SA99 - TARGETED SEQUENCING OF 187 PUTATIVE SCHIZOPHRENIA RISK GENES IN 5,207 CASES AND 4,991 CONTROLS.

Recent sequencing studies have shown a small fraction of SZ risk comes from rare mutations. They have also advanced our understanding of SZ pathophysiology, with multiple studies implicating post-synaptic proteins, including the activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-d-aspartate receptor (NMDAR) complexes. Thus far, only one gene, SETD1A, has been associated with SZ at genome-wide levels of significance. We aimed to identify novel SZ genes by sequencing 187 genes in 5,207 cases and 4,991 controls. Included among these genes are members of ARC and NMDAR complexes, as well as Voltage-Gated Sodium (VGSC) and Calcium Channels (VGCC), all of which have been previously implicated in SZ. A total of 5,724 cases, 5,769 controls were selected for Ion Torrent sequencing of 187 candidate SZ genes. None of these samples have been included in previous SZ sequencing studies. After stringent quality control (low sequence quality, relatedness and ancestry), our sample consisted 5,207 cases and 4,991 controls. Gene-set and single-gene association statistics were generated using a Firth's penalised-likelihood logistic regression model. Cases had a significant excess of Loss-of-Function (LoF) mutations (< 0.1%) in all 187 genes after correction for multiple testing (P=0.0023, OR=1.33). No other class of mutation was enriched in cases after correction for multiple testing. For gene-sets previously implicated in SZ, cases had higher rates of LoF mutations in ARC (P=0.047, OR=2.7), NMDAR (P=0.024, OR=1.7), and VGSCs (P=0.015, OR=1.98). No support was found for association with VGCCs (P=0.22, OR=0.72). We observed strong enrichment of LoF alleles in genes previously associated with Developmental Disorders (DD) (P=0.0025, OR=8.21). No single gene was significantly associated with SZ after correction for multiple testing. In a new, independent sequencing study of SZ, we found an excess of LoF alleles in cases in all 187 targeted genes, and provide independent support for the involvement of ARC and NMDAR post-synaptic protein complexes, and voltage-gated sodium channels, in SZ pathogenesis. We also provide further evidence for a shared genetic risk between SZ and DD. However, our study was underpowered to identify specific risk genes. [ABSTRACT FROM AUTHOR]