The relationship between schizophrenia and rheumatoid arthritis revisited: genetic and epidemiological analyses.

Epidemiological studies are inconsistent on the relationship between schizophrenia (SCZ) and rheumatoid arthritis (RA). Several studies have shown that SCZ has a protective effect on RA, with RA occurring less frequently in SCZ cases than would be expected by chance, whilst other studies have failed to replicate this. We sought to test the hypothesis that this effect is due to a protective effect of SCZ risk alleles on RA onset. We first reviewed the literature on the comorbidity of RA and SCZ and performed a meta-analysis. We then used polygenic risk scoring in an RA case control study in order to investigate the contribution of SCZ risk alleles to RA risk. Meta-analysis across studies over the past half-century showed that prevalence of RA in SCZ cases was significantly reduced (OR=0.48, 95% CI: 0.34-0.67, p<0.0001). The relationship between SCZ genetic risk and RA status was weak. Polygenic risk of SCZ explained a small (0.1%) and non-significant (p=0.085) proportion of variance in RA case control status. This relationship was nominally positive, with RA cases carrying more SCZ risk alleles than controls. The current findings do not support the assertion that the relationship between RA and SCZ is explained by genetic factors, which appear to have little or no effect. The protective effect of SCZ on RA may be due to environmental factors, such as an anti-inflammatory effect of anti-psychotic medication or merely due to confounding limitations in study designs.