Hexosaminidase activity was enriched (p = 3.47 × 10−5) in our results; this enrichment is not driven by a single highly-associated gene; rather, every single gene in the HEX-A pathway is nominally significant in the SCZ association analysis (Supplementary Table 2). Deficiency of hexosaminidase A (HEX-A) results in serious neurological and mental problems, most commonly presenting in infants as “Tay-Sachs” disease39. Adult-onset HEX-A deficiency presents with neurological and psychiatric symptoms, notably including onset of psychosis and schizophrenia40. Five pathways corresponding to Ras- and Rab- signaling, protein regulation and GTPase activity were enriched (p < 6 × 10−5). These pathways have a crucial role in neuron cell differentiation41 and migration42, and have been implicated in the development of schizophrenia and autism43-46. We also find significant enrichment with protein phosphatase type 2A regulator activity (p = 5.24 × 10−5), which was associated with major depressive disorder (MDD) and across MDD, bipolar disorder (BPD) and SCZ in the same large integrative analysis47, and has been implicated in antidepressant response and serotonergic neurotransmission48.
