.3874",

language = "English",

volume = "49",

pages = "1113--1119",

journal = "Nature Genetics",

issn = "1061-4036",

number = "7",

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CARDIoGRAMplusC4D, Howson, JMM, Zhao, W, Barnes, DR, Ho, W-K, Young, R, Paul, DS, Waite, LL, Freitag, DF, Fauman, EB, Salfati, EL, Sun, BB, Eicher, JD, Johnson, AD, Sheu, WHH, Nielsen, SF, Lin, W-Y, Surendran, P, Malarstig, A, Wilk, JB, Tybjærg-Hansen, A, Rasmussen, KL, Kamstrup, PR, Deloukas, P, Erdmann, J, Kathiresan, S, Samani, NJ, Schunkert, H, Watkins, H, Do, R, Rader, DJ, Johnson, JA, Hazen, SL, Quyyumi, AA, Spertus, JA, Pepine, CJ, Franceschini, N, Justice, A, Reiner, AP, Buyske, S, Hindorff, LA, Carty, CL, North, KE, Kooperberg, C, Boerwinkle, E, Young, K, Graff, M, Peters, U, Absher, D, Hsiung, CA & Lee, W-J 2017, 'Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms', Nature Genetics, vol. 49, no. 7, pp. 1113-1119. https://doi.org/10.1038/ng.3874

TY - JOUR

T1 - Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

AU - CARDIoGRAMplusC4D

AU - Howson, Joanna M M

AU - Zhao, Wei

AU - Barnes, Daniel R

AU - Ho, Weang-Kee

AU - Young, Robin

AU - Paul, Dirk S

AU - Waite, Lindsay L

AU - Freitag, Daniel F

AU - Fauman, Eric B

AU - Salfati, Elias L

AU - Sun, Benjamin B

AU - Eicher, John D

AU - Johnson, Andrew D

AU - Sheu, Wayne H H

AU - Nielsen, Sune F

AU - Lin, Wei-Yu

AU - Surendran, Praveen

AU - Malarstig, Anders

AU - Wilk, Jemma B

AU - Tybjærg-Hansen, Anne

AU - Rasmussen, Katrine L

AU - Kamstrup, Pia R

AU - Deloukas, Panos

AU - Erdmann, Jeanette

AU - Kathiresan, Sekar

AU - Samani, Nilesh J

AU - Schunkert, Heribert

AU - Watkins, Hugh

AU - Do, Ron

AU - Rader, Daniel J

AU - Johnson, Julie A

AU - Hazen, Stanley L

AU - Quyyumi, Arshed A

AU - Spertus, John A

AU - Pepine, Carl J

AU - Franceschini, Nora

AU - Justice, Anne

AU - Reiner, Alex P

AU - Buyske, Steven

AU - Hindorff, Lucia A

AU - Carty, Cara L

AU - North, Kari E

AU - Kooperberg, Charles

AU - Boerwinkle, Eric

AU - Young, Kristin

AU - Graff, Mariaelisa

AU - Peters, Ulrike

AU - Absher, Devin

AU - Hsiung, Chao A

AU - Lee, Wen-Jane

PY - 2017/7

Y1 - 2017/7

N2 - Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10-8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

AB - Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10-8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

U2 - 10.1038/ng.3874

DO - 10.1038/ng.3874

M3 - Journal articles

C2 - 28530674

SN - 1061-4036

VL - 49

SP - 1113

EP - 1119

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Abstract

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