Search

Context Traditionally, the search for genes involved in predisposition to major psychoses has proceeded with separate studies of schizophrenia and bipolar disorder. However, twin data suggest that, in addition to genes with specificity for these phenotypes, there exist genes that simultaneously influence susceptibility to schizophrenia, bipolar disorder, and schizoaffective disorder. Objective To undertake, to our knowledge, the first systematic search for such loci. Design Genomewide linkage scan. Setting Affected individuals were ascertained in the United Kingdom and Ireland from general psychiatric inpatient and outpatient services. Participants The families were selected for linkage studies of either schizophrenia or bipolar disorder. Pedigrees were selected for the current analysis where there was at least 1 member with DSM-IV schizoaffective disorder, bipolar type. Within these pedigrees, individuals were coded as affected if they had been diagnosed with DSM-IV schizophrenia, schizoaffective disorder of bipolar type, or bipolar I disorder. A total of 24 pedigrees contributed 35 affected sibling pairs to the sample. Method A 10-centimorgan genome scan using microsatellite markers was analyzed using MAPMAKER/SIBS software. Results A genomewide significant signal (LOD = 3.54) was observed at chromosome 1q42 (near D1S2800), and suggestive LOD scores were observed at chromosomes 22q11 (LOD = 1.96) and 19p13 (LOD = 1.85). No linkage was observed in these regions in our original schizophrenia or bipolar scans in individuals from the United Kingdom. Conclusions Our linkage findings strongly support the existence of loci that influence susceptibility across the functional psychosis spectrum. The DISC1 gene lies within 2.5 megabases of our peak marker on chromosome 1q42 and has been previously implicated in schizophrenia, bipolar disorder, and, recently, schizoaffective disorder. Follow-up of this region should use samples enriched for cases of schizoaffective disorder. Our findings have similar implications for the search for genetic variation on chromosome 22q11 that influences susceptibility to psychosis. [ABSTRACT FROM AUTHOR]

Presents an editorial about schizophrenia. Speculation on the causes of schizophrenia; Discussion of a recent study; Hypotheses regarding dopamine and neurodevelopment; Assertion that the fundamental causes of schizophrenia are exerted from early in life and well before the changes in neurotransmission at the onset of acute psychosis; Vagueness of the hypotheses regarding schizophrenia; Need for the specific mechanisms to be identified by which the current crop of genes alters risk of schizophrenia and the molecular processes that link these primary events to altered function.

Abstract: AKT1 (V-akt murine thyoma viral oncogene homolog 1) is involved in intracellular signalling pathways postulated as of aetiological importance in schizophrenia. Markers in the AKT1 gene have also recently been associated with schizophrenia in two samples of European origin and in Japanese and Iranian samples. Aiming to replicate these findings, we examined ten SNPs spanning AKT1 in a UK case-control sample (schizophrenia cases n =673, controls n =716). These included all SNPs previously reported to be associated in European, Japanese and Iranian samples, alone or in haplotypes, as well as additional markers defined by the Haploview Tagger program (pair-wise tagging, minimum r 2 =0.8, minor allele frequency=0.02). We found no association with single markers (min p =0.17). We found weak evidence for association (p =0.04) with a four marker haplotype reported as significant in the original positive European sample of Emamian et al. [Emamian, E.S., Hall, D., Birnbaum, M.J., Karayiorgou, M., Gogos, J.A., 2004. Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat. Genet. 36, 131–137] and also an overlapping three marker haplotype (p =0.016) that had previously been reported as significant in a Japanese sample. Nominal p-values for these haplotypes did not survive correction for multiple testing. Our study provides at best weak support for the hypothesis that AKT1 is a susceptibility gene for schizophrenia. Examination of our own data and those of other groups leads us to conclude that overall, the evidence for association of AKT1 as a susceptibility gene for schizophrenia is weakly positive, but not yet convincing. [Copyright &y& Elsevier]

Abstract: Synergistic interaction between genes on chromosome 22q11 recently has been proposed as a possible mechanism which could confer increased risk for schizophrenia. Based on this hypothesis, our study aimed to explore main, cis- and trans-interacting effects of three candidate genes on 22q11, ProDH, COMT and ZDHHC8. We selected four putative risk variants, residing within these genes, ProDH 1945, ProDH 2026, COMT ValMet and ZDHHC8 rs175174, and studied these in a large family-based schizophrenia association sample of European origin (488 Bulgarian parent–offspring trios). The presence of interaction between the variants was tested by conditional logistic regression analysis based on a case–pseudocontrol design. Our study did not find statistical evidence for allelic (investigation of ProDH markers only), genotypic, haplotypic, or interactive effects between ProDH, COMT and ZDHHC8. Our data do not support the hypothesis that an interaction between these genes influences susceptibility to schizophrenia. [Copyright &y& Elsevier]

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.

Background: Several studies support the dysbindin (dystrobrevin binding protein 1) gene (DTNBP1) as a susceptibility gene for schizophrenia. We previously reported that variation at a specific 3-locus haplotype influences susceptibility to schizophrenia in a large United Kingdom (UK) Caucasian case-control sample. Methods: Using similar methodology to our schizophrenia study, we have investigated this same 3-locus haplotype in a large, well-characterized bipolar sample (726 Caucasian UK DSM-IV bipolar I patients; 1407 ethnically matched controls). Results: No significant differences were found in the distribution of the 3-locus haplotype in the full sample. Within the subset of bipolar I cases with predominantly psychotic episodes of mood disturbance (n = 133) we found nominally significant support for association at this haploptype (p < .042) and at SNP rs2619538 (p = .003), with a pattern of findings similar to that in our schizophrenia sample. This finding was not significant after correction for multiple testing. Conclusions: Our data suggest that variation at the polymorphisms examined does not make a major contribution to susceptibility to bipolar disorder in general. They are consistent with the possibility that DTNBP1 influences susceptibility to a subset of bipolar disorder cases with psychosis. However, our subset sample is small and the hypothesis requires testing in independent, adequately powered samples. [Copyright &y& Elsevier]

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]