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Highlights from the article: B Background: b Historically, gene X environment examinations in psychotic disorders have employed candidate gene methods and environmental determinants impacting on similar biological mechanisms. Indeed, candidate gene approaches might be complementary to GWAS to test gene X cannabis interaction. B Discussion: b Our results suggest that dopamine signaling is implicated in cannabis associated psychosis, and, more specifically, that variation within the DRD2 gene may modulate the effect of cannabis use on psychosis phenotypes.

Highlights from the article: 50de novo lof and damaging missense variants associated with schizophrenia are concentrated in lof intolerant genes B Background: b Exome sequencing studies have shown de novo coding variants to be important risk factors for neuro-psychiatric disorders, such as intellectual disability (ID), autism spectrum disorder (ASD), and schizophrenia. To refine de novo risk variants, we followed published methods by comparing the rate of de novo variants not observed/observed in ExAC and occurring in LoF intolerant/LoF tolerant genes between schizophrenia and unaffected siblings from published ASD studies.

There is strong evidence for partial overlap of genetic influence on Schizophrenia (SCZ), Schizoaffective Disorder (SAD) and Bipolar Affective Disorder (BAD). Part of this is due to common genetic variants, detected by GWAS, with a small individual effect on risk. Recent studies using next generation sequencing reveal growing evidence of the role of rare genetic variants in both diseases. We performed targeted NGS on 187 candidate genes to further investigate the genetic architecture of Bulgarian patients with bipolar disorder and schizophrenia. A total of 300 individuals with BAD, 151 with SCZ, 15 SAD according to DSMIV and ICD-10, as well as 85 healthy population controls and 40 healthy relatives were recruited. The samples were sequenced on the Ion PROTON platform. The sequencing panel comprised of 187 preselected strong candidate genes, based on the results from GWAS and previous NGS studies. Only samples with coverage of at least 95% of the target region at 20x were included in the analyses. Case-control association testing was done using PLINK. The rare variants have been evaluated and divided into groups based on their functional relevance: LOF variants (frameshift and nonsense); with potentially damaging effect on protein function (splice site, missense variants, 3'-UTR/5'-UTR variants); and with no known effect on function (synonymous and intron variants). Genes were prioritized by mutation burden analysis based on the average number of functional occurrences per 1000 bp of the gene CDS. The RVIS scoring system for assessing the intolerance of individual genes to protein-altering variants (Petrovski et al., 2013) was used in conjunction with the burden score for the final ordering. 5373 variants were detected, of which 2826 were found in affecteds (1831 singletons and 995 recurrent). No significant associations between cases and controls could be detected, that survived the correction for multiple testing. In total we found in patients 14 rare LOF variants; 889 non-synonymous variants (243 of which were potentially damaging); 109 splice site variants and 32 in regulatory regions. We could find no significant association of common or rare variants in the analyzed samples, most likely due to small sample size. However, we could identify both recurrent and singleton rare variants with potential functional relevance in genes associated with ion channels, postsynaptic plasticity, neurogenesis and signalling cascade pathways. [ABSTRACT FROM AUTHOR]

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]