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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 27 Benjamin Lehne Diego Vozzi Marie Verbanck Ginevra Biino 45 Yasaman Saba Ingrid Meulenbelt 46 Jeff O’connell Markku Laakso 47 Franco Giulianini Patrik K.E. Magnusson Christie Ballantyne Jouke Jan Hottenga 48 Grant Montgomery 48 Fernando Rivadineira Rico Rueedi Maristella Steri Karl-Heinz Herzig David Stott Cristina Menni Mattias Frånberg Beate St. Pourcain Stephan Felix 49 Tune Pers 50 Stephan J.L. Bakker 51 Peter Kraft 52 Annette Peters 53 Dhananjay Vaidya 54 Graciela Delgado Johannes Smit 48 Vera Großmann Juha Sinisalo Ilkka Seppälä Stephen Williams 55 Elizabeth Holliday Matthijs Moed Claudia Langenberg 56 Katri Räikkönen 48 Jingzhong Ding Harry Campbell 57 Michele Sale Yii-Der Chen Alan James 58 Daniela Ruggiero 59 Nicole Soranzo 16 Catharina Hartman 48 Erin Smith 60 Gerald Berenson 61 Christian Fuchsberger 62 Dena Hernandez 63 Carla M.T. Tiesler Vilmantas Giedraitis 64 David Liewald 57 Krista Fischer 65 Dan Mellström Anders Larsson 66 Yunmei Wang William Scott Matthias Lorentzon John Beilby Kathleen Ryan Craig Pennell Dragana Vuckovic Beverly Balkau 67 Maria Pina Concas Reinhold Schmidt 68 Carlos Mendes de Leon Erwin Bottinger 69 Margreet Kloppenburg 70 Lavinia Paternoster Michael Boehnke 71 A.W. Musk Gonneke Willemsen 48 David Evans 72 Pamela A.F. Madden Mika Kähönen 73 Zoltán Kutalik 74 Magdalena Zoledziewska Ville Karhunen Stephen Kritchevsky Naveed Sattar 75 Genevieve Lachance Robert Clarke 76 Tamara Harris 7 Olli Raitakari 73 John Attia 77 Diana van Heemst 78 Eero Kajantie Rossella Sorice 26 Giovanni Gambaro Robert Scott 79 Luigi Ferrucci 48 Marie Standl Cecilia Lindgren 80 John Starr 57 Magnus Karlsson 81 Lars Lind 82 Jun Li 83 John Chambers 40 Trevor Mori Eco J.C.N. de Geus Andrew Heath Nicholas Martin 84 Juha Auvinen Brendan Buckley Anton J.M. de Craen 85 Melanie Waldenberger 53 Konstantin Strauch 86 Thomas Meitinger 87 Rodney Scott 88 Mark Mcevoy Marian Beekman 89 Cristina Bombieri Paul Ridker 8 Karen Mohlke 90 Nancy Pedersen 10 Dorret Boomsma 91 John Whitfield 84 David Strachan 92 Albert Hofman 1 Peter Vollenweider 93 Francesco Cucca Marjo-Riitta Järvelin 94 J. Wouter Jukema 54 Tim Spector Anders Hamsten 95 Tanja Zeller 96 Matthias Nauck 97 Vilmundur Gudnason 98 Lu Qi 99 Harald Grallert 100 Ingrid Borecki 18 Winfried März 101 Philipp Wild 96 Marja-Liisa Lokki 102 Michael Boyle Veikko Salomaa 103 Mads Melbye 104 Brenda W.J.H. Penninx 105 Diane Becker Bradford Worrall Greg Gibson Ronald Krauss Marina Ciullo 26 Gianluigi Zaza Nicholas Wareham 79 Albertine Oldehinkel Lyle Palmer Sarah Murray Peter Pramstaller 106 Stefania Bandinelli 107 Joachim Heinrich 108 Erik Ingelsson 10 Ian Deary 54 Reedik Mägi Liesbeth Vandenput Karl Desch Jaspal Kooner Claes Ohlsson 109 Caroline Hayward 110 Alan Shuldiner 111 Donna Arnett Lawrence Beilin Antonietta Robino Philippe Froguel 112 Mario Pirastu 45 Tine Jess Ruth J.F. Loos Denis Evans Helena Schmidt 113 George Davey Smith 114 P. Eline Slagboom 115 Sophie Visvikis-Siest 5 Alex Reiner 116 Joshua Bis 117 Oscar Franco 118 H. Marike Boezen 119 Pim van der Harst 120 Gerjan Navis 51 Marianne Rots Morris Swertz 121 Bruce H.R. Wolffenbuttel Cisca Wijmenga 122 Emelia Benjamin Daniel Chasman 8 Abbas Dehghan Tarunveer Singh Ahluwalia James Meigs Russell Tracy Behrooz Alizadeh Josh Bis Gudny Eiriksdottir 123 Nathan Pankratz Myron Gross Alex Rainer Harold Snieder 40 James Wilson 124 Bruce Psaty 125 Josée Dupuis 12 Bram Prins 126 Urmo Vaso Lude Franke Terho Lehtimäki 127 Wolfgang Koenig 128 Yalda Jamshidi Sophie Siest Ali Abbasi Andre Uitterlinden 1 Mohammadreza Abdollahi Renate Schnabel 96 Ursula Schick Ilja Nolte 120 Aldi Kraja Yi-Hsiang Hsu Daniel Tylee Alyson Zwicker Rudolf Uher 129 George Davey-Smith 130 Alanna Morrison Andrew Hicks 62 Cornelia van Duijn 131 Cavin Ward-Caviness Eric Boerwinkle 6 Jerome Rotter 132 Ken Rice Leslie Lange 133 Markus Perola 134 Eco de Geus 91 Andrew Morris 135 Kari Matti Makela David Stacey 136 Johan Eriksson 48 Tim Frayling Eline Slagboom 46
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 : Tuesday, May 25, 2021 - 11:36:38 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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