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

LifeLines Cohort Study, CHARGE Inflammation Working Group

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)691-706
Number of pages16
JournalAmerican Journal of Human Genetics
Volume103
Issue number5
DOIs
Publication statusPublished - 1 Nov 2018

Fingerprint

C-Reactive Protein
Genome
Inflammation
Mendelian Randomization Analysis
Genome-Wide Association Study
HapMap Project
Genetic Loci
Metabolic Networks and Pathways
Bipolar Disorder
Computer Simulation
Meta-Analysis
Schizophrenia
Body Mass Index
Biomarkers
Regression Analysis
Liver
Genes

Cite this

@article{2760b7655e4a477faa9279cc686c37f7,
title = "Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders",
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.",
keywords = "C-reactive protein, coronary artery disease, DEPICT, genome-wide association study, inflammation, inflammatory disorders, Mendelian randomization, schizophrenia, system biology",
author = "{LifeLines Cohort Study} and {CHARGE Inflammation Working Group} and Symen Ligthart and Ahmad Vaez and Urmo V{\~o}sa and Stathopoulou, {Maria G.} and {de Vries}, {Paul S.} and Prins, {Bram P.} and {Van der Most}, {Peter J.} and Toshiko Tanaka and Elnaz Naderi and Rose, {Lynda M.} and Ying Wu and Robert Karlsson and Maja Barbalic and Honghuang Lin and Ren{\'e} Pool and Gu Zhu and Aur{\'e}lien Mac{\'e} and Carlo Sidore and Stella Trompet and Massimo Mangino and Maria Sabater-Lleal and Kemp, {John P.} and Ali Abbasi and Tim Kacprowski and Niek Verweij and Smith, {Albert V.} and Tao Huang and Carola Marzi and Feitosa, {Mary F.} and Lohman, {Kurt K.} and Kleber, {Marcus E.} and Yuri Milaneschi and Christian Mueller and Mahmudul Huq and Efthymia Vlachopoulou and Lyytik{\"a}inen, {Leo Pekka} and Christopher Oldmeadow and Joris Deelen and Markus Perola and Zhao, {Jing Hua} and Bjarke Feenstra and Alizadeh, {Behrooz Z.} and Boezen, {H. Marike} and Lude Franke and {van der Harst}, Pim and Gerjan Navis and Marianne Rots and Harold Snieder and Morris Swertz and Wolffenbuttel, {Bruce H.R.} and Cisca Wijmenga and Marzyeh Amini and Emelia Benjamin and Chasman, {Daniel I.} and Abbas Dehghan and Ahluwalia, {Tarunveer Singh} and James Meigs and Russell Tracy and Alizadeh, {Behrooz Z.} and Symen Ligthart and Josh Bis and Gudny Eiriksdottir and Nathan Pankratz and Myron Gross and Alex Rainer and Harold Snieder and Wilson, {James G.} and Psaty, {Bruce M.} and Josee Dupuis and Bram Prins and Urmo Vaso and Maria Stathopoulou and Lude Franke and Terho Lehtim{\"a}ki and Wolfgang Koenig and Yalda Jamshidi and Sophie Siest and Ali Abbasi and Uitterlinden, {Andr{\'e} G.} and Mohammadreza Abdollahi and Renate Schnabel and Schick, {Ursula M.} and Nolte, {Ilja M.} and Aldi Kraja and Hsu, {Yi Hsiang} and Tylee, {Daniel S.} and Alyson Zwicker and Rudolf Uher and George Davey-Smith and Morrison, {Alanna C.} and Andrew Hicks and {van Duijn}, {Cornelia M.} and Cavin Ward-Caviness and Eric Boerwinkle and J. Rotter and Ken Rice and Leslie Lange and Markus Perola and {de Geus}, Eco and Morris, {Andrew P.} and Makela, {Kari Matti} and David Stacey and Johan Eriksson and Frayling, {Tim M.} and Slagboom, {Eline P.} and Jari Lahti and Schraut, {Katharina E.} and Myriam Fornage and Bhoom Suktitipat and Chen, {Wei Min} and Xiaohui Li and Teresa Nutile and Giovanni Malerba and Jian'an Luan and Tom Bak and Nicholas Schork and {Del Greco M.}, Fabiola and Elisabeth Thiering and Anubha Mahajan and Marioni, {Riccardo E.} and Evelin Mihailov and Joel Eriksson and Ozel, {Ayse Bilge} and Weihua Zhang and Maria Nethander and Cheng, {Yu Ching} and Stella Aslibekyan and Wei Ang and Ilaria Gandin and Lo{\"i}c Yengo and Laura Portas and Charles Kooperberg and Edith Hofer and Rajan, {Kumar B.} and Claudia Schurmann and {den Hollander}, Wouter and Ahluwalia, {Tarunveer S.} and Jing Zhao and Draisma, {Harmen H.M.} and Ian Ford and Nicholas Timpson and Alexander Teumer and Hongyan Huang and Simone Wahl and Liu, {Yong Mei} and Jie Huang and Uh, {Hae Won} and Frank Geller and Joshi, {Peter K.} and Yanek, {Lisa R.} and Elisabetta Trabetti and Benjamin Lehne and Diego Vozzi and Marie Verbanck and Ginevra Biino and Yasaman Saba and Ingrid Meulenbelt and O'Connell, {Jeff R.} and Markku Laakso and Franco Giulianini and Magnusson, {Patrik K.E.} and Ballantyne, {Christie M.} and Hottenga, {Jouke Jan} and Montgomery, {Grant W.} and Fernando Rivadineira and Rico Rueedi and Maristella Steri and Herzig, {Karl Heinz} and Stott, {David J.} and Cristina Menni and Mattias Fr{\aa}nberg and {St. Pourcain}, Beate and Felix, {Stephan B.} and Pers, {Tune H.} and Bakker, {Stephan J.L.} and Peter Kraft and Annette Peters and Dhananjay Vaidya and Graciela Delgado and Smit, {Johannes H.} and Vera Gro{\ss}mann and Juha Sinisalo and Ilkka Sepp{\"a}l{\"a} and Williams, {Stephen R.} and Holliday, {Elizabeth G.} and Matthijs Moed and Claudia Langenberg and Katri R{\"a}ikk{\"o}nen and Jingzhong Ding and Harry Campbell and Sale, {Michele M.} and Chen, {Yii Der I.} and James, {Alan L.} and Daniela Ruggiero and Nicole Soranzo and Hartman, {Catharina A.} and Smith, {Erin N.} and Berenson, {Gerald S.} and Christian Fuchsberger and Dena Hernandez and Tiesler, {Carla M.T.} and Vilmantas Giedraitis and David Liewald and Krista Fischer and Dan Mellstr{\"o}m and Anders Larsson and Yunmei Wang and Scott, {William R.} and Matthias Lorentzon and John Beilby and Ryan, {Kathleen A.} and Pennell, {Craig E.} and Dragana Vuckovic and Beverly Balkau and Concas, {Maria Pina} and Reinhold Schmidt and {Mendes de Leon}, {Carlos F.} and Bottinger, {Erwin P.} and Margreet Kloppenburg and Lavinia Paternoster and Michael Boehnke and Musk, {A. W.} and Gonneke Willemsen and Evans, {David M.} and Madden, {Pamela A.F.} and Mika K{\"a}h{\"o}nen and Zolt{\'a}n Kutalik and Magdalena Zoledziewska and Ville Karhunen and Kritchevsky, {Stephen B.} and Naveed Sattar and Genevieve Lachance and Robert Clarke and Harris, {Tamara B.} and Raitakari, {Olli T.} and Attia, {John R.} and {van Heemst}, Diana and Eero Kajantie and Rossella Sorice and Giovanni Gambaro and Scott, {Robert A.} and Hicks, {Andrew A.} and Luigi Ferrucci and Marie Standl and Lindgren, {Cecilia M.} and Starr, {John M.} and Magnus Karlsson and Lars Lind and Li, {Jun Z.} and Chambers, {John C.}",
year = "2018",
month = "11",
day = "1",
doi = "10.1016/j.ajhg.2018.09.009",
language = "English",
volume = "103",
pages = "691--706",
journal = "The American Journal of Human Genetics",
issn = "0002-9297",
publisher = "UNIV CHICAGO PRESS",
number = "5",

}

Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. / LifeLines Cohort Study; CHARGE Inflammation Working Group.

In: American Journal of Human Genetics, Vol. 103, No. 5, 01.11.2018, p. 691-706.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

AU - LifeLines Cohort Study

AU - CHARGE Inflammation Working Group

AU - Ligthart, Symen

AU - Vaez, Ahmad

AU - Võsa, Urmo

AU - Stathopoulou, Maria G.

AU - de Vries, Paul S.

AU - Prins, Bram P.

AU - Van der Most, Peter J.

AU - Tanaka, Toshiko

AU - Naderi, Elnaz

AU - Rose, Lynda M.

AU - Wu, Ying

AU - Karlsson, Robert

AU - Barbalic, Maja

AU - Lin, Honghuang

AU - Pool, René

AU - Zhu, Gu

AU - Macé, Aurélien

AU - Sidore, Carlo

AU - Trompet, Stella

AU - Mangino, Massimo

AU - Sabater-Lleal, Maria

AU - Kemp, John P.

AU - Abbasi, Ali

AU - Kacprowski, Tim

AU - Verweij, Niek

AU - Smith, Albert V.

AU - Huang, Tao

AU - Marzi, Carola

AU - Feitosa, Mary F.

AU - Lohman, Kurt K.

AU - Kleber, Marcus E.

AU - Milaneschi, Yuri

AU - Mueller, Christian

AU - Huq, Mahmudul

AU - Vlachopoulou, Efthymia

AU - Lyytikäinen, Leo Pekka

AU - Oldmeadow, Christopher

AU - Deelen, Joris

AU - Perola, Markus

AU - Zhao, Jing Hua

AU - Feenstra, Bjarke

AU - Alizadeh, Behrooz Z.

AU - Boezen, H. Marike

AU - Franke, Lude

AU - van der Harst, Pim

AU - Navis, Gerjan

AU - Rots, Marianne

AU - Snieder, Harold

AU - Swertz, Morris

AU - Wolffenbuttel, Bruce H.R.

AU - Wijmenga, Cisca

AU - Amini, Marzyeh

AU - Benjamin, Emelia

AU - Chasman, Daniel I.

AU - Dehghan, Abbas

AU - Ahluwalia, Tarunveer Singh

AU - Meigs, James

AU - Tracy, Russell

AU - Alizadeh, Behrooz Z.

AU - Ligthart, Symen

AU - Bis, Josh

AU - Eiriksdottir, Gudny

AU - Pankratz, Nathan

AU - Gross, Myron

AU - Rainer, Alex

AU - Snieder, Harold

AU - Wilson, James G.

AU - Psaty, Bruce M.

AU - Dupuis, Josee

AU - Prins, Bram

AU - Vaso, Urmo

AU - Stathopoulou, Maria

AU - Franke, Lude

AU - Lehtimäki, Terho

AU - Koenig, Wolfgang

AU - Jamshidi, Yalda

AU - Siest, Sophie

AU - Abbasi, Ali

AU - Uitterlinden, André G.

AU - Abdollahi, Mohammadreza

AU - Schnabel, Renate

AU - Schick, Ursula M.

AU - Nolte, Ilja M.

AU - Kraja, Aldi

AU - Hsu, Yi Hsiang

AU - Tylee, Daniel S.

AU - Zwicker, Alyson

AU - Uher, Rudolf

AU - Davey-Smith, George

AU - Morrison, Alanna C.

AU - Hicks, Andrew

AU - van Duijn, Cornelia M.

AU - Ward-Caviness, Cavin

AU - Boerwinkle, Eric

AU - Rotter, J.

AU - Rice, Ken

AU - Lange, Leslie

AU - Perola, Markus

AU - de Geus, Eco

AU - Morris, Andrew P.

AU - Makela, Kari Matti

AU - Stacey, David

AU - Eriksson, Johan

AU - Frayling, Tim M.

AU - Slagboom, Eline P.

AU - Lahti, Jari

AU - Schraut, Katharina E.

AU - Fornage, Myriam

AU - Suktitipat, Bhoom

AU - Chen, Wei Min

AU - Li, Xiaohui

AU - Nutile, Teresa

AU - Malerba, Giovanni

AU - Luan, Jian'an

AU - Bak, Tom

AU - Schork, Nicholas

AU - Del Greco M., Fabiola

AU - Thiering, Elisabeth

AU - Mahajan, Anubha

AU - Marioni, Riccardo E.

AU - Mihailov, Evelin

AU - Eriksson, Joel

AU - Ozel, Ayse Bilge

AU - Zhang, Weihua

AU - Nethander, Maria

AU - Cheng, Yu Ching

AU - Aslibekyan, Stella

AU - Ang, Wei

AU - Gandin, Ilaria

AU - Yengo, Loïc

AU - Portas, Laura

AU - Kooperberg, Charles

AU - Hofer, Edith

AU - Rajan, Kumar B.

AU - Schurmann, Claudia

AU - den Hollander, Wouter

AU - Ahluwalia, Tarunveer S.

AU - Zhao, Jing

AU - Draisma, Harmen H.M.

AU - Ford, Ian

AU - Timpson, Nicholas

AU - Teumer, Alexander

AU - Huang, Hongyan

AU - Wahl, Simone

AU - Liu, Yong Mei

AU - Huang, Jie

AU - Uh, Hae Won

AU - Geller, Frank

AU - Joshi, Peter K.

AU - Yanek, Lisa R.

AU - Trabetti, Elisabetta

AU - Lehne, Benjamin

AU - Vozzi, Diego

AU - Verbanck, Marie

AU - Biino, Ginevra

AU - Saba, Yasaman

AU - Meulenbelt, Ingrid

AU - O'Connell, Jeff R.

AU - Laakso, Markku

AU - Giulianini, Franco

AU - Magnusson, Patrik K.E.

AU - Ballantyne, Christie M.

AU - Hottenga, Jouke Jan

AU - Montgomery, Grant W.

AU - Rivadineira, Fernando

AU - Rueedi, Rico

AU - Steri, Maristella

AU - Herzig, Karl Heinz

AU - Stott, David J.

AU - Menni, Cristina

AU - Frånberg, Mattias

AU - St. Pourcain, Beate

AU - Felix, Stephan B.

AU - Pers, Tune H.

AU - Bakker, Stephan J.L.

AU - Kraft, Peter

AU - Peters, Annette

AU - Vaidya, Dhananjay

AU - Delgado, Graciela

AU - Smit, Johannes H.

AU - Großmann, Vera

AU - Sinisalo, Juha

AU - Seppälä, Ilkka

AU - Williams, Stephen R.

AU - Holliday, Elizabeth G.

AU - Moed, Matthijs

AU - Langenberg, Claudia

AU - Räikkönen, Katri

AU - Ding, Jingzhong

AU - Campbell, Harry

AU - Sale, Michele M.

AU - Chen, Yii Der I.

AU - James, Alan L.

AU - Ruggiero, Daniela

AU - Soranzo, Nicole

AU - Hartman, Catharina A.

AU - Smith, Erin N.

AU - Berenson, Gerald S.

AU - Fuchsberger, Christian

AU - Hernandez, Dena

AU - Tiesler, Carla M.T.

AU - Giedraitis, Vilmantas

AU - Liewald, David

AU - Fischer, Krista

AU - Mellström, Dan

AU - Larsson, Anders

AU - Wang, Yunmei

AU - Scott, William R.

AU - Lorentzon, Matthias

AU - Beilby, John

AU - Ryan, Kathleen A.

AU - Pennell, Craig E.

AU - Vuckovic, Dragana

AU - Balkau, Beverly

AU - Concas, Maria Pina

AU - Schmidt, Reinhold

AU - Mendes de Leon, Carlos F.

AU - Bottinger, Erwin P.

AU - Kloppenburg, Margreet

AU - Paternoster, Lavinia

AU - Boehnke, Michael

AU - Musk, A. W.

AU - Willemsen, Gonneke

AU - Evans, David M.

AU - Madden, Pamela A.F.

AU - Kähönen, Mika

AU - Kutalik, Zoltán

AU - Zoledziewska, Magdalena

AU - Karhunen, Ville

AU - Kritchevsky, Stephen B.

AU - Sattar, Naveed

AU - Lachance, Genevieve

AU - Clarke, Robert

AU - Harris, Tamara B.

AU - Raitakari, Olli T.

AU - Attia, John R.

AU - van Heemst, Diana

AU - Kajantie, Eero

AU - Sorice, Rossella

AU - Gambaro, Giovanni

AU - Scott, Robert A.

AU - Hicks, Andrew A.

AU - Ferrucci, Luigi

AU - Standl, Marie

AU - Lindgren, Cecilia M.

AU - Starr, John M.

AU - Karlsson, Magnus

AU - Lind, Lars

AU - Li, Jun Z.

AU - Chambers, John C.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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.

AB - 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.

KW - C-reactive protein

KW - coronary artery disease

KW - DEPICT

KW - genome-wide association study

KW - inflammation

KW - inflammatory disorders

KW - Mendelian randomization

KW - schizophrenia

KW - system biology

UR - http://www.scopus.com/inward/record.url?scp=85055557317&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2018.09.009

DO - 10.1016/j.ajhg.2018.09.009

M3 - Article

VL - 103

SP - 691

EP - 706

JO - The American Journal of Human Genetics

JF - The American Journal of Human Genetics

SN - 0002-9297

IS - 5

ER -