Shared genetic architecture of schizophrenia and lupus identifies pleiotropic loci with distinct downstream...

Schizophrenia (SCZ) and systemic lupus erythematosus (SLE) exhibit epidemiological overlap, suggesting shared genetic underpinnings. Using the largest SLE genome-wide association study (GWAS) to date, we identified a significant genetic correlation between SCZ and SLE (rg = 0.25, p = 9.0 × 10-4). Cross-trait analysis nominated multiple candidate shared loci outside the major histocompatibility complex (MHC), most with aligned effects. The strongest candidate shared association was found at the FURIN-FES locus, previously implicated in SCZ and newly associated with SLE. In addition to FURIN-FES, FCGR2A, DOT1L and an intergenic noncoding RNA locus on chromosome 2 showed additional evidence consistent with shared association. Functional annotation showed that this locus modulated the expression of FURIN, which encodes a proprotein convertase involved in diverse biological processes, and FES, which encodes a tyrosine kinase important in innate immune signalling. The shared risk allele was also associated with altered plasma levels of FURIN, FES, and their functional partners (GDF2, BMP10, NTF4, FER). Tissue- and cell-type-specific eQTL analysis revealed distinct regulatory effects: FURIN expression was perturbed in neuronal and immune cells, while FES expression was altered in immune cells. Mendelian randomisation supported a causal role for FES protein in both disorders. These findings highlight that pleiotropy at the FURIN-FES locus for SCZ and SLE is compatible with disease-specific mechanisms. This underscores that shared genetics across traits does not necessarily mean shared biology.