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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 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 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 35 Kumar Rajan Claudia Schurmann 36 Wouter den Hollander Tarunveer Ahluwalia 37 Jing Zhao Harmen H.M. Draisma Ian Ford 38 Nicholas Timpson 39 Alexander Teumer 40 Hongyan Huang Simone Wahl Yongmei Liu 41 Jie Huang 42 Hae-Won Uh 43 Frank Geller Peter Joshi Lisa Yanek 44 Elisabetta Trabetti 45 Benjamin Lehne Diego Vozzi Marie Verbanck Ginevra Biino 46 Yasaman Saba Ingrid Meulenbelt 47 Jeff O’connell Markku Laakso 48 Franco Giulianini Patrik K.E. Magnusson Christie Ballantyne Jouke Jan Hottenga 49 Grant Montgomery 49 Fernando Rivadineira Rico Rueedi Maristella Steri Karl-Heinz Herzig David Stott Cristina Menni Mattias Frånberg Beate St. Pourcain Stephan Felix 50 Tune Pers 51 Stephan J.L. Bakker 52 Peter Kraft 53 Annette Peters 54 Dhananjay Vaidya 55 Graciela Delgado Johannes Smit 49 Vera Großmann Juha Sinisalo Ilkka Seppälä Stephen Williams 56 Elizabeth Holliday Matthijs Moed Claudia Langenberg 57 Katri Räikkönen 49 Jingzhong Ding Harry Campbell 58 Michele Sale Yii-Der Chen Alan James 59 Daniela Ruggiero 60 Nicole Soranzo 16 Catharina Hartman 49 Erin Smith 61 Gerald Berenson 62 Christian Fuchsberger 63 Dena Hernandez 64 Carla M.T. Tiesler Vilmantas Giedraitis 65 David Liewald 58 Krista Fischer 66 Dan Mellström Anders Larsson 67 Yunmei Wang William Scott Matthias Lorentzon John Beilby Kathleen Ryan Craig Pennell Dragana Vuckovic Beverly Balkau 68 Maria Pina Concas Reinhold Schmidt 69 Carlos Mendes de Leon Erwin Bottinger 70 Margreet Kloppenburg 71 Lavinia Paternoster Michael Boehnke 72 A.W. Musk Gonneke Willemsen 49 David Evans 73 Pamela A.F. Madden Mika Kähönen 74 Zoltán Kutalik 75 Magdalena Zoledziewska Ville Karhunen Stephen Kritchevsky Naveed Sattar 76 Genevieve Lachance Robert Clarke 77 Tamara Harris 7 Olli Raitakari 74 John Attia 78 Diana van Heemst 79 Eero Kajantie Rossella Sorice 26 Giovanni Gambaro Robert Scott 80 Luigi Ferrucci 49 Marie Standl Cecilia Lindgren 81 John Starr 58 Magnus Karlsson 82 Lars Lind 83 Jun Li 84 John Chambers 40 Trevor Mori Eco J.C.N. de Geus Andrew Heath Nicholas Martin 85 Juha Auvinen Brendan Buckley Anton J.M. de Craen 86 Melanie Waldenberger 54 Konstantin Strauch 87 Thomas Meitinger 88 Rodney Scott 89 Mark Mcevoy Marian Beekman 90 Cristina Bombieri Paul Ridker 8 Karen Mohlke 91 Nancy Pedersen 10 Dorret Boomsma 92 John Whitfield 85 David Strachan 93 Albert Hofman 1 Peter Vollenweider 94 Francesco Cucca Marjo-Riitta Järvelin 95 J. Wouter Jukema 55 Tim Spector Anders Hamsten 96 Tanja Zeller 97 Matthias Nauck 98 Vilmundur Gudnason 99 Lu Qi 100 Harald Grallert 101 Ingrid Borecki 18 Winfried März 102 Philipp Wild 97 Marja-Liisa Lokki 103 Michael Boyle Veikko Salomaa 104 Mads Melbye 105 Brenda W.J.H. Penninx 106 Diane Becker Bradford Worrall Greg Gibson Ronald Krauss Marina Ciullo 26 Gianluigi Zaza Nicholas Wareham 80 Albertine Oldehinkel Lyle Palmer Sarah Murray Peter Pramstaller 107 Stefania Bandinelli 108 Joachim Heinrich 109 Erik Ingelsson 10 Ian Deary 55 Reedik Mägi Liesbeth Vandenput Karl Desch Jaspal Kooner Claes Ohlsson 110 Caroline Hayward 111 Alan Shuldiner 112 Donna Arnett Lawrence Beilin Antonietta Robino Philippe Froguel 113 Mario Pirastu 46 Tine Jess Ruth J.F. Loos Denis Evans Helena Schmidt 114 George Davey Smith 115 P. Eline Slagboom 116 Sophie Visvikis-Siest 5 Alex Reiner 117 Joshua Bis 118 Oscar Franco 119 H. Marike Boezen 120 Pim van der Harst 121 Gerjan Navis 52 Marianne Rots Morris Swertz 122 Bruce H.R. Wolffenbuttel Cisca Wijmenga 123 Emelia Benjamin Daniel Chasman 8 Abbas Dehghan Tarunveer Singh Ahluwalia James Meigs Russell Tracy Behrooz Alizadeh Josh Bis Gudny Eiriksdottir 124 Nathan Pankratz Myron Gross Alex Rainer Harold Snieder 40 James Wilson 125 Bruce Psaty 126 Josée Dupuis 12 Bram Prins 127 Urmo Vaso Lude Franke Terho Lehtimäki 128 Wolfgang Koenig 129 Yalda Jamshidi Sophie Siest Ali Abbasi Andre Uitterlinden 1 Mohammadreza Abdollahi Renate Schnabel 97 Ursula Schick Ilja Nolte 121 Aldi Kraja Yi-Hsiang Hsu Daniel Tylee Alyson Zwicker Rudolf Uher 130 George Davey-Smith 131 Alanna Morrison Andrew Hicks 63 Cornelia van Duijn 132 Cavin Ward-Caviness Eric Boerwinkle 6 Jerome Rotter 133 Ken Rice Leslie Lange 134 Markus Perola 135 Eco de Geus 92 Andrew Morris 136 Kari Matti Makela David Stacey 137 Johan Eriksson 49 Tim Frayling Eline Slagboom 47
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.
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Submitted on : Wednesday, April 1, 2020 - 3:05:24 PM
Last modification on : Thursday, January 14, 2021 - 9:26:03 AM

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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, Elsevier (Cell Press), 2018, 103 (5), pp.691-706. ⟨10.1016/j.ajhg.2018.09.009⟩. ⟨hal-02527859⟩

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