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1.  A t(1;11) translocation linked to schizophrenia and affective disorders gives rise to aberrant chimeric DISC1 transcripts that encode structurally altered, deleterious mitochondrial proteins 
Human Molecular Genetics  2012;21(15):3374-3386.
Disrupted-In-Schizophrenia 1 (DISC1) was identified as a risk factor for psychiatric illness through its disruption by a balanced chromosomal translocation, t(1;11)(q42.1;q14.3), that co-segregates with schizophrenia, bipolar disorder and depression. We previously reported that the translocation reduces DISC1 expression, consistent with a haploinsufficiency disease model. Here we report that, in lymphoblastoid cell lines, the translocation additionally results in the production of abnormal transcripts due to the fusion of DISC1 with a disrupted gene on chromosome 11 (DISC1FP1/Boymaw). These chimeric transcripts encode abnormal proteins, designated CP1, CP60 and CP69, consisting of DISC1 amino acids 1–597 plus 1, 60 or 69 amino acids, respectively. The novel 69 amino acids in CP69 induce increased α-helical content and formation of large stable protein assemblies. The same is predicted for CP60. Both CP60 and CP69 exhibit profoundly altered functional properties within cell lines and neurons. Both are predominantly targeted to mitochondria, where they induce clustering and loss of membrane potential, indicative of severe mitochondrial dysfunction. There is currently no access to neural material from translocation carriers to confirm these findings, but there is no reason to suppose that these chimeric transcripts will not also be expressed in the brain. There is thus potential for the production of abnormal chimeric proteins in the brains of translocation carriers, although at substantially lower levels than for native DISC1. The mechanism by which inheritance of the translocation increases risk of psychiatric illness may therefore involve both DISC1 haploinsufficiency and mitochondrial deficiency due to the effects of abnormal chimeric protein expression.
GenBank accession numbers: DISC1FP1 (EU302123), Boymaw (GU134617), der 11 chimeric transcript DISC1FP1 exon 2 to DISC1 exon 9 (JQ650115), der 1 chimeric transcript DISC1 exon 4 to DISC1FP1 exon 4 (JQ650116), der 1 chimeric transcript DISC1 exon 6 to DISC1FP1 exon 3a (JQ650117).
PMCID: PMC3392113  PMID: 22547224
2.  A novel balanced chromosomal translocation found in subjects with schizophrenia and schizotypal personality disorder: altered L-serine level associated with disruption of PSAT1 gene expression 
Neuroscience research  2010;69(2):154-160.
L-Serine is required for the synthesis of glycine and D-serine, both of which are NMDA receptor co-agonists. Although roles for D-serine and glycine have been suggested in schizophrenia, little is known about the role of the L-serine synthesizing cascade in schizophrenia or related psychiatric conditions. Here we report a patient with schizophrenia carrying a balanced chromosomal translocation with the breakpoints localized to 3q13.12 and 9q21.2. We examined this proband and her son with schizotypal personality disorder for chromosomal abnormalities, molecular expression profiles, and serum amino acids. Marked decrease of L-serine and glutamate was observed in the sera of the patient and her son, compared with those in normal controls. Interestingly, expression of PSAT1 gene, which is located next to the breakpoint and encodes one of the enzymes in the L-serine synthesizing cascade, was reduced in both patient and her son. Direct effect of impaired PSAT1 gene expression on decreased serum L-serine level was strongly implicated by rat astrocyte experiments. In summary, we propose an idea that PSAT1 may be implicated in altered serine metabolism and schizophrenia spectrum conditions.
PMCID: PMC3049551  PMID: 20955740
schizophrenia; balanced chromosomal translocation; PSAT1; L-serine; D-serine; glycine; glutamate; expression
3.  Clustered Coding Variants in the Glutamate Receptor Complexes of Individuals with Schizophrenia and Bipolar Disorder 
PLoS ONE  2011;6(4):e19011.
Current models of schizophrenia and bipolar disorder implicate multiple genes, however their biological relationships remain elusive. To test the genetic role of glutamate receptors and their interacting scaffold proteins, the exons of ten glutamatergic ‘hub’ genes in 1304 individuals were re-sequenced in case and control samples. No significant difference in the overall number of non-synonymous single nucleotide polymorphisms (nsSNPs) was observed between cases and controls. However, cluster analysis of nsSNPs identified two exons encoding the cysteine-rich domain and first transmembrane helix of GRM1 as a risk locus with five mutations highly enriched within these domains. A new splice variant lacking the transmembrane GPCR domain of GRM1 was discovered in the human brain and the GRM1 mutation cluster could perturb the regulation of this variant. The predicted effect on individuals harbouring multiple mutations distributed in their ten hub genes was also examined. Diseased individuals possessed an increased load of deleteriousness from multiple concurrent rare and common coding variants. Together, these data suggest a disease model in which the interplay of compound genetic coding variants, distributed among glutamate receptors and their interacting proteins, contribute to the pathogenesis of schizophrenia and bipolar disorders.
PMCID: PMC3084736  PMID: 21559497
4.  A case-control association study and family-based expression analysis of the bipolar disorder candidate gene PI4K2B 
Journal of Psychiatric Research  2009;43(16-3):1272-1277.
Bipolar disorder, schizophrenia and recurrent major depression are complex psychiatric illnesses with a substantial, yet unknown genetic component. Linkage of bipolar disorder and recurrent major depression with markers on chromosome 4p15–p16 has been identified in a large Scottish family and three smaller families. Analysis of haplotypes in the four chromosome 4p-linked families, identified two regions, each shared by three of the four families, which are also supported by a case-control association study. The candidate gene phosphatidylinositol 4-kinase type-II beta (PI4K2B) lies within one of these regions. PI4K2B is a strong functional candidate as it is a member of the phosphatidylinositol pathway, which is targeted by lithium for therapeutic effect in bipolar disorder. Two approaches were undertaken to test the PI4K2B candidate gene as a susceptibility factor for psychiatric illness. First, a case-control association study, using tagging SNPs from the PI4K2B genomic region, in bipolar disorder (n = 368), schizophrenia (n = 386) and controls (n = 458) showed association with a two-marker haplotype in schizophrenia but not bipolar disorder (rs10939038 and rs17408391, global P = 0.005, permuted global P = 0.039). Second, expression studies at the allele-specific mRNA and protein level using lymphoblastoid cell lines from members of the large Scottish family, which showed linkage to 4p15–p16 in bipolar disorder and recurrent major depression, showed no difference in expression differences between affected and non-affected family members. There is no evidence to suggest that PI4K2B is contributing to bipolar disorder in this family but a role for this gene in schizophrenia has not been excluded.
PMCID: PMC2789249  PMID: 19539307
Bipolar disorder; Chromosome 4p15; PI4K2B; Phosphatidylinositol pathway; Association; Expression studies
5.  Genomewide Association for Major Depressive Disorder: A possible role for the presynaptic protein Piccolo 
Molecular psychiatry  2008;14(4):359-375.
Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network (GAIN) initiative of the US Foundation for the National Institutes of Health, we conducted a genomewide association study of 435,291 SNPs genotyped in 1,738 MDD cases and 1,802 controls selected to be at low liability for MDD. Eleven of the top 200 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and plays an important role in monoaminergic neurotransmission in the brain) with p-values of 7.7×10−7 for rs2715148 and 1.2×10−6 for rs2522833. We undertook replication of SNPs in this region in 5 independent samples (6,079 MDD independent cases and 5,893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded p=6.4×10−8 for the non-synonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding-domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.
PMCID: PMC2717726  PMID: 19065144
major depressive disorder; genome-wide association; Netherlands Study of Depression and Anxiety; Netherlands Twin Registry
6.  Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder 
Nature genetics  2008;40(9):1056-1058.
To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 × 10-9) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 × 10-8, rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder.
PMCID: PMC2703780  PMID: 18711365
7.  A 4q35.2 subtelomeric deletion identified in a screen of patients with co-morbid psychiatric illness and mental retardation 
BMC Medical Genetics  2004;5:21.
Cryptic structural abnormalities within the subtelomeric regions of chromosomes have been the focus of much recent research because of their discovery in a percentage of people with mental retardation (UK terminology: learning disability). These studies focused on subjects (largely children) with various severities of intellectual impairment with or without additional physical clinical features such as dysmorphisms. However it is well established that prevalence of schizophrenia is around three times greater in those with mild mental retardation. The rates of bipolar disorder and major depressive disorder have also been reported as increased in people with mental retardation. We describe here a screen for telomeric abnormalities in a cohort of 69 patients in which mental retardation co-exists with severe psychiatric illness.
We have applied two techniques, subtelomeric fluorescence in situ hybridisation (FISH) and multiplex amplifiable probe hybridisation (MAPH) to detect abnormalities in the patient group.
A subtelomeric deletion was discovered involving loss of 4q in a patient with co-morbid schizoaffective disorder and mental retardation.
The precise region of loss has been defined allowing us to identify genes that may contribute to the clinical phenotype through hemizygosity. Interestingly, the region of 4q loss exactly matches that linked to bipolar affective disorder in a large multiply affected Australian kindred.
PMCID: PMC515177  PMID: 15310400
8.  SNP genotyping on pooled DNAs: comparison of genotyping technologies and a semi automated method for data storage and analysis 
Nucleic Acids Research  2002;30(15):e74.
We have compared the accuracy, efficiency and robustness of three methods of genotyping single nucleotide polymorphisms on pooled DNAs. We conclude that (i) the frequencies of the two alleles in pools should be corrected with a factor for unequal allelic amplification, which should be estimated from the mean ratio of a set of heterozygotes (k); (ii) the repeatability of an assay is more important than pinpoint accuracy when estimating allele frequencies, and assays should therefore be optimised to increase the repeatability; and (iii) the size of a pool has a relatively small effect on the accuracy of allele frequency estimation. We therefore recommend that large pools are genotyped and replicated a minimum of four times. In addition, we describe statistical approaches to allow rigorous comparison of DNA pool results. Finally, we describe an extension to our ACeDB database that facilitates management and analysis of the data generated by association studies.
PMCID: PMC137092  PMID: 12140336

Results 1-8 (8)