Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification

Maryam Kavousi; Maxime M. Bos; Hanna J. Barnes; Christian L. Lino Cardenas; Doris Wong; Haojie Lu; Chani J. Hodonsky; Lennart P. L. Landsmeer; Adam W. Turner; Minjung Kho; Natalie R. Hasbani; Paul S. de Vries; Donald W. Bowden; Sandesh Chopade; Joris Deelen; Ernest Diez Benavente; Xiuqing Guo; Edith Hofer; Shih-Jen Hwang; Sharon M. Lutz; Leo-Pekka Lyytikäinen; Lotte Slenders; Albert V. Smith; Maggie A. Stanislawski; Jessica van Setten; Quenna Wong; Lisa R. Yanek; Diane M. Becker; Marian Beekman; Matthew J. Budoff; Mary F. Feitosa; Chris Finan; Austin T. Hilliard; Sharon L. R. Kardia; Jason C. Kovacic; Brian G. Kral; Carl D. Langefeld; Lenore J. Launer; Shaista Malik; Firdaus A. A. Mohamed Hoesein; Michal Mokry; Reinhold Schmidt; Jennifer A. Smith; Kent D. Taylor; James G. Terry; Jeroen van der Grond; Joyce van Meurs; Rozemarijn Vliegenthart; Jianzhao Xu; Kendra A. Young; Nuno R. Zilhão; Robert Zweiker; Themistocles L. Assimes; Lewis C. Becker; Daniel Bos; J. Jeffrey Carr; L. Adrienne Cupples; Dominique P. v. de Kleijn; Menno de Winther; Hester M. den Ruijter; Myriam Fornage; Barry I. Freedman; Vilmundur Gudnason; Aroon D. Hingorani; John E. Hokanson; M. Arfan Ikram; Ivana Išgum; David R. Jacobs; Mika Kähönen; Leslie A. Lange; Terho Lehtimäki; Gerard Pasterkamp; Olli T. Raitakari; Helena Schmidt; P. Eline Slagboom; André G. Uitterlinden; Meike W. Vernooij; Joshua C. Bis; Nora Franceschini; Bruce M. Psaty; Wendy S. Post; Jerome I. Rotter; Johan L. M. Björkegren; Christopher J. O’Donnell; Lawrence F. Bielak; Patricia A. Peyser; Rajeev Malhotra; Sander W. van der Laan; Clint L. Miller

doi:https://doi.org/10.1038/s41588-023-01518-4

Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification

Maryam Kavousi, Maxime M. Bos, Hanna J. Barnes, Christian L. Lino Cardenas, Doris Wong, Haojie Lu, Chani J. Hodonsky, Lennart P. L. Landsmeer, Adam W. Turner, Minjung Kho, Natalie R. Hasbani, Paul S. de Vries, Donald W. Bowden, Sandesh Chopade, Joris Deelen, Ernest Diez Benavente, Xiuqing Guo, Edith Hofer, Shih-Jen Hwang, Sharon M. LutzLeo-Pekka Lyytikäinen, Lotte Slenders, Albert V. Smith, Maggie A. Stanislawski, Jessica van Setten, Quenna Wong, Lisa R. Yanek, Diane M. Becker, Marian Beekman, Matthew J. Budoff, Mary F. Feitosa, Chris Finan, Austin T. Hilliard, Sharon L. R. Kardia, Jason C. Kovacic, Brian G. Kral, Carl D. Langefeld, Lenore J. Launer, Shaista Malik, Firdaus A. A. Mohamed Hoesein, Michal Mokry, Reinhold Schmidt, Jennifer A. Smith, Kent D. Taylor, James G. Terry, Jeroen van der Grond, Joyce van Meurs, Rozemarijn Vliegenthart, Jianzhao Xu, Kendra A. Young, Nuno R. Zilhão, Robert Zweiker, Themistocles L. Assimes, Lewis C. Becker, Daniel Bos, J. Jeffrey Carr, L. Adrienne Cupples, Dominique P. v. de Kleijn, Menno de Winther, Hester M. den Ruijter, Myriam Fornage, Barry I. Freedman, Vilmundur Gudnason, Aroon D. Hingorani, John E. Hokanson, M. Arfan Ikram, Ivana Išgum, David R. Jacobs, Mika Kähönen, Leslie A. Lange, Terho Lehtimäki, Gerard Pasterkamp, Olli T. Raitakari, Helena Schmidt, P. Eline Slagboom, André G. Uitterlinden, Meike W. Vernooij, Joshua C. Bis, Nora Franceschini, Bruce M. Psaty, Wendy S. Post, Jerome I. Rotter, Johan L. M. Björkegren, Christopher J. O’Donnell, Lawrence F. Bielak, Patricia A. Peyser, Rajeev Malhotra, Sander W. van der Laan, Clint L. Miller

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

Original language	English
Pages (from-to)	1651-1664
Number of pages	14
Journal	Nature Genetics
Volume	55
Issue number	10
Early online date	2023
DOIs	https://doi.org/10.1038/s41588-023-01518-4
Publication status	Published - Oct 2023

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Kavousi, M., Bos, M. M., Barnes, H. J., Cardenas, C. L. L., Wong, D., Lu, H., Hodonsky, C. J., Landsmeer, L. P. L., Turner, A. W., Kho, M., Hasbani, N. R., de Vries, P. S., Bowden, D. W., Chopade, S., Deelen, J., Benavente, E. D., Guo, X., Hofer, E., Hwang, S.-J., ... Miller, C. L. (2023). Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification. Nature Genetics, 55(10), 1651-1664. https://doi.org/10.1038/s41588-023-01518-4

@article{61eabde440844e438a7461f1c0361a4d,

title = "Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification",

abstract = "Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.",

author = "Maryam Kavousi and Bos, {Maxime M.} and Barnes, {Hanna J.} and Cardenas, {Christian L. Lino} and Doris Wong and Haojie Lu and Hodonsky, {Chani J.} and Landsmeer, {Lennart P. L.} and Turner, {Adam W.} and Minjung Kho and Hasbani, {Natalie R.} and {de Vries}, {Paul S.} and Bowden, {Donald W.} and Sandesh Chopade and Joris Deelen and Benavente, {Ernest Diez} and Xiuqing Guo and Edith Hofer and Shih-Jen Hwang and Lutz, {Sharon M.} and Leo-Pekka Lyytik{\"a}inen and Lotte Slenders and Smith, {Albert V.} and Stanislawski, {Maggie A.} and {van Setten}, Jessica and Quenna Wong and Yanek, {Lisa R.} and Becker, {Diane M.} and Marian Beekman and Budoff, {Matthew J.} and Feitosa, {Mary F.} and Chris Finan and Hilliard, {Austin T.} and Kardia, {Sharon L. R.} and Kovacic, {Jason C.} and Kral, {Brian G.} and Langefeld, {Carl D.} and Launer, {Lenore J.} and Shaista Malik and Hoesein, {Firdaus A. A. Mohamed} and Michal Mokry and Reinhold Schmidt and Smith, {Jennifer A.} and Taylor, {Kent D.} and Terry, {James G.} and {van der Grond}, Jeroen and {van Meurs}, Joyce and Rozemarijn Vliegenthart and Jianzhao Xu and Young, {Kendra A.} and Zilh{\~a}o, {Nuno R.} and Robert Zweiker and Assimes, {Themistocles L.} and Becker, {Lewis C.} and Daniel Bos and Carr, {J. Jeffrey} and Cupples, {L. Adrienne} and {de Kleijn}, {Dominique P. v.} and {de Winther}, Menno and {den Ruijter}, {Hester M.} and Myriam Fornage and Freedman, {Barry I.} and Vilmundur Gudnason and Hingorani, {Aroon D.} and Hokanson, {John E.} and Ikram, {M. Arfan} and Ivana I{\v s}gum and Jacobs, {David R.} and Mika K{\"a}h{\"o}nen and Lange, {Leslie A.} and Terho Lehtim{\"a}ki and Gerard Pasterkamp and Raitakari, {Olli T.} and Helena Schmidt and Slagboom, {P. Eline} and Uitterlinden, {Andr{\'e} G.} and Vernooij, {Meike W.} and Bis, {Joshua C.} and Nora Franceschini and Psaty, {Bruce M.} and Post, {Wendy S.} and Rotter, {Jerome I.} and Bj{\"o}rkegren, {Johan L. M.} and O{\textquoteright}Donnell, {Christopher J.} and Bielak, {Lawrence F.} and Peyser, {Patricia A.} and Rajeev Malhotra and {van der Laan}, {Sander W.} and Miller, {Clint L.}",

note = "Funding Information: This work was supported by grants from the National Institutes of Health (R01HL148239 and R01HL164577 to C.L.M.; R01HL142809 and R01HL159514 to R.M.; F31HL156463 to D.W.; R01HL125863 to J.L.M.B.; R01HL146860 to P.S.d.V., K01HL164687 to C.L.L.C., N.R.H., P.A.P. and L.F.B.; R01HL163972 to N.F.; P30DK063491 to J.I.R.; R01DK114183 to T.L.A.; European Union funded H2020 TO_AITION (grant 848146 to S.W.v.d.L.); Netherlands CardioVascular Research Initiative of the Netherlands Heart Foundation (CVON 2011/B019 and CVON 2017-20 (to S.W.v.d.L. and M.d.W.)—generating the best evidence-based pharmaceutical targets for atherosclerosis (GENIUS I&II)), the ERA-CVD program {\textquoteleft}druggable-MI-targets{\textquoteright} (01KL1802 to S.W.v.d.L.) and the Leducq Foundation ({\textquoteleft}PlaqOmics{\textquoteright} 18CVD02 to C.L.M., J.L.M.B., G.P. and S.W.v.d.L.). The CHARGE Consortium was supported by NHLBI (grant R01HL105756). M.d.W. was supported by the Netherlands Heart Foundation and Spark-Holding BV (2019B016); Leducq Foundation (LEAN 16CVD01); Amsterdam UMC; ZonMW (Open Competition 09120011910025). A full list of the funding support for each study is provided in . A full list of acknowledged funding support for individual studies is provided in Supplementary Table . Funding Information: S.W.v.d.L. has received Roche funding for unrelated work. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. R.M. receives research funding from Angea Biotherapeutics and Amgen and serves as a consultant for Myokardia/BMS, Renovacor, Epizon Pharma and Third Pole, all unrelated to the current project. C.L.M. has received funding from AstraZeneca on an unrelated project. J.C.K. is the recipient of an Agilent Thought Leader Award (January 2022), which includes funding for research that is unrelated to the current paper. The other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = oct,

doi = "https://doi.org/10.1038/s41588-023-01518-4",

language = "English",

volume = "55",

pages = "1651--1664",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "10",

}

Kavousi, M, Bos, MM, Barnes, HJ, Cardenas, CLL, Wong, D, Lu, H, Hodonsky, CJ, Landsmeer, LPL, Turner, AW, Kho, M, Hasbani, NR, de Vries, PS, Bowden, DW, Chopade, S, Deelen, J, Benavente, ED, Guo, X, Hofer, E, Hwang, S-J, Lutz, SM, Lyytikäinen, L-P, Slenders, L, Smith, AV, Stanislawski, MA, van Setten, J, Wong, Q, Yanek, LR, Becker, DM, Beekman, M, Budoff, MJ, Feitosa, MF, Finan, C, Hilliard, AT, Kardia, SLR, Kovacic, JC, Kral, BG, Langefeld, CD, Launer, LJ, Malik, S, Hoesein, FAAM, Mokry, M, Schmidt, R, Smith, JA, Taylor, KD, Terry, JG, van der Grond, J, van Meurs, J, Vliegenthart, R, Xu, J, Young, KA, Zilhão, NR, Zweiker, R, Assimes, TL, Becker, LC, Bos, D, Carr, JJ, Cupples, LA, de Kleijn, DPV, de Winther, M, den Ruijter, HM, Fornage, M, Freedman, BI, Gudnason, V, Hingorani, AD, Hokanson, JE, Ikram, MA, Išgum, I, Jacobs, DR, Kähönen, M, Lange, LA, Lehtimäki, T, Pasterkamp, G, Raitakari, OT, Schmidt, H, Slagboom, PE, Uitterlinden, AG, Vernooij, MW, Bis, JC, Franceschini, N, Psaty, BM, Post, WS, Rotter, JI, Björkegren, JLM, O’Donnell, CJ, Bielak, LF, Peyser, PA, Malhotra, R, van der Laan, SW & Miller, CL 2023, 'Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification', Nature Genetics, vol. 55, no. 10, pp. 1651-1664. https://doi.org/10.1038/s41588-023-01518-4

TY - JOUR

T1 - Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification

AU - Kavousi, Maryam

AU - Bos, Maxime M.

AU - Barnes, Hanna J.

AU - Cardenas, Christian L. Lino

AU - Wong, Doris

AU - Lu, Haojie

AU - Hodonsky, Chani J.

AU - Landsmeer, Lennart P. L.

AU - Turner, Adam W.

AU - Kho, Minjung

AU - Hasbani, Natalie R.

AU - de Vries, Paul S.

AU - Bowden, Donald W.

AU - Chopade, Sandesh

AU - Deelen, Joris

AU - Benavente, Ernest Diez

AU - Guo, Xiuqing

AU - Hofer, Edith

AU - Hwang, Shih-Jen

AU - Lutz, Sharon M.

AU - Lyytikäinen, Leo-Pekka

AU - Slenders, Lotte

AU - Smith, Albert V.

AU - Stanislawski, Maggie A.

AU - van Setten, Jessica

AU - Wong, Quenna

AU - Yanek, Lisa R.

AU - Becker, Diane M.

AU - Beekman, Marian

AU - Budoff, Matthew J.

AU - Feitosa, Mary F.

AU - Finan, Chris

AU - Hilliard, Austin T.

AU - Kardia, Sharon L. R.

AU - Kovacic, Jason C.

AU - Kral, Brian G.

AU - Langefeld, Carl D.

AU - Launer, Lenore J.

AU - Malik, Shaista

AU - Hoesein, Firdaus A. A. Mohamed

AU - Mokry, Michal

AU - Schmidt, Reinhold

AU - Smith, Jennifer A.

AU - Taylor, Kent D.

AU - Terry, James G.

AU - van der Grond, Jeroen

AU - van Meurs, Joyce

AU - Vliegenthart, Rozemarijn

AU - Xu, Jianzhao

AU - Young, Kendra A.

AU - Zilhão, Nuno R.

AU - Zweiker, Robert

AU - Assimes, Themistocles L.

AU - Becker, Lewis C.

AU - Bos, Daniel

AU - Carr, J. Jeffrey

AU - Cupples, L. Adrienne

AU - de Kleijn, Dominique P. v.

AU - de Winther, Menno

AU - den Ruijter, Hester M.

AU - Fornage, Myriam

AU - Freedman, Barry I.

AU - Gudnason, Vilmundur

AU - Hingorani, Aroon D.

AU - Hokanson, John E.

AU - Ikram, M. Arfan

AU - Išgum, Ivana

AU - Jacobs, David R.

AU - Kähönen, Mika

AU - Lange, Leslie A.

AU - Lehtimäki, Terho

AU - Pasterkamp, Gerard

AU - Raitakari, Olli T.

AU - Schmidt, Helena

AU - Slagboom, P. Eline

AU - Uitterlinden, André G.

AU - Vernooij, Meike W.

AU - Bis, Joshua C.

AU - Franceschini, Nora

AU - Psaty, Bruce M.

AU - Post, Wendy S.

AU - Rotter, Jerome I.

AU - Björkegren, Johan L. M.

AU - O’Donnell, Christopher J.

AU - Bielak, Lawrence F.

AU - Peyser, Patricia A.

AU - Malhotra, Rajeev

AU - van der Laan, Sander W.

AU - Miller, Clint L.

N1 - Funding Information: This work was supported by grants from the National Institutes of Health (R01HL148239 and R01HL164577 to C.L.M.; R01HL142809 and R01HL159514 to R.M.; F31HL156463 to D.W.; R01HL125863 to J.L.M.B.; R01HL146860 to P.S.d.V., K01HL164687 to C.L.L.C., N.R.H., P.A.P. and L.F.B.; R01HL163972 to N.F.; P30DK063491 to J.I.R.; R01DK114183 to T.L.A.; European Union funded H2020 TO_AITION (grant 848146 to S.W.v.d.L.); Netherlands CardioVascular Research Initiative of the Netherlands Heart Foundation (CVON 2011/B019 and CVON 2017-20 (to S.W.v.d.L. and M.d.W.)—generating the best evidence-based pharmaceutical targets for atherosclerosis (GENIUS I&II)), the ERA-CVD program ‘druggable-MI-targets’ (01KL1802 to S.W.v.d.L.) and the Leducq Foundation (‘PlaqOmics’ 18CVD02 to C.L.M., J.L.M.B., G.P. and S.W.v.d.L.). The CHARGE Consortium was supported by NHLBI (grant R01HL105756). M.d.W. was supported by the Netherlands Heart Foundation and Spark-Holding BV (2019B016); Leducq Foundation (LEAN 16CVD01); Amsterdam UMC; ZonMW (Open Competition 09120011910025). A full list of the funding support for each study is provided in . A full list of acknowledged funding support for individual studies is provided in Supplementary Table . Funding Information: S.W.v.d.L. has received Roche funding for unrelated work. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. R.M. receives research funding from Angea Biotherapeutics and Amgen and serves as a consultant for Myokardia/BMS, Renovacor, Epizon Pharma and Third Pole, all unrelated to the current project. C.L.M. has received funding from AstraZeneca on an unrelated project. J.C.K. is the recipient of an Agilent Thought Leader Award (January 2022), which includes funding for research that is unrelated to the current paper. The other authors declare no competing interests. Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2023/10

Y1 - 2023/10

N2 - Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

AB - Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

UR - http://www.scopus.com/inward/record.url?scp=85172796432&partnerID=8YFLogxK

U2 - https://doi.org/10.1038/s41588-023-01518-4

DO - https://doi.org/10.1038/s41588-023-01518-4

M3 - Article

C2 - 37770635

SN - 1061-4036

VL - 55

SP - 1651

EP - 1664

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification

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