Uppsala universitet, Molekylär epidemiologi, Uppsala universitet, Science for Life Laboratory, SciLifeLab, Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Stanford, CA USA; Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA USA
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.
MEDICIN OCH HÄLSOVETENSKAP -- Hälsovetenskaper -- Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Health Sciences -- Public Health, Global Health, Social Medicine and Epidemiology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Medicinska grundvetenskaper -- Medicinsk genetik (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
NATURVETENSKAP -- Biologiska vetenskaper -- Genetik (hsv//swe)