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Title: Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders
Authors: Symen Ligthart
Ahmad Vaez
Urmo Võsa
Maria G. Stathopoulou
Paul S. de Vries
Bram P. Prins
Peter J. Van der Most
Toshiko Tanaka
Elnaz Naderi
Lynda M. Rose
Ying Wu
Robert Karlsson
Maja Barbalic
Honghuang Lin
René Pool
Gu Zhu
Aurélien Macé
Carlo Sidore
Stella Trompet
Massimo Mangino
Maria Sabater-Lleal
John P. Kemp
Ali Abbasi
Tim Kacprowski
Niek Verweij
Albert V. Smith
Tao Huang
Carola Marzi
Mary F. Feitosa
Kurt K. Lohman
Marcus E. Kleber
Yuri Milaneschi
Christian Mueller
Mahmudul Huq
Efthymia Vlachopoulou
Leo Pekka Lyytikäinen
Christopher Oldmeadow
Joris Deelen
Markus Perola
Jing Hua Zhao
Bjarke Feenstra
Behrooz Z. Alizadeh
H. Marike Boezen
Lude Franke
Pim van der Harst
Gerjan Navis
Marianne Rots
Harold Snieder
Morris Swertz
Bruce H.R. Wolffenbuttel
Cisca Wijmenga
Marzyeh Amini
Emelia Benjamin
Daniel I. Chasman
Abbas Dehghan
Tarunveer Singh Ahluwalia
James Meigs
Russell Tracy
Josh Bis
Gudny Eiriksdottir
Nathan Pankratz
Myron Gross
Alex Rainer
James G. Wilson
Bruce M. Psaty
Josee Dupuis
Bram Prins
Urmo Vaso
Maria Stathopoulou
Terho Lehtimaki
Wolfgang Koenig
Yalda Jamshidi
Sophie Siest
Andre G. Uitterlinden
Mohammadreza Abdollahi
Renate Schnabel
Ursula M. Schick
Ilja M. Nolte
Aldi Kraja
Yi Hsiang Hsu
Daniel S. Tylee
Alyson Zwicker
Rudolf Uher
George Davey-Smith
Alanna C. Morrison
Andrew Hicks
Cornelia M. van Duijn
Cavin Ward-Caviness
Eric Boerwinkle
J. Rotter
Ken Rice
Leslie Lange
Markus Perola
Eco de Geus
Andrew P. Morris
Amsterdam Public Health
Fimlab Laboratoriot Oy
Deutsches Zentrum für Herz-Kreislauf-Forschung e. V.
National Institute for Health and Welfare
Institut dInvestigació Biomèdica Sant Pau (IIB Sant Pau)
Université de Lorraine
Max Planck Institute for Biology of Ageing
Hunter Medical Research Institute, Australia
Icelandic Heart Association
Haskoli Islands
University of Tartu
Harvard School of Public Health
Erasmus University Medical Center
University of Cambridge
University of Queensland
Swiss Institute of Bioinformatics
Wake Forest University Health Sciences
University of Cambridge, School of Clinical Medicine
Statens Serum Institut
The University of North Carolina at Chapel Hill
QIMR Berghofer Medical Research Institute
Helmholtz Center Munich German Research Center for Environmental Health
Washington University School of Medicine in St. Louis
Institut Universitaire de Médecine Sociale et Préventive Lausanne
Ernst-Moritz-Arndt-Universität Greifswald
Consiglio Nazionale delle Ricerche
Isfahan University of Medical Sciences
National Institute on Aging
University of Newcastle, Faculty of Health and Medicine
Brigham and Women's Hospital
Leiden University Medical Center - LUMC
Universitätsklinikum Schleswig-Holstein Campus Lübeck
Peking University
University of Bristol, Faculty of Medicine and Dentistry
University of Texas School of Public Health
Karolinska Institutet
King's College London
Tampereen Yliopisto
Vrije Universiteit Amsterdam
Sveučilište u Splitu
Boston University School of Medicine
University of Groningen, University Medical Center Groningen
Guy's and St Thomas' NHS Foundation Trust
Wellcome Sanger Institute
Universitätsklinikum Hamburg-Eppendorf und Medizinische Fakultät
Helsingin Yliopisto
Universitätsklinikum Mannheim
Université de Lausanne (UNIL)
German Center for Diabetes Research (DZD)
German Center for Cardiovascular Research, Partner Site RheinMain
Keywords: Biochemistry, Genetics and Molecular Biology;Medicine
Issue Date: 1-Nov-2018
Citation: American Journal of Human Genetics. Vol.103, No.5 (2018), 691-706
Abstract: © 2018 American Society of Human Genetics 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.
ISSN: 15376605
Appears in Collections:Scopus 2018

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