C-reactive protein polygenic risk is associated with obesity-related traits in schizophrenia spectrum disorders

Patients with schizophrenia spectrum disorders (SSDs) are at increased risk of cardiometabolic dysregulations, which substantially contribute to cardiovascular morbidity and reduced life expectancy. Chronic low-grade inflammation is a key factor in the development of cardiometabolic outcomes. Polygenic risk scores (PRS) for inflammatory biomarkers like for C-reactive protein (CRP) and interleukin 6 (IL-6) may help clarify the genetic contribution to this risk, yet evidence in SSDs populations remains limited.

We investigated the associations of PRSes for CRP and IL6 with cardiometabolic outcomes in 671 patients with SSDs from the longitudinal Dutch Genetic Risk and Outcome in Psychosis (GROUP) study. Seven PRS_CRP and seven PRS_IL-6 were constructed using clumping and threshold method at seven P-value thresholds (P _{t_x}) based on large, independent genome-wide association studies. We examined 11 cardiometabolic outcomes measured at three years after diagnosis, including body mass index (BMI), waist circumference (WC), lipid levels, blood pressures, glycaemic markers, and a metabolic composite score. Linear regression models adjusted for age, sex, and population substructure tested the associations between PRSes, with multiple testing correction and bootstrapping for validation. Regression coefficients (β _P-threshold ) and 95% confidence intervals and unadjusted R² (variance explained) were reported. Sensitivity analyses were conducted by further adjusting for smoking and antipsychotic medication use.

Higher standardized PRS_CRP was significantly associated with increased BMI (β_{Pt_0.5} = 0.64, 95%CI=0.21-1.02, P_bootstapping  = 0.003) and WC (β_{Pt_0.5} = 2.25, 1.00-3.53, P_bootstapping  < 0.001), explaining up to 1.85% variance in BMI, and 2.52% in WC. Nominal associations were also observed between PRS_CRP and triglycerides (TG) levels (β_{Pt_0.2} = 0.13, 0.01-0.26, P_bootstapping  = 0.036), and metabolic composite score (β_{Pt_0.2} = 0.14, 0.04-0.24, P_bootstapping  = 0.006), and between PRS_IL-6 and HbA1c level (β_{Pt_5e06}=-0.66, -1.26 to -0.05, P_bootstapping  = 0.033); however these associations did not remain significant after correction for multiple testing.

Higher genetic susceptibility for low grade inflammation as captured by PRS_CRP is modestly but robustly associated with increased levels of obesity-related traits in SSDs independent from antipsychotics use. These results support CRP-related genetics pathways as potential contributors to risk of cardiometabolic vulnerability in SSDs and may inform genetic-based personalized risk stratification and prevention strategies in SSDs patients.