Elevated C-reactive protein associated with late- and very-late-onset schizophrenia in the general population: a prospective study

Abstract

Background: Individuals with autoimmune diseases and severe infections have persistent or acutely elevated inflammatory biomarkers and increased risk of schizophrenia. We tested the hypothesis that baseline elevated plasma levels of the inflammatory biomarker, C-reactive protein (CRP), associate with increased risk of late- and very-late-onset schizophrenia in the general population, and if such an association possibly is causal.

Method: We analyzed data from 78 810 men and women, aged 20-100 years, from 2 large population studies. Endpoints were hospitalization with schizophrenia and schizophrenia and schizophrenia-like psychosis combined. We performed prospective and cross-sectional analyses adjusted for potential confounders with up to 20 years of follow-up. Furthermore, we used genetic variants influencing plasma CRP levels to perform a Mendelian randomization study.

Results: Age- and gender-adjusted hazard ratios vs individuals in the first quartile of CRP were 1.7 (95% CI: 0.3-8.9) for second quartile, 2.1 (0.4-10) for third quartile, and 11 (2.8-40) for fourth quartile individuals. The corresponding hazard ratio for fourth quartile individuals after multifactorial adjustment was 5.9 (1.4-24). Furthermore, individuals with vs without schizophrenia had 63% increased plasma levels of CRP (P = 1 × 10(-4)). Finally, when CRP was on a continuous scale, a doubling in CRP yielded an age- and gender-adjusted observational OR of 1.5 (1.3-1.8) and a corresponding causal OR of 1.4 (0.5-4.3) (observed vs causal: P = .89).

Conclusion: Baseline elevated plasma CRP is associated with a 6- to 11-fold increased risk of late- and very-late-onset schizophrenia in the general population. We cannot exclude that this is a causal association. These are novel findings.

Keywords: epidemiology; genetics; inflammation; schizophrenia.

Fig. 1.

Prospective analyses of the associations between schizophrenia and C-reactive protein (CRP) quartiles (top) and between schizophrenia and schizophrenia-like psychosis combined and CRP quartiles (bottom) in the general population. Based on 78 810 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study combined, followed for up to 20 years; individuals with a hospitalization with the relevant endpoint before CRP measurements were excluded (schizophrenia, n = 34; schizophrenia + schizophrenia-like psychosis, n = 73). Multifactorially adjusted was for age, gender, alcohol consumption, smoking, education, income, body mass index, chronic disease, plasma cholesterol, plasma triglycerides, plasma high-density lipoprotein cholesterol, and use of statins. For a color version, see this figure online.

Fig. 2.

Cumulative incidence of schizophrenia (top) and the combined endpoint of schizophrenia and schizophrenia-like psychosis (bottom) as a function of age by quartiles of C-reactive protein (CRP). Based on 78 810 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study combined, followed for up to 20 years; individuals with a hospitalization with the relevant endpoint before CRP measurements were excluded (schizophrenia, n = 34; schizophrenia + schizophrenia-like psychosis, n = 73). For a color version, see this figure online.

Fig. 3.

Plasma C-reactive protein (CRP) levels in individuals with and without schizophrenia (top) or the combined endpoint of schizophrenia and schizophrenia-like psychosis (bottom) before or after CRP measurement. Based on 78 810 individuals from the Copenhagen General Population Study and Copenhagen City Heart Study combined. Multifactorially adjusted was for age, gender, alcohol consumption, smoking, education, income, body mass index, chronic disease, plasma cholesterol, plasma triglycerides, plasma high-density lipoprotein cholesterol, and use of statins. Plasma CRP is shown as mean ± SE. For a color version, see this figure online.

Fig. 4.

Mendelian randomization. (A) Theoretically predicted and observed risk of schizophrenia as a function of C-reactive protein (CRP) gene SNPs and genotype combination. (B) Instrumental variable analysis. Based on 78 810 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study combined. Theoretically predicted risk was adjusted for age and gender (A). Multifactorially adjusted was for age, gender, alcohol consumption, smoking, education, income, body mass index, chronic disease, plasma cholesterol, plasma triglycerides, plasma high-density lipoprotein cholesterol, and use of statins (B). Causal risk estimates were not adjusted.