Genetic predisposition to schizophrenia and circulating proteins in 44,661 UK Biobank participants

Schizophrenia (SCZ) is a highly polygenic disorder and is associated with several comorbidities, including depression, cardiovascular disease, and diabetes; yet the biological pathways underlying this clustering remain poorly understood. This study examined associations between a polygenic risk score for SCZ (PRS-SCZ) and circulating protein levels in 44,661 participants of the UK Biobank. We assessed 1,459 proteins (with ≤ 10% missingness) spanning neurological, inflammatory, cardiometabolic, and oncology panels. After adjustment for technical (population structure, genotyping chip), individual (age, sex, lifestyle), and clinical (comorbidities and medication) variables and multiple testing correction, the standardised PRS-SCZ was significantly negatively associated with C2, RNASET2, BTN2A1, CDSN, HLAE, LTA, MICA-MICB, CNTN3, FCER2, INHBC and CPVL concentrations, and positively with ICAM3, BTN3A2, IL5RA, SLAM7 concentrations. These protein biomarkers may provide insights into the biological pathways underlying schizophrenia and/or its comorbidities.