nominally significantP <1 × 10 −5
In fact, the largest schizophrenia GWAS to date found SNPs in three genes ( CACNA1C , ITPR3 and CYP2D6 ) within the serotonergic synapse pathway reached GWAS significance ( P <5 × 10 −8 ) and SNPs in another 17 genes within this pathway were nominally significant ( P <1 × 10 −5 ). 2 Furthermore, a recent gene-set enrichment analysis of the SZGene database 25 identified 24 pathways significantly enriched for schizophrenia candidate genes among which the serotonin receptor signaling pathway was ranked second. 7 The ubiquitin mediated proteolysis pathway (UPP), a critical system for the removal of damaged/toxic proteins in the cell, has been shown to be dysregulated at the transcript 26 , 27 , 28 , 29 and protein levels 30 in both peripheral and central tissue among individuals with schizophrenia.