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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

, ; , ; Ligthart, Symen; Karlsson, Magnus LU and Alizadeh, Behrooz Z. (2018) In American Journal of Human Genetics 103(5). p.691-706
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,... (More)
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. © 2018 American Society of Human Genetics (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
C-reactive protein, coronary artery disease, DEPICT, genome-wide association study, inflammation, inflammatory disorders, Mendelian randomization, schizophrenia, system biology
in
American Journal of Human Genetics
volume
103
issue
5
pages
16 pages
publisher
Cell Press
external identifiers
  • scopus:85055557317
ISSN
0002-9297
DOI
10.1016/j.ajhg.2018.09.009
language
English
LU publication?
yes
id
caad1057-4d76-46a3-85ca-8fec3806a685
date added to LUP
2018-11-15 09:44:00
date last changed
2019-09-11 04:07:18
@article{caad1057-4d76-46a3-85ca-8fec3806a685,
  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 &lt; 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. © 2018 American Society of Human Genetics},
  author       = {,  and ,  and Ligthart, Symen and Karlsson, Magnus and Alizadeh, Behrooz Z.},
  issn         = {0002-9297},
  keyword      = {C-reactive protein,coronary artery disease,DEPICT,genome-wide association study,inflammation,inflammatory disorders,Mendelian randomization,schizophrenia,system biology},
  language     = {eng},
  number       = {5},
  pages        = {691--706},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2018.09.009},
  volume       = {103},
  year         = {2018},
}