Identification of genetic loci that overlap between schizophrenia and metabolic syndrome

Patients with schizophrenia (SCZ) frequently exhibit an elevated risk of metabolic syndrome (MetS), which may lead to a worse clinical outcome. Even though these two phenotypes are genetically linked, little is known about their shared genetic determinants. Here, we investigated whether SCZ and MetS share genetic risk factors. To examine the genetic overlap between the two disorders, we applied a comprehensive genetic overlap analysis by integrating GWAS data for SCZ (n = 320,404) and MetS (n = 291,107) at the genome, genetic variants, and gene levels. At the genome level, we observed polygenic overlap between SCZ and MetS by utilizing LDSC (r_g=-0.09, P = 1 × 10^-4) and GNOVA (rho=-0.04, P = 1.39 × 10^-8) analysis. At the SNP level, we performed conjunctional FDR (conjFDR) analysis to identify genetic variants simultaneously associated with two phenotypes. Based on conjFDR < 0.05, we identified 22 loci shared between SCZ and MetS. At the gene level, we further demonstrated that SCZ- and MetS-inferred gene expression overlapped across 49 GTEx tissues and highlighted the PCCB and KCTD13 genes as putative mediators of the genetic association. Overall, these findings shed novel light on the association between SCZ and MetS, and potentially enhance our knowledge of the high comorbidity and genetic processes that overlap between the two disorders.