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

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 (US)
Pages (from-to)691-706
Number of pages16
JournalAmerican Journal of Human Genetics
Volume103
Issue number5
DOIs
StatePublished - Nov 1 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

Keywords

  • C-reactive protein
  • coronary artery disease
  • DEPICT
  • genome-wide association study
  • inflammation
  • inflammatory disorders
  • Mendelian randomization
  • schizophrenia
  • system biology

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

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

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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 Lisa Yanek and Dhananjay Vaidya and Becker, {Diane M}",
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AU - Võsa, Urmo

AU - Stathopoulou, Maria G.

AU - de Vries, Paul S.

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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 - Yanek, Lisa

AU - Vaidya, Dhananjay

AU - Becker, Diane M

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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.

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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

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