Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders - Université de Lorraine Access content directly
Journal Articles American Journal of Human Genetics Year : 2018

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

Symen Ligthart (1) , Ahmad Vaez (2, 3) , Urmo Võsa (2, 4) , Maria Stathopoulou (5) , Paul de Vries (1, 6) , Peter van Der Most (2) , Toshiko Tanaka (7) , Elnaz Naderi (2) , Lynda Rose (8) , Ying Wu (9) , Robert Karlsson (10) , Maja Barbalic (11) , Honghuang Lin (12) , René Pool (13) , Gu Zhu , Aurélien Macé (14) , Carlo Sidore , Stella Trompet (15) , Massimo Mangino (16) , Maria Sabater-Lleal , John Kemp , Tim Kacprowski , Niek Verweij , Albert Smith , Tao Huang (17) , Carola Marzi , Mary F. Feitosa (18) , Kurt Lohman , Marcus Kleber , Yuri Milaneschi (19) , Christian Mueller (20) , Mahmudul Huq , Efthymia Vlachopoulou , Leo-Pekka Lyytikäinen , Christopher Oldmeadow , Joris Deelen (21) , Jing Hua Zhao (22) , Bjarke Feenstra , Marzyeh Amini , Jari Lahti , Katharina Schraut , Myriam Fornage (6) , Bhoom Suktitipat (23) , Wei-Min Chen (24) , Xiaohui Li (25) , Teresa Nutile (26) , Giovanni Malerba (27) , Jian’an Luan , Tom Bak , Nicholas J. Schork (28) , Fabiola del Greco M. , Elisabeth Thiering , Anubha Mahajan (29) , Riccardo Marioni , Evelin Mihailov , Joel Eriksson (30) , Ayse Bilge Ozel , Weihua Zhang (31) , Maria Nethander , Yu-Ching Cheng (32) , Stella Aslibekyan , Wei Ang , Ilaria Gandin , Loïc Yengo (33) , Laura Portas (34) , Charles Kooperberg , Edith Hofer , Kumar Rajan , Claudia Schurmann (35) , Wouter den Hollander , Tarunveer S Ahluwalia (36) , Jing Zhao , Harmen H.M. Draisma , Ian Ford (37) , Nicholas J. Timpson (38) , Alexander Teumer (16) , Hongyan Huang , Simone Wahl , Yongmei Liu (39) , Jie Huang (40) , Hae-Won Uh (41) , Frank Geller , Peter Joshi , Lisa Yanek (42) , Elisabetta Trabetti (27) , Benjamin Lehne , Diego Vozzi , Marie Verbanck , Ginevra Biino (43) , Yasaman Saba , Ingrid Meulenbelt (44) , Jeff O’connell , Markku Laakso (45) , Franco Giulianini , Patrik K.E. Magnusson , Christie Ballantyne , Jouke Jan Hottenga (46) , Grant W. Montgomery (46) , Fernando Rivadineira , Rico Rueedi , Maristella Steri , Karl-Heinz Herzig , David Stott , Cristina Menni , Mattias Frånberg , Beate St. Pourcain , Stephan B. Felix (47) , Tune H. Pers (48) , Stephan J.L. Bakker (49) , Peter Kraft (50) , Annette Peters (51) , Dhananjay Vaidya (52) , Graciela Delgado , Johannes Smit (46) , Vera Grossmann , Juha Sinisalo , Ilkka Seppälä , Stephen Williams (53) , Elizabeth Holliday , Matthijs Moed , Claudia Langenberg (54) , Katri Räikkönen (46) , Jingzhong Ding , Harry Campbell (55) , Michele Sale , Yii-Der Chen , Alan James (56) , Daniela Ruggiero (57) , Nicole Soranzo (16) , Catharina Hartman (46) , Erin N. Smith (58) , Gerald Berenson (59) , Christian Fuchsberger (60) , Dena Hernandez (61) , Carla M.T. Tiesler , Vilmantas Giedraitis (62) , David C Liewald (55) , Krista Fischer (63) , Dan Mellström , Anders Larsson (64) , Yunmei Wang , William Scott , Matthias Lorentzon , John Beilby , Kathleen Ryan , Craig Pennell , Dragana Vuckovic , Beverly Balkau (65) , Maria Pina Concas , Reinhold Schmidt (66) , Carlos Mendes de Leon , Erwin Bottinger (67) , Margreet Kloppenburg (68) , Lavinia Paternoster , Michael Boehnke (69) , A.W. Musk , Gonneke Willemsen (46) , David Evans (70) , Pamela A.F. Madden , Mika Kähönen (71) , Zoltán Kutalik (72) , Magdalena Zoledziewska , Ville Karhunen , Stephen Kritchevsky , Naveed Sattar (73) , Genevieve Lachance , Robert Clarke (74) , Tamara B. Harris (7) , Olli Raitakari (71) , John Attia (75) , Diana van Heemst (76) , Eero Kajantie , Rossella Sorice (26) , Giovanni Gambaro , Robert A. Scott (77) , Luigi Ferrucci (46) , Marie Standl , Cecilia Lindgren (78) , John M Starr (55) , Magnus Karlsson (79) , Lars Lind (80) , Jun Li , John Chambers (16) , Trevor Mori , Eco J.C.N. de Geus , Andrew Heath , Nicholas Martin (81) , Juha Auvinen , Brendan Buckley , Anton J.M. de Craen (82) , Melanie Waldenberger (51) , Konstantin Strauch (83) , Thomas Meitinger (84) , Rodney J Scott (85) , Mark Mcevoy , Marian Beekman , Cristina Bombieri , Paul Ridker (8) , Karen L. Mohlke (86) , Nancy L. Pedersen (10) , Dorret I. Boomsma (87) , John Whitfield (81) , David P. Strachan (88) , Albert Hofman (1) , Peter Vollenweider (89) , Francesco Cucca , Marjo-Riitta Järvelin (90) , J. Wouter Jukema (52) , Tim Spector , Anders Hamsten (91) , Tanja Zeller (92) , Matthias Nauck (93) , Vilmundur Gudnason (94) , Lu Qi (95) , Harald Grallert (96) , Ingrid B. Borecki (18) , Winfried März (97) , Philipp S. Wild (92) , Marja-Liisa Lokki (98) , Michael Boyle , Veikko Salomaa (99) , Mads Melbye (100) , Brenda W.J.H. Penninx (101) , Diane Becker , Bradford Worrall , Greg Gibson , Ronald Krauss , Marina Ciullo (26) , Gianluigi Zaza , Nicholas J. Wareham (77) , Albertine Oldehinkel , Lyle Palmer , Sarah Murray , Peter Pramstaller (102) , Stefania Bandinelli (103) , Joachim Heinrich (104) , Erik Ingelsson (10) , Ian Deary (52) , Reedik Mägi , Liesbeth Vandenput , Karl Desch , Jaspal Kooner , Claes Ohlsson (105) , Caroline Hayward (106) , Alan Shuldiner (107) , Donna Arnett , Lawrence Beilin , Antonietta Robino , Philippe Froguel (108) , Mario Pirastu (43) , Tine Jess , Ruth J.F. Loos , Denis Evans , Helena Schmidt (109) , George Davey Smith (110) , P. Eline Slagboom (111) , Sophie Visvikis-Siest (5) , Alex Reiner (112) , Joshua Bis (113) , Oscar Franco (114) , H. Marike Boezen (115) , Pim van Der Harst (116) , Gerjan Navis (49) , Marianne Rots , Morris Swertz (117) , Bruce H.R. Wolffenbuttel , Cisca Wijmenga (118) , Emelia Benjamin , Daniel Chasman (8) , Abbas Dehghan , Tarunveer Singh Ahluwalia , James Meigs , Russell Tracy , Behrooz Alizadeh , Josh Bis , Gudny Eiriksdottir (119) , Nathan Pankratz , Myron Gross , Alex Rainer , Harold Snieder (16) , James Wilson (120) , Bruce Psaty (121) , Josée Dupuis (12) , Bram Prins (122) , Urmo Vaso , Lude Franke , Terho Lehtimäki (123) , Wolfgang Koenig (124) , Yalda Jamshidi , Sophie Siest , Ali Abbasi , Andre Uitterlinden (1) , Mohammadreza Abdollahi , Renate B. Schnabel (92) , Ursula Schick , Ilja Nolte (116) , Aldi Kraja , Yi-Hsiang Hsu , Daniel Tylee , Alyson Zwicker , Rudolf Uher (125) , George Davey-Smith (126) , Alanna Morrison , Andrew Hicks (60) , Cornelia M. van Duijn (127) , Cavin Ward-Caviness , Eric Boerwinkle (6) , Jerome Rotter (128) , Ken Rice , Leslie Lange (129) , Markus Perola (130) , Eco de Geus (87) , Andrew Morris (131) , Kari Matti Makela , David Stacey (132) , Johan Eriksson (46) , Tim Frayling , Eline Slagboom (44)
1 Erasmus MC - Erasmus University Medical Center [Rotterdam]
2 UMCG - University Medical Center Groningen [Groningen]
3 University of Isfahan
4 University of Tartu
5 IGE-PCV - Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire
6 UTHealth - The University of Texas Health Science Center at Houston
7 NIA - National Institute on Aging [Bethesda, USA]
8 Brigham and Women's Hospital [Boston]
9 UNC - University of North Carolina [Chapel Hill]
10 MEB - Department of Medical Epidemiology and Biostatistics
11 University of Split
12 BUSM - Boston University School of Medicine
13 Process & Energy Laboratory
14 Grand Lyon : communauté urbaine de Lyon
15 Interuniversity Cardiology Institute Netherlands
16 King‘s College London
17 HUST - Huazhong University of Science and Technology [Wuhan]
18 Division of Statistical Genomics
19 Department of Psychiatry
20 Institut fuer Theoretische Physik - Institut fuer Theoretische Physik
21 Molecular Epidemiology
22 MRC Epidemiology Unit, Institute of Metabolic Science
23 Mahidol University [Bangkok]
24 Northwest A and F University
25 LOSI - Laboratoire d'Optimisation des Systèmes Industriels
26 Institute of Genetics and Biophysics, CNR, Naples
27 UNIVR - Università degli studi di Verona = University of Verona
28 Department of Molecular Medicine [Scripps Research Institute]
29 Department of Physics
30 Deptartment of Medical Biochemistry and Microbiology
31 ECE - Department of Electrical and Computer Engineering [Waterloo]
32 University of Maryland School of Medicine
33 INERIS - Institut National de l'Environnement Industriel et des Risques
34 Institute of Pop. Genetics, CNR, Sassari
35 Interfaculty Institute for Genetics and Functional Genomics
36 ITU - IT University of Copenhagen
37 Robertson Centre for Biostatistics, University of Glasgow
38 Centre for Causal Analyses in Translational Epidemiology
39 Jinan University [Guangzhou]
40 Institute of Oceanology [China]
41 School Medicine
42 General Internal Medicine, Johns Hopkins School of Medicine
43 Institute of Pop. Genetics, CNR, Sassari;Shardna life science Pula Cagliari
44 Section Molecular Epidemiology, Leiden University Medical Center (LUMC)
45 Department of Medicine
46 Medstar Research Institute
47 Department of Cardiology
48 Center for Biological Sequence Analysis [Lyngby]
49 Department of Internal Medicine
50 Department of Epidemiology
51 German Research Center for Environmental Health - Helmholtz Center München (GmbH)
52 Metacohorts Consortium
53 INEOS Technologies (SWITZERLAND)
54 MRC Epidemiology Unit
55 University of Edinburgh
56 School of Population Health [Crawley, Western Australia]
57 Institute of Genetics and Biophysics
58 The Scripps Translational Science Institute and Scripps Health
59 Tulane Center for Cardiovascular Health
60 Centre for Population Health Sciences
61 Genomic Research Laboratory, Service of Infectious Disease
62 Uppsala University
63 Infectious diseases division, Department of internal medicine
64 LUT - Luleå University of Technology
65 Recherche en épidémiologie et biostatistique
66 AIT - Austrian Institute of Technology [Vienna]
67 MSSM - Icahn School of Medicine at Mount Sinai [New York]
68 Department of Rheumatology and Clinical Epidemiology, Leiden University Medical Center (LUMC)
69 Department of Biostatistics and Center for Statistical Genetics
70 University of Virginia
71 Tampere University Hospital
72 Department of Medical Genetics
73 Department of Pathological Biochemistry
74 Oxford University
75 UoN - University of Newcastle [Callaghan, Australia]
76 Department of neurology
77 Institute of Metabolic Science
78 The Wellcome Trust Centre for Human Genetics [Oxford]
79 DTU - Danmarks Tekniske Universitet = Technical University of Denmark
80 Uppsala Universitet [Uppsala]
81 QIMR Berghofer Medical Research Institute
82 Molecular Epidemiology
83 Institute of Genetic Epidemiology [Neuherberg, Germany]
84 Institute of Human Genetics
85 Schizophrenia Research Institute [Sydney]
86 Department of Genetics
87 VUB - Vrije Universiteit Brussel
88 Population Health Sciences and Education
89 Department of Internal Medicine
90 Institute of Health Sciences and Biocenter Oulu
91 Karolinska Institutet [Stockholm]
92 Medizinische Klinik und Poliklinik
93 Institute of Clinical Chemistry and Laboratory Medicine
94 Icelandic Heart Association
95 Departments of Epidemiology and Nutrition
96 EPI - Institute of Epidemiology [Neuherberg]
97 Medical University Graz
98 Transplantation Laboratory [Helsinki]
99 Department of Chronic Disease Prevention
100 Dept. of Epidemiology Research
101 CLinical Psychology
102 Genetics and Pathology
103 Geriatric Rehabilitation Unit
104 Center For Narcolepsy
105 Centre for Bone and Arthritis Research
106 MRC Human Gentics Unit, Inst Genet and Mol Med, Western General Hospital, Edinburgh
107 University of Maryland School of Medicine [Baltimore, MD, USA]
108 GMM - Génétique des maladies multifactorielles
109 Department of Physics [Stockholm]
110 University of Bristol [Bristol]
111 LUMC - Leiden University Medical Center
112 Department of Epidemiology, University of Washington
113 Department of Medicine
114 Department of Epidemiology [Rotterdam]
115 Department of Epidemiology
116 University of Groningen [Groningen]
117 Department of Genetics
118 ICC - Dutch Initiative on Crohn and Colitis
119 IHA - Icelandic Heart Association [Kopavogur, Iceland]
120 Department of Physiology and Biophysics [Jackson, MS, USA]
121 University of Washington [Seattle]
122 Human Genetics Branch
123 Faculty of Medicine and Life Sciences [Tampere]
124 DZHK - German Center for Cardiovascular Research
125 MRC Centre for Neuropsychiatric Genetics and Genomics
126 Department of Social Medicine
127 Department of Internal Medicine
128 School of Medicine [Los Angeles]
129 Department of Medicine [Aurora, CO, USA]
130 FIMM - Institute for Molecular Medicine Finland [Helsinki]
131 MI - Mathematical Institute [Oxford]
132 Institute of Psychiatry, Psychology & Neuroscience, King's College London
Ying Wu
René Pool
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Bjarke Feenstra
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Marzyeh Amini
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Jari Lahti
Katharina Schraut
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Jian’an Luan
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Tom Bak
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Fabiola del Greco M.
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Elisabeth Thiering
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Riccardo Marioni
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Evelin Mihailov
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Ayse Bilge Ozel
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Maria Nethander
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Stella Aslibekyan
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Wei Ang
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Ilaria Gandin
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Charles Kooperberg
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Edith Hofer
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Harmen H.M. Draisma
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Hae-Won Uh
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Frank Geller
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Peter Joshi
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Benjamin Lehne
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Diego Vozzi
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Marie Verbanck
Yasaman Saba
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Jeff O’connell
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Franco Giulianini
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Patrik K.E. Magnusson
Christie Ballantyne
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Fernando Rivadineira
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Rico Rueedi
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Maristella Steri
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Karl-Heinz Herzig
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David Stott
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Cristina Menni
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Mattias Frånberg
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Beate St. Pourcain
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Peter Kraft
Graciela Delgado
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Vera Grossmann
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Juha Sinisalo
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Ilkka Seppälä
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Elizabeth Holliday
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Matthijs Moed
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Jingzhong Ding
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Harry Campbell
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Michele Sale
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Yii-Der Chen
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Nicole Soranzo
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Carla M.T. Tiesler
  • Function : Author
Dan Mellström
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Anders Larsson
Yunmei Wang
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William Scott
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Matthias Lorentzon
  • Function : Author
John Beilby
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Kathleen Ryan
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Craig Pennell
  • Function : Author
Dragana Vuckovic
  • Function : Author
Maria Pina Concas
  • Function : Author
Carlos Mendes de Leon
  • Function : Author
Lavinia Paternoster
  • Function : Author
A.W. Musk
  • Function : Author
Pamela A.F. Madden
  • Function : Author
Mika Kähönen
Magdalena Zoledziewska
  • Function : Author
Ville Karhunen
  • Function : Author
Stephen Kritchevsky
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Naveed Sattar
Genevieve Lachance
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Robert Clarke
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Diana van Heemst
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Eero Kajantie
Giovanni Gambaro
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Marie Standl
Lars Lind
Jun Li
Trevor Mori
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Eco J.C.N. de Geus
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Andrew Heath
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Juha Auvinen
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Ronald Krauss
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Reedik Mägi
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Liesbeth Vandenput
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Karl Desch
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Jaspal Kooner
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Donna Arnett
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Lawrence Beilin
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Antonietta Robino
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Tine Jess
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Ruth J.F. Loos
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Denis Evans
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Marianne Rots
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Morris Swertz
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Bruce H.R. Wolffenbuttel
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Emelia Benjamin
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Abbas Dehghan
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Tarunveer Singh Ahluwalia
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James Meigs
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Russell Tracy
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Behrooz Alizadeh
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Josh Bis
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Nathan Pankratz
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Myron Gross
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Alex Rainer
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Bram Prins
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Urmo Vaso
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Lude Franke
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Yalda Jamshidi
Sophie Siest
Ali Abbasi
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Mohammadreza Abdollahi
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Ursula Schick
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Aldi Kraja
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Yi-Hsiang Hsu
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Daniel Tylee
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Alyson Zwicker
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Alanna Morrison
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Cavin Ward-Caviness
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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. Copyright © 2018 American Society of Human Genetics. All rights reserved.

Dates and versions

hal-02527859 , version 1 (01-04-2020)

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Symen Ligthart, Ahmad Vaez, Urmo Võsa, Maria Stathopoulou, Paul de Vries, et al.. Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. American Journal of Human Genetics, 2018, 103 (5), pp.691-706. ⟨10.1016/j.ajhg.2018.09.009⟩. ⟨hal-02527859⟩
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