Analysis of exome sequencing data implicates rare coding variants in STAG1 and ZNF136 in schizophrenia

Rare coding variants across many genes contribute to schizophrenia liability, but they have only been implicated in 12 genes at exome-wide levels of significance. To increase power for gene discovery, we analysed exome-sequencing data for rare coding variants in a new sample of 4,650 schizophrenia cases and 5,719 controls, and combined these with published sequencing data for a total of 28,898 cases, 103,041 controls and 3,444 proband-parent trios. Novel associations were identified for STAG1 and ZNF136 at exome-wide significance and for six additional genes at a false discovery rate of 5%. Among these genes, SLC6A1 and KLC1 are associated with damaging missense variants alone. Four of the eight novel genes are also enriched for rare coding variants in other developmental and psychiatric disorders. Moreover, STAG1 and KLC1 have fine-mapped common variant signals in schizophrenia. These findings provide novel insights into the neurobiology of schizophrenia, including an aetiological role for disrupted chromatin organisation.