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GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Author

Listed:
  • Nora Franceschini

    (University of North Carolina)

  • Claudia Giambartolomei

    (University of California (UCLA), Los Angeles)

  • Paul S. Vries

    (The University of Texas Health Science Center at Houston)

  • Chris Finan

    (University College London)

  • Joshua C. Bis

    (University of Washington)

  • Rachael P. Huntley

    (University College London)

  • Ruth C. Lovering

    (University College London)

  • Salman M. Tajuddin

    (Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health)

  • Thomas W. Winkler

    (University of Regensburg)

  • Misa Graff

    (University of North Carolina)

  • Maryam Kavousi

    (Erasmus Medical Center)

  • Caroline Dale

    (University College London)

  • Albert V. Smith

    (Icelandic Heart Association
    University of Iceland)

  • Edith Hofer

    (Medical University of Graz
    Medical University of Graz)

  • Elisabeth M. Leeuwen

    (Erasmus Medical Center)

  • Ilja M. Nolte

    (University of Groningen, University Medical Center Groningen)

  • Lingyi Lu

    (Wake Forest University School of Medicine)

  • Markus Scholz

    (, University of Leipzig
    University of Leipzig)

  • Muralidharan Sargurupremraj

    (Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, CHU Bordeaux)

  • Niina Pitkänen

    (University of Turku)

  • Oscar Franzén

    (The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai
    Clinical Gene Networks AB)

  • Peter K. Joshi

    (University of Edinburgh)

  • Raymond Noordam

    (Leiden University Medical Center)

  • Riccardo E. Marioni

    (University of Edinburgh
    University of Edinburgh)

  • Shih-Jen Hwang

    (Population Sciences Branch, Division of Intramural Research, NHLBI, NIH
    National Heart, Lung and Blood Institute’s Intramural Research Program, Framingham Heart Study)

  • Solomon K. Musani

    (University of Mississippi Medical Center)

  • Ulf Schminke

    (University Medicine Greifswald)

  • Walter Palmas

    (Columbia University)

  • Aaron Isaacs

    (Erasmus Medical Center
    Maastricht University)

  • Adolfo Correa

    (University of Mississippi Medical Center)

  • Alan B. Zonderman

    (Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health)

  • Albert Hofman

    (Erasmus Medical Center
    Harvard T.H. Chan School of Public Health)

  • Alexander Teumer

    (University Medicine Greifswald
    DZHK (German Center for Cardiovascular Research), partner site Greifswald)

  • Amanda J. Cox

    (Center for Diabetes Research, Wake Forest School of Medicine
    Griffith University)

  • André G. Uitterlinden

    (Erasmus Medical Center
    University Medical Center Rotterdam)

  • Andrew Wong

    (MRC Unit for Lifelong Health and Ageing at UCL)

  • Andries J. Smit

    (University of Groningen, University Medical Center Groningen)

  • Anne B. Newman

    (University of Pittsburgh)

  • Annie Britton

    (University College London)

  • Arno Ruusalepp

    (Clinical Gene Networks AB
    University of Tartu, Biomeedikum
    Tartu University Hospital)

  • Bengt Sennblad

    (Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet
    Uppsala University)

  • Bo Hedblad

    (Lund University)

  • Bogdan Pasaniuc

    (University of California (UCLA), Los Angeles
    University of California (UCLA))

  • Brenda W. Penninx

    (VU University Medical Center)

  • Carl D. Langefeld

    (Wake Forest University School of Medicine)

  • Christina L. Wassel

    (Applied Sciences, Premier, Inc.)

  • Christophe Tzourio

    (Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, CHU Bordeaux)

  • Cristiano Fava

    (Lund University
    Department of Medicine, University of Verona)

  • Damiano Baldassarre

    (Università di Milano
    Centro Cardiologico Monzino, IRCCS)

  • Daniel H. O’Leary

    (Tufts University School of Medicine)

  • Daniel Teupser

    (University of Leipzig
    University Hospital Munich)

  • Diana Kuh

    (MRC Unit for Lifelong Health and Ageing at UCL)

  • Elena Tremoli

    (Centro Cardiologico Monzino, IRCCS
    Università di Milano)

  • Elmo Mannarino

    (University of Perugia)

  • Enzo Grossi

    (Centro Diagnostico Italiano)

  • Eric Boerwinkle

    (The University of Texas Health Science Center at Houston
    Human Genome Sequencing Center, Baylor College of Medicine)

  • Eric E. Schadt

    (The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai
    Clinical Gene Networks AB)

  • Erik Ingelsson

    (Stanford University School of Medicine
    Uppsala University
    Stanford University)

  • Fabrizio Veglia

    (Centro Cardiologico Monzino, IRCCS)

  • Fernando Rivadeneira

    (Erasmus Medical Center
    University Medical Center Rotterdam)

  • Frank Beutner

    (Heart Center Leipzig)

  • Ganesh Chauhan

    (Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, CHU Bordeaux
    Centre for Brain Research, Indian Institute of Science)

  • Gerardo Heiss

    (University of North Carolina)

  • Harold Snieder

    (University of Groningen, University Medical Center Groningen)

  • Harry Campbell

    (University of Edinburgh)

  • Henry Völzke

    (University Medicine Greifswald
    DZHK (German Center for Cardiovascular Research), partner site Greifswald)

  • Hugh S. Markus

    (University of Cambridge)

  • Ian J. Deary

    (University of Edinburgh
    University of Edinburgh)

  • J. Wouter Jukema

    (Leiden University Medical Center)

  • Jacqueline Graaf

    (Radboud University Medical Center)

  • Jacqueline Price

    (University of Edinburgh)

  • Janne Pott

    (, University of Leipzig
    University of Leipzig)

  • Jemma C. Hopewell

    (University of Oxford)

  • Jingjing Liang

    (Case Western Reserve University)

  • Joachim Thiery

    (University of Leipzig
    University of Leipzig)

  • Jorgen Engmann

    (University College London)

  • Karl Gertow

    (Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet)

  • Kenneth Rice

    (University of Washington)

  • Kent D. Taylor

    (Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center)

  • Klodian Dhana

    (Rush University Medical Center)

  • Lambertus A. L. M. Kiemeney

    (Radboud University Medical Center)

  • Lars Lind

    (Uppsala University)

  • Laura M. Raffield

    (University of North Carolina)

  • Lenore J. Launer

    (Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health)

  • Lesca M. Holdt

    (University of Leipzig
    University Hospital Munich)

  • Marcus Dörr

    (DZHK (German Center for Cardiovascular Research), partner site Greifswald
    University Medicine Greifswald)

  • Martin Dichgans

    (University Hospital, Ludwig-Maximilians-University (LMU)
    Munich Cluster for Systems Neurology (SyNergy))

  • Matthew Traylor

    (University of Cambridge)

  • Matthias Sitzer

    (Johann Wolfgang Goethe-University)

  • Meena Kumari

    (University College London
    Essex University)

  • Mika Kivimaki

    (University College London)

  • Mike A. Nalls

    (Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health
    Data Tecnica International)

  • Olle Melander

    (Lund University)

  • Olli Raitakari

    (University of Turku
    Turku University Hospital)

  • Oscar H. Franco

    (Erasmus Medical Center
    University of Bern)

  • Oscar L. Rueda-Ochoa

    (Erasmus Medical Center
    Universidad Industrial de Santander)

  • Panos Roussos

    (The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx)

  • Peter H. Whincup

    (University of London)

  • Philippe Amouyel

    (Inserm U1167
    Institut Pasteur de Lille, U1167
    Université de Lille, U1167 - RID-AGE & Centre Hospitalier Universitaire de Lille, U1167)

  • Philippe Giral

    (Sorbonne Université, Cardiovascular Prevention Unit, Pitié Salpétrière Hospital)

  • Pramod Anugu

    (University of Mississippi Medical Center)

  • Quenna Wong

    (University of Washington)

  • Rainer Malik

    (University Hospital, Ludwig-Maximilians-University (LMU))

  • Rainer Rauramaa

    (Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine
    Kuopio University Hospital)

  • Ralph Burkhardt

    (University of Leipzig
    University of Leipzig
    University Hospital Regensburg)

  • Rebecca Hardy

    (MRC Unit for Lifelong Health and Ageing at UCL)

  • Reinhold Schmidt

    (Medical University of Graz)

  • Renée Mutsert

    (Leiden University Medical Center)

  • Richard W. Morris

    (Bristol Medical School, University of Bristol)

  • Rona J. Strawbridge

    (Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet
    University of Glasgow)

  • S. Goya Wannamethee

    (University College London)

  • Sara Hägg

    (Karolinska Institutet)

  • Sonia Shah

    (University College London)

  • Stela McLachlan

    (University of Edinburgh)

  • Stella Trompet

    (Leiden University Medical Center
    Leiden University Medical Center)

  • Sudha Seshadri

    (Boston University School of Medicine)

  • Sudhir Kurl

    (University of Eastern Finland, Kuopio Campus)

  • Susan R. Heckbert

    (University of Washington
    Kaiser Permanente Washington Health Research Institute)

  • Susan Ring

    (Bristol Medical School, University of Bristol
    MRC Integrative Epidemiology Unit at the University of Bristol)

  • Tamara B. Harris

    (Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health)

  • Terho Lehtimäki

    (Fimlab Laboratories
    University of Tampere School of Medicine)

  • Tessel E. Galesloot

    (Radboud University Medical Center)

  • Tina Shah

    (University College London)

  • Ulf Faire

    (Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet
    Karolinska University Hospital)

  • Vincent Plagnol

    (University College London)

  • Wayne D. Rosamond

    (University of North Carolina)

  • Wendy Post

    (Johns Hopkins University)

  • Xiaofeng Zhu

    (Case Western Reserve University)

  • Xiaoling Zhang

    (National Heart, Lung and Blood Institute’s Intramural Research Program, Framingham Heart Study
    Boston University)

  • Xiuqing Guo

    (Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
    Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center)

  • Yasaman Saba

    (Medical University of Graz)

  • Abbas Dehghan

    (Erasmus Medical Center
    Imperial College London)

  • Adrie Seldenrijk

    (Amsterdam University Medical Center)

  • Alanna C. Morrison

    (The University of Texas Health Science Center at Houston)

  • Anders Hamsten

    (Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet)

  • Bruce M. Psaty

    (Kaiser Permanente Washington Health Research Institute
    University of Washington)

  • Cornelia M. Duijn

    (Erasmus Medical Center
    University of Oxford)

  • Deborah A. Lawlor

    (Bristol Medical School, University of Bristol
    MRC Integrative Epidemiology Unit at the University of Bristol)

  • Dennis O. Mook-Kanamori

    (Leiden University Medical Center
    Leiden University Medical Center)

  • Donald W. Bowden

    (Wake Forest University School of Medicine)

  • Helena Schmidt

    (Medical University of Graz)

  • James F. Wilson

    (University of Edinburgh
    University of Edinburgh, Western General Hospital)

  • James G. Wilson

    (University of Mississippi Medical Center)

  • Jerome I. Rotter

    (Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
    Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center)

  • Joanna M. Wardlaw

    (University of Edinburgh
    and UK Dementia Research Institute at the University of Edinburgh)

  • John Deanfield

    (University College London)

  • Julian Halcox

    (Swansea University Medical School)

  • Leo-Pekka Lyytikäinen

    (Fimlab Laboratories
    University of Tampere School of Medicine)

  • Markus Loeffler

    (, University of Leipzig
    University of Leipzig)

  • Michele K. Evans

    (Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health)

  • Stéphanie Debette

    (Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, CHU Bordeaux)

  • Steve E. Humphries

    (Centre for Cardiovascular Genetics, Institute Cardiovascular Science, University College London)

  • Uwe Völker

    (DZHK (German Center for Cardiovascular Research), partner site Greifswald
    Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald)

  • Vilmundur Gudnason

    (Icelandic Heart Association
    University of Iceland)

  • Aroon D. Hingorani

    (University College London)

  • Johan L. M. Björkegren

    (The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai
    Clinical Gene Networks AB
    University of Tartu, Biomeedikum
    Karolinska Institutet, Karolinska Universitetssjukhuset)

  • Juan P. Casas

    (University College London)

  • Christopher J. O’Donnell

    (Intramural Administration Management Branch, National Heart, Lung, and Blood Institute, NIH
    Cardiology Section, Boston Veteran’s Administration Healthcare
    Harvard Medical School)

Abstract

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

Suggested Citation

  • Nora Franceschini & Claudia Giambartolomei & Paul S. Vries & Chris Finan & Joshua C. Bis & Rachael P. Huntley & Ruth C. Lovering & Salman M. Tajuddin & Thomas W. Winkler & Misa Graff & Maryam Kavousi , 2018. "GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07340-5
    DOI: 10.1038/s41467-018-07340-5
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