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

  • 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
  • Marzyeh Amini
  • Jari Lahti
  • Katharina E Schraut
  • Myriam Fornage
  • Bhoom Suktitipat
  • Wei-Min Chen
  • Xiaohui Li
  • Teresa Nutile
  • Giovanni Malerba
  • Jian'an Luan
  • Tom Bak
  • Nicholas Schork
  • Fabiola Del Greco M
  • Elisabeth Thiering
  • Anubha Mahajan
  • Riccardo E Marioni
  • Evelin Mihailov
  • Joel Eriksson
  • Ayse Bilge Ozel
  • Weihua Zhang
  • Maria Nethander
  • Yu-Ching Cheng
  • Stella Aslibekyan
  • Wei Ang
  • Ilaria Gandin
  • Loïc Yengo
  • Laura Portas
  • Charles Kooperberg
  • Edith Hofer
  • Kumar B Rajan
  • Claudia Schurmann
  • Wouter den Hollander
  • Tarunveer S Ahluwalia
  • Jing Zhao
  • Harmen H M Draisma
  • Ian Ford
  • Nicholas Timpson
  • Alexander Teumer
  • Hongyan Huang
  • Simone Wahl
  • YongMei Liu
  • Jie Huang
  • Hae-Won Uh
  • Frank Geller
  • Peter K Joshi
  • Lisa R Yanek
  • Elisabetta Trabetti
  • Benjamin Lehne
  • Diego Vozzi
  • Marie Verbanck
  • Ginevra Biino
  • Yasaman Saba
  • Ingrid Meulenbelt
  • Jeff R O'Connell
  • Markku Laakso
  • Franco Giulianini
  • Patrik K E Magnusson
  • Christie M Ballantyne
  • Jouke Jan Hottenga
  • Grant W Montgomery
  • Fernando Rivadineira
  • Rico Rueedi
  • Maristella Steri
  • Karl-Heinz Herzig
  • David J Stott
  • Cristina Menni
  • Mattias Frånberg
  • Beate St Pourcain
  • Stephan B Felix
  • Tune H Pers
  • Stephan J L Bakker
  • Peter Kraft
  • Annette Peters
  • Dhananjay Vaidya
  • Graciela Delgado
  • Johannes H Smit
  • Vera Großmann
  • Juha Sinisalo
  • Ilkka Seppälä
  • Stephen R Williams
  • Elizabeth G Holliday
  • Matthijs Moed
  • Claudia Langenberg
  • Katri Räikkönen
  • Jingzhong Ding
  • Harry Campbell
  • Michele M Sale
  • Yii-Der I Chen
  • Alan L James
  • Daniela Ruggiero
  • Nicole Soranzo
  • Catharina A Hartman
  • Erin N Smith
  • Gerald S Berenson
  • Christian Fuchsberger
  • Dena Hernandez
  • Carla M T Tiesler
  • Vilmantas Giedraitis
  • David Liewald
  • Krista Fischer
  • Dan Mellström
  • Anders Larsson
  • Yunmei Wang
  • William R Scott
  • Matthias Lorentzon
  • John Beilby
  • Kathleen A Ryan
  • Craig E Pennell
  • Dragana Vuckovic
  • Beverly Balkau
  • Maria Pina Concas
  • Reinhold Schmidt
  • Carlos F Mendes de Leon
  • Erwin P Bottinger
  • Margreet Kloppenburg
  • Lavinia Paternoster
  • Michael Boehnke
  • A W Musk
  • Gonneke Willemsen
  • David M Evans
  • Pamela A F Madden
  • Mika Kähönen
  • Zoltán Kutalik
  • Magdalena Zoledziewska
  • Ville Karhunen
  • Stephen B Kritchevsky
  • Naveed Sattar
  • Genevieve Lachance
  • Robert Clarke
  • Tamara B Harris
  • Olli T Raitakari
  • John R Attia
  • Diana van Heemst
  • Eero Kajantie
  • Rossella Sorice
  • Giovanni Gambaro
  • Robert A Scott
  • Andrew A Hicks
  • Luigi Ferrucci
  • Marie Standl
  • Cecilia M Lindgren
  • John M Starr
  • Magnus Karlsson
  • Lars Lind
  • Jun Z Li
  • John C Chambers
  • Trevor A Mori
  • Eco J C N de Geus
  • Andrew C Heath
  • Nicholas G Martin
  • Juha Auvinen
  • Brendan M Buckley
  • Anton J M de Craen
  • Melanie Waldenberger
  • Konstantin Strauch
  • Thomas Meitinger
  • Rodney J Scott
  • Mark McEvoy
  • Marian Beekman
  • Cristina Bombieri
  • Paul M Ridker
  • Karen L Mohlke
  • Nancy L Pedersen
  • Alanna C Morrison
  • Dorret I Boomsma
  • John B Whitfield
  • David P Strachan
  • Albert Hofman
  • Peter Vollenweider
  • Francesco Cucca
  • Marjo-Riitta Jarvelin
  • J Wouter Jukema
  • Tim D Spector
  • Anders Hamsten
  • Tanja Zeller
  • André G Uitterlinden
  • Matthias Nauck
  • Vilmundur Gudnason
  • Lu Qi
  • Harald Grallert
  • Ingrid B Borecki
  • Jerome I Rotter
  • Winfried März
  • Philipp S Wild
  • Marja-Liisa Lokki
  • Michael Boyle
  • Veikko Salomaa
  • Mads Melbye
  • Johan G Eriksson
  • James F Wilson
  • Brenda W J H Penninx
  • Diane M Becker
  • Bradford B Worrall
  • Greg Gibson
  • Ronald M Krauss
  • Marina Ciullo
  • Gianluigi Zaza
  • Nicholas J Wareham
  • Albertine J Oldehinkel
  • Lyle J Palmer
  • Sarah S Murray
  • Peter P Pramstaller
  • Stefania Bandinelli
  • Joachim Heinrich
  • Erik Ingelsson
  • Ian J Deary
  • Reedik Mägi
  • Liesbeth Vandenput
  • Pim van der Harst
  • Karl C Desch
  • Jaspal S Kooner
  • Claes Ohlsson
  • Caroline Hayward
  • Terho Lehtimäki
  • Alan R Shuldiner
  • Donna K Arnett
  • Lawrence J Beilin
  • Antonietta Robino
  • Philippe Froguel
  • Mario Pirastu
  • Tine Jess
  • Wolfgang Koenig
  • Ruth J F Loos
  • Denis A Evans
  • Helena Schmidt
  • George Davey Smith
  • P Eline Slagboom
  • Gudny Eiriksdottir
  • Andrew P Morris
  • Bruce M Psaty
  • Russell P Tracy
  • Ilja M Nolte
  • Eric Boerwinkle
  • Sophie Visvikis-Siest
  • Alex P Reiner
  • Myron Gross
  • Joshua C Bis
  • Lude Franke
  • Oscar H Franco
  • Emelia J Benjamin
  • Daniel I Chasman
  • Josée Dupuis
  • Harold Snieder
  • Abbas Dehghan
  • Behrooz Z Alizadeh
  • LifeLines Cohort Study

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.

Bibliographical metadata

Original languageEnglish
ISSN0002-9297
DOIs
Publication statusPublished - 01.11.2018
PubMed 30388399