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: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. 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^*

^*Corresponding author for this work

Harvard Medical School
University of Virginia
University of Virginia School of Medicine
University Medical Centre Utrecht
University of Michigan, Ann Arbor
Seoul National University
University of Texas Health Science Center at Houston
Wake Forest University
University College London
Leiden University Medical Centre
Max Planck Institute for Biology of Ageing
Utrecht University
The Lundquist Institute
Medical University of Graz
National Institutes of Health
Harvard Pilgrim Health Care
Tampere University
Icelandic Heart Association
University of Colorado Anschutz Medical Campus
University of Washington
Johns Hopkins School of Medicine
Washington University School of Medicine in St. Louis
VA Palo Alto Health Care System
Victor Chang Cardiac Research Institute
University of New South Wales
Icahn School of Medicine at Mount Sinai
University of California at Irvine
Vanderbilt University School of Medicine
University of Groningen
University Medical Centre Groningen
University of Colorado Denver
Stanford University School of Medicine
Erasmus University Rotterdam
Boston University School of Public Health
Amsterdam UMC
University of Iceland
School of Public Health
Tampere University Hospital and Tampere University
University of Turku
Turku University Hospital
University of Washington School of Medicine
University of North Carolina at Chapel Hill
Johns Hopkins Bloomberg School of Public Health
Karolinska Institutet
Hebrew SeniorLife
VA Medical Center

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

65 Citations (Scopus)

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
DOIs	https://doi.org/10.1038/s41588-023-01518-4
Publication status	Published - Oct 2023

Bibliographical note

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

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10.1038/s41588-023-01518-4

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10601987/pdf/nihms-1937930.pdf

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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{1e0ef6ec81b94d3d8f28e6b5cb88e6bf,

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 Hwang, \{Shih Jen\} and Lutz, \{Sharon M.\} and Lyytik{\"a}inen, \{Leo Pekka\} 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 = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = oct,

doi = "10.1038/s41588-023-01518-4",

language = "English",

volume = "55",

pages = "1651--1664",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

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, SJ, Lutz, SM, Lyytikäinen, LP, 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.

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 - https://www.scopus.com/pages/publications/85172796432

U2 - 10.1038/s41588-023-01518-4

DO - 10.1038/s41588-023-01518-4

M3 - Article

C2 - 37770635

AN - SCOPUS:85172796432

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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