We used these genic associations to search for enrichments with molecular pathways and gene sets, and identified 36 significant enriched pathways. Among novel pathways, we identified a significant association with HEX-A deficiency. Despite the well-studied and documented symptomatic overlap between adult-onset HEX-A deficiency and schizophrenia, we believe that this is the first demonstration of shared genetics between the disorders. Notably, this overlap is not driven by a single highly-associated gene which is shared by both disorders; rather, every single gene in the HEX-A pathway is nominally significant in the SCZ association analysis, and five genes have p < 1 × 10−3, indicating that there may be substantial shared genetic etiology between the two disorders that warrants further investigation. Additionally, we identified a significant overlap between our SCZ-associated genes and a number of pathways associated with porphyrin metabolism. Porphyric disorders have been well characterized and are among early descriptions of “schizophrenic” and psychotic presentations of schizophrenia, as described in the likely eponymous mid-19th century poem “Porphyria’s Lover”, by Robert Browning61, and have been cited as a likely diagnosis for the various psychiatric and metabolic ailments of Vincent van Gogh62-67 and King George III68.
