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Adolescent
Adult
Aged
Aged, 80 and over
Biomarkers/metabolism
Bipolar Disorder/genetics/metabolism
Body Mass Index
C-Reactive Protein/genetics
Child
Female
Genetic Loci/*genetics
Genome-Wide Association Study/methods
Humans
Inflammation/*genetics/metabolism
Liver/metabolism/pathology
Male
Mendelian Randomization Analysis/methods
Metabolic Networks and Pathways/*genetics
Middle Aged
Schizophrenia/genetics/metabolism
Young Adult
*C-reactive protein
*depict
*Mendelian randomization
*coronary artery disease
*genome-wide association study
*inflammation
*inflammatory disorders
*schizophrenia
*system biology
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 x 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.
