Gene-set enrichment analyses using Gene Ontology data suggested involvement of pleiotropic risk loci in neurodevelopmental processes (Table S6.1). The 109 pleiotropic risk loci were enriched for genes involved in neurogenesis (gene-set enrichment p = 9.67 × 10−6), regulation of nervous system development (p = 3.41 × 10−5), and neuron differentiation (p = 3.30 × 10−5), while enrichment of these gene-sets was not seen for the 37 disorder-specific risk loci (adjusted enrichment p > 0.05; Table S6.2). Pleiotropic risk loci also showed enrichment of genes involved in specific neurotransmitter-related pathways -- glutamate receptor signaling (p = 2.45 × 10−6) and voltage-gated calcium channel complex (p = 5.72 × 10−4) -- while non-pleiotropic risk loci, which were predominantly SCZ-associated, were over-represented among acetylcholine receptor genes (p = 7.25 × 10−8). Analysis of cortical gene expression data also suggested enrichment of pleiotropic risk genes in cortical glutamatergic neurons through layers 2–6 (Table S6.3), further supporting the shared role of glutamate receptor signaling in the pathogenesis of diverse neuropsychiatric disorders.
