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Nat Commun. 2018 Dec 3;9(1):5141. doi: 10.1038/s41467-018-07340-5.

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

Franceschini N1, Giambartolomei C2, de Vries PS3, Finan C4, Bis JC5, Huntley RP4, Lovering RC4, Tajuddin SM6, Winkler TW7, Graff M1, Kavousi M8, Dale C9, Smith AV10,11, Hofer E12,13, van Leeuwen EM8, Nolte IM14, Lu L15, Scholz M16,17, Sargurupremraj M18, Pitkänen N19, Franzén O20,21, Joshi PK22, Noordam R23, Marioni RE24,25, Hwang SJ26,27, Musani SK28, Schminke U29, Palmas W30, Isaacs A8,31, Correa A28, Zonderman AB6, Hofman A8,32, Teumer A33,34, Cox AJ35,36, Uitterlinden AG8,37, Wong A38, Smit AJ39, Newman AB40, Britton A41, Ruusalepp A21,42,43, Sennblad B44,45, Hedblad B46, Pasaniuc B2,47, Penninx BW48, Langefeld CD15, Wassel CL49, Tzourio C18, Fava C46,50, Baldassarre D51,52, O'Leary DH53, Teupser D17,54, Kuh D38, Tremoli E52,55, Mannarino E56, Grossi E57, Boerwinkle E3,58, Schadt EE20,21, Ingelsson E59,60,61, Veglia F52, Rivadeneira F8,37, Beutner F62, Chauhan G18,63, Heiss G1, Snieder H14, Campbell H22, Völzke H33,34, Markus HS64, Deary IJ24,65, Jukema JW66, de Graaf J67, Price J22, Pott J16,17, Hopewell JC68, Liang J69, Thiery J17,70, Engmann J4, Gertow K44, Rice K71, Taylor KD72, Dhana K73, Kiemeney LALM74, Lind L75, Raffield LM76, Launer LJ6, Holdt LM17,54, Dörr M34,77, Dichgans M78,79, Traylor M64, Sitzer M80, Kumari M41,81, Kivimaki M41, Nalls MA82,83, Melander O46, Raitakari O19,84, Franco OH8,85, Rueda-Ochoa OL8,86, Roussos P20,87,88, Whincup PH89, Amouyel P90,91,92, Giral P93, Anugu P28, Wong Q94, Malik R78, Rauramaa R95,96, Burkhardt R17,97,98, Hardy R38, Schmidt R12, de Mutsert R99, Morris RW100, Strawbridge RJ44,101, Wannamethee SG102, Hägg S103, Shah S4, McLachlan S22, Trompet S23,66, Seshadri S104, Kurl S105, Heckbert SR5,106, Ring S107,108, Harris TB6, Lehtimäki T109,110, Galesloot TE74, Shah T4, de Faire U111,112, Plagnol V113, Rosamond WD1, Post W114, Zhu X69, Zhang X27,115, Guo X72,116, Saba Y117; MEGASTROKE Consortium, Dehghan A8,118, Seldenrijk A119, Morrison AC3, Hamsten A44, Psaty BM106,120, van Duijn CM8,68, Lawlor DA107,108, Mook-Kanamori DO99,121, Bowden DW122, Schmidt H117, Wilson JF22,123, Wilson JG124, Rotter JI72,116, Wardlaw JM24,125, Deanfield J4, Halcox J126, Lyytikäinen LP109,110, Loeffler M16,17, Evans MK6, Debette S18, Humphries SE127, Völker U34,128, Gudnason V10,11, Hingorani AD4, Björkegren JLM129,130,131,132, Casas JP9, O'Donnell CJ133,134,135.

Collaborators (145)

Okada Y, Mishra A, Rutten-Jacobs L, Giese AK, van der Laan SW, Gretarsdottir S, Anderson CD, Chong M, Adams HHH, Ago T, Almgren P, Amouyel P, Ay H, Bartz TM, Benavente OR, Bevan S, Boncoraglio GB, Brown RD Jr, Butterworth AS, Carrera C, Carty CL, Chasman DI, Chen WM, Cole JW, Cotlarciuc I, Cruchaga C, Danesh J, de Bakker PIW, DeStefano AL, den Hoed M, Duan Q, Engelter ST, Falcone GJ, Gottesman RF, Grewal RP, Gustafsson S, Haessler J, Harris TB, Hassan A, Havulinna AS, Holliday EG, Howard G, Hsu FC, Hyacinth HI, Ikram MA, Irvin MR, Jian X, Jiménez-Conde J, Johnson JA, Jukema JW, Kanai M, Keene KL, Kissela BM, Kleindorfer DO, Kooperberg C, Kubo M, Lange L, Langefeld CD, Langenberg C, Lee JM, Lemmens R, Leys D, Lewis CM, Lin WY, Lindgren AG, Lorentzen E, Magnusson PK, Maguire J, Manichaikul A, McArdle PF, Meschia JF, Mosley TH, Ninomiya T, O'Donnell MJ, Pulit SL, Rannikmäe K, Reiner AP, Rexrode KM, Rich SS, Ridker PM, Rost NS, Rothwell PM, Rundek T, Sacco RL, Sakaue S, Sale MM, Salomaa V, Sapkota BR, Schmidt R, Schmidt CO, Schminke U, Sharma P, Slowik A, Sudlow CLM, Tanislav C, Tatlisumak T, Thijs VNS, Thorleifsson G, Thorsteinsdottir U, Tiedt S, Trompet S, Walters M, Wareham NJ, Wassertheil-Smoller S, Wiggins KL, Yang Q, Yusuf S, Pastinen T, Ruusalepp A, Schadt EE, Koplev S, Codoni V, Civelek M, Smith N, Trégouët DA, Christophersen IE, Roselli C, Lubitz SA, Ellinor PT, Tai ES, Kooner JS, Kato N, He J, van der Harst P, Elliott P, Chambers JC, Takeuchi F, Johnson AD, Sanghera DK, Melander O, Jern C, Strbian D, Fernandez-Cadenas I, Longstreth WT Jr, Rolfs A, Hata J, Woo D, Rosand J, Pare G, Saleheen D, Stefansson K, Worrall BB, Kittner SJ, Howson JMM, Kamatani Y.

Author information

1
Department of Epidemiology, University of North Carolina, Chapel Hill, NC, 27516, USA.
2
Department of Pathology and Laboratory Medicine, University of California (UCLA), Los Angeles, Los Angeles, CA, 90095, USA.
3
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
4
Institute of Cardiovascular Science, University College London, London, WC1 6BT, UK.
5
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, 98101, USA.
6
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 20892, USA.
7
Department of Genetic Epidemiology, University of Regensburg, Regensburg, 93053, Germany.
8
Department of Epidemiology, Erasmus Medical Center, Rotterdam, 3015, The Netherlands.
9
Institute of Health Informatics, University College London, London, WC1E 6BT, UK.
10
Icelandic Heart Association, Kopavogur, IS-201, Iceland.
11
University of Iceland, Reykjavik, 101, Iceland.
12
Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, 8036, Austria.
13
Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, 8036, Austria.
14
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, 3015, The Netherlands.
15
Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.
16
Institute for Medical Informatics, Statistics and Epidemiology, , University of Leipzig, Leipzig, 04107, Germany.
17
LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, 04107, Germany.
18
Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, CHU Bordeaux, F-33000, Bordeaux, France.
19
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, 20520, Finland.
20
Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
21
Clinical Gene Networks AB, Stockholm, 104 62, Sweden.
22
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, EH8 9AG, UK.
23
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, 2300, RC, The Netherlands.
24
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
25
Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
26
Population Sciences Branch, Division of Intramural Research, NHLBI, NIH, Framingham, MA, 01702-5827, USA.
27
National Heart, Lung and Blood Institute's Intramural Research Program, Framingham Heart Study, Framingham, MA, 01702-5827, USA.
28
Department of Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
29
Department of Neurology, University Medicine Greifswald, Greifswald, 17475, Germany.
30
Department of Medicine, Columbia University, New York, NY, 10032, USA.
31
Department of Biochemistry, Maastricht Centre for Systems Biology (MaCSBio), CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, 6229, The Netherlands.
32
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
33
Institute for Community Medicine, University Medicine Greifswald, Greifswald, 17475, Germany.
34
DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, 17475, Germany.
35
Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, 25157, USA.
36
Menzies Health Institute Queensland, Griffith University, Southport, QLD, 4222, Australia.
37
Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, 3015, The Netherlands.
38
MRC Unit for Lifelong Health and Ageing at UCL, London, WC1E 6BT, UK.
39
Department of Medicine, University of Groningen, University Medical Center Groningen, Groningen, 2300, The Netherlands.
40
Department of Epidemiology, and School of Medicine, Division of Geriatric Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
41
Department of Epidemiology and Public Health, University College London, London, WC1E 6BT, UK.
42
Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Biomeedikum, Tartu, 51010, Estonia.
43
Department of Cardiac Surgery, Tartu University Hospital, Tartu, 51010, Estonia.
44
Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, 17177, Sweden.
45
Department of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, 75108, Sweden.
46
Department of Clinical Sciences in Malmö, Lund University, Malmö, SE-205 02, Sweden.
47
Department of Human Genetics, University of California (UCLA), Los Angeles, CA, 90095, USA.
48
Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, 1081, HL, The Netherlands.
49
Applied Sciences, Premier, Inc., Charlotte, NC, 28277, USA.
50
Department of Medicine, University of Verona, Verona, 37134, Italy.
51
Department of Medical Biotechnology and Translational Medicine, Università di Milano, Milan, 20133, Italy.
52
Centro Cardiologico Monzino, IRCCS, Milan, 20138, Italy.
53
St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, 02135, USA.
54
Institute of Laboratory Medicine, University Hospital Munich, LMU Munich, 80539, Germany.
55
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, 20133, Italy.
56
Department of Clinical and Experimental Medicine, Internal Medicine, Angiology and Arteriosclerosis Diseases, University of Perugia, Perugia, 06123, Italy.
57
Centro Diagnostico Italiano, Milan, 20147, Italy.
58
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030-3411, USA.
59
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, 94309, USA.
60
Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala, 75185, Sweden.
61
Stanford Cardiovascular Institute, Stanford University, Stanford, CA, G1120, USA.
62
Heart Center Leipzig, Leipzig, 04103, Germany.
63
Centre for Brain Research, Indian Institute of Science, Bangalore, 560012, India.
64
Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ, UK.
65
Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
66
Department of Cardiology, Leiden University Medical Center, Leiden, 2300, RC, The Netherlands.
67
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, 6525, GA, The Netherlands.
68
Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK.
69
Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA.
70
Institute for Laboratory Medicine, University of Leipzig, Leipzig, 04109, Germany.
71
Department of Biostatistics, University of Washington, Seattle, WA, 98105, USA.
72
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
73
Department of Internal Medicine, Rush University Medical Center, Chicago, IL, 60612, USA.
74
Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, GA, 6525, The Netherlands.
75
Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, 751 05, Sweden.
76
Department of Genetics, University of North Carolina, Chapel Hill, NC, 27516, USA.
77
Department of Internal Medicine B, University Medicine Greifswald, Greifswald, 17475, Germany.
78
Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU), Munich, 80539, Germany.
79
Munich Cluster for Systems Neurology (SyNergy), Munich, 81377, Germany.
80
Department of Neurology, Center for Neurology and Neurosurgery, Johann Wolfgang Goethe-University, Frankfurt am Main, 60323, Germany.
81
Institute for Social and Economic Research, Essex University, Colchester, CO4 3SQ, UK.
82
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
83
Data Tecnica International, Glen Echo, MD, 20812, USA.
84
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, 20521, Finland.
85
Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, 3012, Switzerland.
86
Electrocardiography Research Group, School of Medicine, Universidad Industrial de Santander, Bucaramanga, Santander, 680003, Colombia.
87
Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
88
Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, New York, NY, 10468, USA.
89
Population Health Research Institute, St George's, University of London, London, SW17 0RE, UK.
90
Inserm U1167, F-59000, Lille, France.
91
Institut Pasteur de Lille, U1167, F-59000, Lille, France.
92
Université de Lille, U1167 - RID-AGE & Centre Hospitalier Universitaire de Lille, U1167, F-59000, Lille, France.
93
Sorbonne Université, Cardiovascular Prevention Unit, Pitié Salpétrière Hospital, Paris, 75013, France.
94
Collaborative Health Studies Coordinating Center, Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA.
95
Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, 70100, Finland.
96
Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, 70210, Finland.
97
Institute of Laboratory Medicine, University of Leipzig, Leipzig, 04109, Germany.
98
Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, 93053, Germany.
99
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2333, The Netherlands.
100
Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 1QU, UK.
101
Mental Health and Wellbeing, Institute of Health and Wellbeing, University of Glasgow, Glasgow, G12 0XH, UK.
102
Department of Primary Care & Population Health, University College London, London, WC1E 6BT, UK.
103
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SE-171 77, Sweden.
104
Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA.
105
Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio Campus, Kuopio, FI-70210, Finland.
106
Kaiser Permanente Washington Health Research Institute, Seattle, WA, 98101, USA.
107
Population Health Science, Bristol Medical School, University of Bristol, Bristol, BS8 1QU, UK.
108
MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, BS8 1TH, UK.
109
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33014, Finland.
110
Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, 33014, Finland.
111
Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, S-171 77, Sweden.
112
Department of Cardiology, Karolinska University Hospital, Stockholm, S-171 77, Sweden.
113
Genetics Institute, University College London, London, WC1E 6BT, UK.
114
Departments of Medicine and Epidemiology, Johns Hopkins University, Baltimore, MD, 21205, USA.
115
Section of Biomedical Genetics, School of Medicine, Boston University, Boston, MA, 02215, USA.
116
Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
117
Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, Graz, 8010, Austria.
118
Department of Epidemiology & Biostatistics, Imperial College London, London, SW7 2AZ, UK.
119
GGZ inGeest and Amsterdam Public Health Research Institute, Department of Psychiatry, Amsterdam University Medical Center, Amsterdam, 1081 HV, The Netherlands.
120
Cardiovascular Health Research Unit and Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, 98195, USA.
121
Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
122
Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.
123
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
124
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
125
Centre for Clinical Brain Sciences, and UK Dementia Research Institute at the University of Edinburgh, Edinburgh, EH16 4SB, UK.
126
Swansea University Medical School, Swansea, SA2 8PP, UK.
127
Centre for Cardiovascular Genetics, Institute Cardiovascular Science, University College London, London, WC1E 6BT, UK.
128
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, 17475, Germany.
129
Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. johan.bjorkegren@mssm.edu.
130
Clinical Gene Networks AB, Stockholm, 104 62, Sweden. johan.bjorkegren@mssm.edu.
131
Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Biomeedikum, Tartu, 51010, Estonia. johan.bjorkegren@mssm.edu.
132
Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset, Huddinge, SE-141 57, Sweden. johan.bjorkegren@mssm.edu.
133
Intramural Administration Management Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, 20892, USA. Christopher.ODonnell@va.gov.
134
Cardiology Section, Boston Veteran's Administration Healthcare, Boston, MA, 02130, USA. Christopher.ODonnell@va.gov.
135
Harvard Medical School, Boston, MA, 02115, USA. Christopher.ODonnell@va.gov.

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.

PMID:
30510157
PMCID:
PMC6277418
DOI:
10.1038/s41467-018-07340-5
[Indexed for MEDLINE]
Free PMC Article

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