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Am J Hum Genet. 2018 Nov 1;103(5):691-706. doi: 10.1016/j.ajhg.2018.09.009.

Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.

Ligthart S1, Vaez A2, Võsa U3, Stathopoulou MG4, de Vries PS5, Prins BP6, Van der Most PJ7, Tanaka T8, Naderi E9, Rose LM10, Wu Y11, Karlsson R12, Barbalic M13, Lin H14, Pool R15, Zhu G16, Macé A17, Sidore C18, Trompet S19, Mangino M20, Sabater-Lleal M21, Kemp JP22, Abbasi A23, Kacprowski T24, Verweij N25, Smith AV26, Huang T27, Marzi C28, Feitosa MF29, Lohman KK30, Kleber ME31, Milaneschi Y32, Mueller C33, Huq M7, Vlachopoulou E34, Lyytikäinen LP35, Oldmeadow C36, Deelen J37, Perola M38, Zhao JH39, Feenstra B40; LifeLines Cohort Study7, Amini M7; CHARGE Inflammation Working Group, Lahti J41, Schraut KE42, Fornage M43, Suktitipat B44, Chen WM45, Li X46, Nutile T47, Malerba G48, Luan J39, Bak T49, Schork N50, Del Greco M F51, Thiering E52, Mahajan A53, Marioni RE54, Mihailov E55, Eriksson J56, Ozel AB57, Zhang W58, Nethander M59, Cheng YC60, Aslibekyan S61, Ang W62, Gandin I63, Yengo L64, Portas L65, Kooperberg C66, Hofer E67, Rajan KB68, Schurmann C69, den Hollander W70, Ahluwalia TS71, Zhao J72, Draisma HHM73, Ford I74, Timpson N75, Teumer A76, Huang H77, Wahl S28, Liu Y30, Huang J78, Uh HW79, Geller F40, Joshi PK42, Yanek LR80, Trabetti E48, Lehne B81, Vozzi D82, Verbanck M83, Biino G84, Saba Y85, Meulenbelt I70, O'Connell JR60, Laakso M86, Giulianini F10, Magnusson PKE12, Ballantyne CM87, Hottenga JJ88, Montgomery GW16, Rivadineira F89, Rueedi R90, Steri M18, Herzig KH91, Stott DJ92, Menni C93, Frånberg M94, St Pourcain B95, Felix SB96, Pers TH97, Bakker SJL98, Kraft P77, Peters A99, Vaidya D80, Delgado G31, Smit JH32, Großmann V100, Sinisalo J101, Seppälä I35, Williams SR102, Holliday EG36, Moed M103, Langenberg C39, Räikkönen K104, Ding J105, Campbell H42, Sale MM45, Chen YI46, James AL106, Ruggiero D107, Soranzo N108, Hartman CA49, Smith EN109, Berenson GS110, Fuchsberger C51, Hernandez D111, Tiesler CMT52, Giedraitis V112, Liewald D113, Fischer K55, Mellström D56, Larsson A114, Wang Y115, Scott WR81, Lorentzon M116, Beilby J117, Ryan KA60, Pennell CE62, Vuckovic D118, Balkau B119, Concas MP82, Schmidt R120, Mendes de Leon CF121, Bottinger EP122, Kloppenburg M123, Paternoster L75, Boehnke M124, Musk AW125, Willemsen G88, Evans DM22, Madden PAF126, Kähönen M127, Kutalik Z128, Zoledziewska M18, Karhunen V129, Kritchevsky SB130, Sattar N131, Lachance G93, Clarke R132, Harris TB133, Raitakari OT134, Attia JR135, van Heemst D136, Kajantie E137, Sorice R47, Gambaro G138, Scott RA39, Hicks AA51, Ferrucci L8, Standl M139, Lindgren CM140, Starr JM141, Karlsson M142, Lind L114, Li JZ57, Chambers JC143, Mori TA62, de Geus EJCN15, Heath AC126, Martin NG16, Auvinen J144, Buckley BM145, de Craen AJM136, Waldenberger M146, Strauch K147, Meitinger T148, Scott RJ149, McEvoy M36, Beekman M103, Bombieri C48, Ridker PM150, Mohlke KL11, Pedersen NL12, Morrison AC151, Boomsma DI88, Whitfield JB16, Strachan DP152, Hofman A1, Vollenweider P153, Cucca F18, Jarvelin MR154, Jukema JW155, Spector TD93, Hamsten A156, Zeller T157, Uitterlinden AG158, Nauck M159, Gudnason V26, Qi L160, Grallert H28, Borecki IB161, Rotter JI162, März W163, Wild PS164, Lokki ML34, Boyle M165, Salomaa V38, Melbye M166, Eriksson JG167, Wilson JF168, Penninx BWJH32, Becker DM80, Worrall BB169, Gibson G72, Krauss RM170, Ciullo M107, Zaza G171, Wareham NJ39, Oldehinkel AJ49, Palmer LJ172, Murray SS173, Pramstaller PP174, Bandinelli S175, Heinrich J176, Ingelsson E177, Deary IJ178, Mägi R55, Vandenput L56, van der Harst P25, Desch KC179, Kooner JS180, Ohlsson C56, Hayward C181, Lehtimäki T35, Shuldiner AR60, Arnett DK182, Beilin LJ62, Robino A82, Froguel P183, Pirastu M65, Jess T184, Koenig W185, Loos RJF186, Evans DA68, Schmidt H187, Smith GD75, Slagboom PE103, Eiriksdottir G188, Morris AP189, Psaty BM190, Tracy RP191, Nolte IM7, Boerwinkle E192, Visvikis-Siest S4, Reiner AP193, Gross M194, Bis JC195, Franke L196, Franco OH197, Benjamin EJ198, Chasman DI150, Dupuis J199, Snieder H7, Dehghan A200, Alizadeh BZ201.

Author information

1
Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000 CA, the Netherlands.
2
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands; Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan 81746-73461, Iran.
3
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, Estonia.
4
Université de Lorraine, INSERM, IGE-PCV, 54000 Nancy, France.
5
Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000 CA, the Netherlands; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
6
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
7
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands.
8
Translational Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA.
9
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands; Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen 9713 GZ, the Netherlands.
10
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
11
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
12
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
13
University of Split School of Medicine, Split 21000, Croatia.
14
Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
15
Department of Biological Psychology, Netherlands Twin Register, Vrije Universiteit, Amsterdam 1081 BT, the Netherlands; Amsterdam Public Health research institute, VU University Medical Center, Amsterdam 1081 BT, the Netherlands.
16
QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
17
Department of Computational Biology, University of Lausanne, Lausanne 1010, Switzerland; Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland; Institute of Social and Preventive Medicine, University Hospital of Lausanne, Lausanne 1010, Switzerland.
18
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Sardinia 08045, Italy.
19
Department of Cardiology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands; Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
20
Department of Twin Research & Genetic Epidemiology, King's College London, London SE1 7EH, UK; NIHR Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust, London SE1 9RT, UK.
21
Unit of Genomics of Complex Diseases, Institut d'Investigació Biomèdica Sant Pau, Barcelona 08025, Spain; Cardiovascular Medicine Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm 17176, Sweden.
22
University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD 4102, Australia; MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK.
23
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands; Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen 9713 GZ, the Netherlands; MRC Epidemiology Unit, University of Cambridge School of Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
24
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Greifswald 17475, Germany; German Centre for Cardiovascular Research, Partner Site Greifswald, Greifswald 17475, Germany.
25
University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen 9713 AV, the Netherlands.
26
Icelandic Heart Association, Kopavogur 201, Iceland; Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.
27
Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
28
Institute of Epidemiology II, Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; German Center for Diabetes Research, Partner Site Munich, Munich 85764, Germany.
29
Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63108-2212, USA.
30
Department of Epidemiology and Prevention, Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.
31
Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany.
32
Department of Psychiatry, Amsterdam Neuroscience and Amsterdam Public Health Research Institute, Amsterdam University Medical Center/GGZ inGeest Research & Innovation, Amsterdam 1081 HJ, the Netherlands.
33
Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg 20246, Germany; Institute of Medical Biometry and Statistics, University Medical Center Schleswig-Holstein, Campus Luebeck, Lübeck 23562, Germany; German Center for Cardiovascular Research, Partner Site RhineMain, 55131 Mainz, Germany.
34
Transplantation Laboratory, Medicum, University of Helsinki, Helsinki 00014, Finland.
35
Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33014, Finland; Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere 33520, Finland.
36
Hunter Medical Research Institute, New Lambon Heights, NSW 2305, Australia; Centre for Clinical Epidemiology & Biostatistics, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia.
37
Molecular Epidemiology, Leiden University Medical Center, Leiden 2333 ZC, the Netherlands; Max Planck Institute for Biology of Ageing, Cologne 50931, Germany.
38
National Institute for Health and Welfare, Helsinki 00271, Finland.
39
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge CB2 0QQ, UK.
40
Department of Epidemiology Research, Statens Serum Institut, Copenhagen 2300, Denmark.
41
Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki 00014, Finland; Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland; Folkhälsan Research Centre, Helsinki 00250, Finland.
42
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH16 4UX, UK.
43
Human Genetics Center, School of Public Health and Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
44
Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
45
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
46
Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
47
Institute of Genetics and Biophysics "A. Buzzati-Traverso," Consiglio Nazionale delle Ricerche, Napoli 80131, Italy.
48
Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona 37134, Italy.
49
Interdisciplinary Center Psychopathology and Emotion regulation, University Medical Center Groningen, University of Groningen, Groningen 9700 RB, the Netherlands.
50
Human Biology, J. Craig Venter Institute, La Jolla, CA 92037, USA; Quantitative Medicine, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
51
Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano 39100, Italy.
52
Institute of Epidemiology, Helmholtz Zentrum München - German Research Centre for Environmental Health, Neuherberg 85764, Germany; Ludwig Maximilian University of Munich, Dr. von Hauner Children's Hospital, Munich 80337, Germany.
53
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
54
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
55
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, Estonia.
56
Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Gothenburg 41345, Sweden.
57
Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA.
58
Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK; Department of Cardiology, Ealing Hospital, Middlesex UB1 3HW, UK.
59
Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg 413 90, Sweden.
60
Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
61
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294-0022, USA.
62
Medical School, University of Western Australia, Perth, WA 6009, Australia.
63
AREA Science Park, Trieste 34149, Italy.
64
Centre National de la Recherche Scientifique UMR 8199, University of Lille, Institut Pasteur de Lille, European Genomic Institute for Diabetes, FR 3508, 59000 Lille, France; Program in Complex Trait Genomics, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia.
65
Support OU, Institute of Genetic and Biomedic Research, Consiglio Nazionale delle Ricerche, Sassari 7100, Italy.
66
Fred Hutchinson Cancer Research Center, Public Health Sciences Division, Mail Stop M3-A410, 1100 Fairview Ave. N., Seattle, WA, USA.
67
Clinical Division of Neurogeriatrics, Department of Neurology, Medical University Graz, Graz 8036, Austria; Institute of Medical Informatics, Statistics and Documentation, Medical University Graz, Graz 8036, Austria.
68
Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612, USA.
69
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
70
Department of Medical Statistics and Bio-informatics, Section Molecular Epidemiology, Leiden University Medical Center, Leiden 2333 ZC, the Netherlands.
71
Steno Diabetes Center Copenhagen, Gentofte 2820, Denmark; Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark.
72
Center for Integrative Genomics, School of Biology, Georgia Institute of Technology, Atlanta, GA 30332, USA.
73
Department of Biological Psychology, Netherlands Twin Register, Vrije Universiteit, Amsterdam 1081 BT, the Netherlands; Amsterdam Public Health research institute, VU University Medical Center, Amsterdam 1081 BT, the Netherlands; Neuroscience Campus Amsterdam, Amsterdam 1081 HV, the Netherlands.
74
Robertson Centre for Biostatistics, University of Glasgow, Glasgow G12 8QQ, UK.
75
MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK.
76
Department SHIP-KEF, Institute for Community Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
77
Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
78
Boston VA Research Institute, Inc., Boston, MA 02130, USA.
79
Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden 2333 ZC, the Netherlands.
80
GeneSTAR Research Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
81
Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK.
82
Institute for Maternal and Child Health, IRCCS "Burlo Garofolo," Trieste 34140, Italy.
83
Centre National de la Recherche Scientifique UMR 8199, University of Lille, Institut Pasteur de Lille, European Genomic Institute for Diabetes, FR 3508, 59000 Lille, France.
84
Institute of Molecular Genetics, Consiglio Nazionale delle Ricerche, Pavia 27100, Italy.
85
Gottfried Schatz Research Center, Institute for Molecular Biology and Biochemistry, 8010 Graz, Austria.
86
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio 70210, Finland.
87
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Methodist DeBakey Heart and Vascular Center, Houston, TX 77030, USA.
88
Department of Biological Psychology, Netherlands Twin Register, Vrije Universiteit, Amsterdam 1081 BT, the Netherlands.
89
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam 3015 CN, the Netherlands.
90
Department of Computational Biology, University of Lausanne, Lausanne 1010, Switzerland; Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland.
91
Department of Physiology, Institute of Biomedicine, University of Oulu, Medical Research Center Oulu and Oulu University Hospital, Oulu 90014, Finland; Biocenter Oulu, University of Oulu, Oulu 90220, Finland; Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan 60-512, Poland.
92
Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow G12 8QQ, UK.
93
Department of Twin Research & Genetic Epidemiology, King's College London, London SE1 7EH, UK.
94
Cardiovascular Medicine Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm 17176, Sweden; Department of Numerical Analysis and Computer Science, Stockholm University, Stockholm 100 44, Sweden.
95
MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK; Donders Institute, Radboud University, Nijmegen 6525 XD, the Netherlands.
96
German Centre for Cardiovascular Research, Partner Site Greifswald, Greifswald 17475, Germany; Department for Internal Medicine B, University Medicine Greifswald, Greifswald 17475, Germany.
97
Department of Epidemiology Research, Statens Serum Institut, Copenhagen 2300, Denmark; Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark.
98
Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen 9713 GZ, the Netherlands.
99
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherber 85764, Germany.
100
Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University Mainz, Mainz 55131, Germany.
101
Heart and Lung Center, Helsinki University Hospital and Helsinki University, Helsinki 00029, Finland.
102
Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA.
103
Molecular Epidemiology, Leiden University Medical Center, Leiden 2333 ZC, the Netherlands.
104
Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland.
105
Department of Internal Medicine/Geriatrics, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.
106
Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia; Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia.
107
Institute of Genetics and Biophysics "A. Buzzati-Traverso," Consiglio Nazionale delle Ricerche, Napoli 80131, Italy; IRCCS Neuromed, Pozzilli (IS) 86077, Italy.
108
Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
109
Department of Pediatrics and Rady Children's Hospital, School of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
110
Center for Cardiovascular Health, Tulane University, New Orleans, LA 70112, USA.
111
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.
112
Department of Public Health and Caring Sciences, Molecular Geriatrics, Uppsala University, Uppsala 752 37, Sweden.
113
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
114
Department of Medical Sciences, Uppsala University, Uppsala 751 41, Sweden.
115
Department of Medicine, Case Cardiovascular Research Institute, Case Western Reserve University, Harrington Heart & Vascular Institute, University Hospitals, Cleveland, OH 44106, USA.
116
Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Gothenburg 41345, Sweden; Geriatric Medicine, Sahlgrenska University Hospital, Mölndal 431 80, Sweden.
117
PathWest Laboratory Medicine WA, Nedlands, WA 6009, Australia; School of Biomedical Sciences, University of Western Australia, Crawley, Perth, WA 6009, Australia.
118
Medical Sciences, Surgical and Health Department, University of Trieste, Trieste 34137, Italy.
119
INSERM U1018, Centre de Recherche en Epidémiologie et Santé des Populations, Team 5 (EpReC, Renal, and Cardiovascular Epidemiology), Université de Versailles Saint-Quentin-en-Yvelines, Université Paris-Saclay, Villejuif 94807, France.
120
Clinical Division of Neurogeriatrics, Department of Neurology, Medical University Graz, Graz 8036, Austria.
121
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
122
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
123
Department of Rheumatology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2333 ZC, the Netherlands.
124
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
125
Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia; Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia.
126
Department of Psychiatry, Washington University School of Medicine, 4560 Clayton Ave., Suite 1000, St. Louis, MO 63110, USA.
127
Department of Clinical Physiology, Tampere University Hospital, Tampere 33520, Finland; Department of Clinical Physiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere 33520, Finland.
128
Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland; Institute of Social and Preventive Medicine, University Hospital of Lausanne, Lausanne 1010, Switzerland.
129
Center for Life Course Health Research, Faculty of Medicine, University of Oulu, 90014 Oulun yliopisto, Finland.
130
Gerontology and Geriatric Medicine, Sticht Center on Aging and Rehabilitation, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.
131
BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, Glasgow G12 8TA, UK.
132
Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK.
133
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USA.
134
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku 20520, Finland; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland.
135
Hunter Medical Research Institute, New Lambon Heights, NSW 2305, Australia; Centre for Clinical Epidemiology & Biostatistics, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia; John Hunter Hospital, New Lambton Heights, NWS 2305, Australia.
136
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
137
Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki 00014, Finland; Hospital for Children and Adolescents, Helsinki University Central Hospital and University of Helsinki, Helsinki 00290, Finland; Department of Obstetrics and Gynaecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu 90014, Finland.
138
Division of Nephrology and Dialysis, Columbus-Gemelli University Hospital, Università Cattolica del Sacro Cuore, Roma 168, Italy.
139
Institute of Epidemiology, Helmholtz Zentrum München - German Research Centre for Environmental Health, Neuherberg 85764, Germany.
140
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7FZ, UK; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
141
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Alzheimer's Scotland Dementia Research Centre, University of Edinburgh, Edinburgh EH8 9JZ, UK.
142
Department of Clinical Sciences and Orthopaedic Surgery, Lund University, Malmo 20502, Sweden.
143
Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK; Department of Cardiology, Ealing Hospital, Middlesex UB1 3HW, UK; Imperial College Healthcare NHS Trust, London W12 0HS, UK; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore; MRC-PHE Centre for Environment and Health, Imperial College London, London W2 1PG, UK.
144
Center for Life Course Health Research, Faculty of Medicine, University of Oulu, 90014 Oulun yliopisto, Finland; Unit of Primary Health Care, Oulu University Hospital, Oulu 90220, Finland.
145
Department of Epidemiology and Public Health, University College Cork, Cork T12 K8AF, Ireland.
146
Institute of Epidemiology II, Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, 80636 Munich, Germany.
147
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; Genetic Epidemiology, Institute of Medical Informatics, Biometry, and Epidemiology, Faculty of Medicine, Ludwig Maximilian University of Munich, Neuherberg 85764, Germany.
148
Institute of Human Genetics, Technische Universität München, Munich 85764, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg 85764, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich 81377, Germany.
149
Hunter Medical Research Institute, New Lambon Heights, NSW 2305, Australia; Information-Based Medicine Stream, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia.
150
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA.
151
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
152
Population Health Research Institute, St. George's, University of London, London SW17 0RE, UK.
153
Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland.
154
Biocenter Oulu, University of Oulu, Oulu 90220, Finland; Center for Life Course Health Research, Faculty of Medicine, University of Oulu, 90014 Oulun yliopisto, Finland; Unit of Primary Health Care, Oulu University Hospital, Oulu 90220, Finland; Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London W2 1PG, UK; Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Kingston Lane, Uxbridge, Middlesex UB8 3PH, UK.
155
Department of Cardiology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands; Durrer Center for Cardiogenetic Research, Amsterdam 3501 DG, the Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht 3511 EP, the Netherlands.
156
Cardiovascular Medicine Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm 17176, Sweden.
157
Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg 20246, Germany; German Center for Cardiovascular Research, Partner Site RhineMain, 55131 Mainz, Germany.
158
Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000 CA, the Netherlands; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam 3015 CN, the Netherlands.
159
German Centre for Cardiovascular Research, Partner Site Greifswald, Greifswald 17475, Germany; Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
160
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
161
Analytical Genetics Group, Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA.
162
Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
163
Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany; Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim 68161, Germany; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8036, Austria.
164
German Center for Cardiovascular Research, Partner Site RhineMain, 55131 Mainz, Germany; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University Mainz, Mainz 55131, Germany; Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany.
165
John Hunter Hospital, New Lambton Heights, NWS 2305, Australia.
166
Department of Epidemiology Research, Statens Serum Institut, Copenhagen 2300, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen 2300, Denmark; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
167
National Institute for Health and Welfare, Helsinki 00271, Finland; Folkhälsan Research Centre, Helsinki 00250, Finland; Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki 00014, Finland.
168
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH16 4UX, UK; MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
169
Departments of Neurology and Public Health Sciences, University of Virginia Charlottesville, Charlottesville, VA 22908-0394, USA.
170
Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
171
Renal Unit, Department of Medicine, Verona University Hospital, Verona 37126, Italy.
172
School of Public Health, University of Adelaide, Adelaide, SA 5000, Australia.
173
Department of Pathology, University of California, San Diego, San Diego, CA 92121, USA.
174
Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano 39100, Italy; General Central Hospital, Department of Neurology, Bolzano 39100, Italy; Department of Neurology, University of Lübeck, Lübeck 23538, Germany.
175
Geriatric Unit, Azienda Sanitaria Firenze, Florence 50122, Italy.
176
Institute of Epidemiology, Helmholtz Zentrum München - German Research Centre for Environmental Health, Neuherberg 85764, Germany; Institute and Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich, Member DZL, German Center for Lung Research, 81377 Munich, Germany.
177
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala 751 41, Sweden; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cardiovascular Institute, Stanford University, Stanford, CA 94305, USA.
178
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
179
Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109, USA.
180
Department of Cardiology, Ealing Hospital, Middlesex UB1 3HW, UK; Imperial College Healthcare NHS Trust, London W12 0HS, UK; MRC-PHE Centre for Environment and Health, Imperial College London, London W2 1PG, UK; National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
181
MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
182
University of Kentucky, College of Public Health, Lexington, KY 40508, USA.
183
Centre National de la Recherche Scientifique UMR 8199, University of Lille, Institut Pasteur de Lille, European Genomic Institute for Diabetes, FR 3508, 59000 Lille, France; Department of Genomics of Common Disease, School of Public Health, Imperial College London, London SW7 2AZ, UK.
184
Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg 2200, Denmark.
185
German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, 80636 Munich, Germany; Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, 80801 Ulm, Germany; Deutsches Herzzentrum München, Technische Universität München, 80636 Munich, Germany.
186
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6542, USA.
187
Department of Neurology, Medical University Graz, Graz 8010, Austria; Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, Graz 8010, Austria.
188
Icelandic Heart Association, Kopavogur 201, Iceland.
189
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Department of Biostatistics, University of Liverpool, Liverpool L69 3GL, UK.
190
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA; Department of Epidemiology, University of Washington, Seattle, WA 98101, USA; Department of Health Services, University of Washington, Seattle, WA 98195-7660, USA; Kaiser Permanente Washington Health Research Institute, Seattle, WA 98101, USA.
191
Department of Pathology, University of Vermont, Colchester, VT 05405, USA.
192
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
193
Department of Epidemiology, University of Washington, Seattle, WA 98101, USA.
194
Department of Lab Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
195
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
196
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands.
197
Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000 CA, the Netherlands; Institute of Social and Preventive Medicine, University of Bern, 3012 Bern, Switzerland.
198
Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA 01702, USA.
199
National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA 01702, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
200
Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000 CA, the Netherlands; Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London W2 1PG, UK. Electronic address: a.dehghan@imperial.ac.uk.
201
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands. Electronic address: b.z.alizadeh@umcg.nl.

Abstract

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

KEYWORDS:

C-reactive protein; DEPICT; Mendelian randomization; coronary artery disease; genome-wide association study; inflammation; inflammatory disorders; schizophrenia; system biology

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