M J Moses

Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

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Publications (13)95.75 Total impact

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    ABSTRACT: A susceptibility locus for bipolar disorder was previously localized to chromosome 4q35 by genetic linkage analysis. We have applied a positional cloning strategy, combined with association analysis and provide evidence that a cadherin gene, FAT, confers susceptibility to bipolar disorder in four independent cohorts (allelic P-values range from 0.003 to 0.024). In two case-control cohorts, association was identified among bipolar cases with a family history of psychiatric illness, whereas in two cohorts of parent-proband trios, association was identified among bipolar cases who had exhibited psychosis. Pooled analysis of the case-control cohort data further supported association (P=0.0002, summary odds ratio=2.31, 95% CI: 1.49-3.59). We localized the bipolar-associated region of the FAT gene to an interval that encodes an intracellular EVH1 domain, a domain that interacts with Ena/VASP proteins, as well as putative beta-catenin binding sites. Expression of Fat, Catnb (beta-catenin), and the three genes (Enah, Evl and Vasp) encoding the Ena/VASP proteins, were investigated in mice following administration of the mood-stabilizing drugs, lithium and valproate. Fat was shown to be significantly downregulated (P=0.027), and Catnb and Enah were significantly upregulated (P=0.0003 and 0.005, respectively), in response to therapeutic doses of lithium. Using a protein interaction map, the expression of genes encoding murine homologs of the FAT (ft)-interacting proteins was investigated. Of 14 interacting molecules that showed expression following microarray analysis (including several members of the Wnt signaling pathway), eight showed significantly altered expression in response to therapeutic doses of lithium (binomial P=0.004). Together, these data provide convergent evidence that FAT and its protein partners may be components of a molecular pathway involved in susceptibility to bipolar disorder.
    No preview · Article · May 2006 · Molecular Psychiatry
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    ABSTRACT: The cause of bipolar disorder remains unknown, with little knowledge of the underlying biological, anatomical, biochemical, or genetic defect. The disorder is genetically complex, with an increasing number of loci being implicated through genetic linkage studies. We previously identified a bipolar disorder susceptibility locus on chromosome 4q35 and refined the interval harboring this susceptibility gene to approximately 5 Mb, a size that is amenable to positional cloning. Several independent studies have reported the presence of a susceptibility gene at this locus. To identify candidate genes for testing for association with bipolar disorder, we previously established a transcript map that encompasses the candidate interval. We have continued to seek novel genes from this region in order to expand this transcript map. Here, we describe the further identification and characterization of eight novel genes from the chromosome 4q35 bipolar candidate interval. Expression analysis determined that six of these novel genes are expressed in the brain, and these genes were therefore analyzed for association with bipolar disorder. Single nucleotide polymorphisms were identified from the candidate genes and tested for association in our case-control cohort. Our data suggest that the six candidate genes analyzed can be excluded from involvement in the disorder.
    No preview · Article · Oct 2005 · Psychiatric Genetics
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    ABSTRACT: Bipolar affective disorder is a major psychiatric illness with a population prevalence of up to 1.6%. The disorder is genetically complex. To date, no specific gene or DNA sequence variation that predisposes to the disorder has been described, however several susceptibility loci have been proposed through genetic linkage analysis. We previously identified one such susceptibility locus on chromosome 4q35, and refined the interval harboring this susceptibility gene to a size that is amenable to positional cloning. Several independent studies have now been described that support the presence of a susceptibility gene at this locus. In order to identify candidate genes for testing association with bipolar disorder, we previously established a comprehensive transcript map that encompasses the chromosome 4q35 susceptibility locus implicated in our linkage analysis. In this study, we have selected full-length genes from the transcript map and determined the genomic structure of each gene. We identified informative, intragenic single nucleotide polymorphisms (SNPs) by screening all exons and flanking intron sequences in affected individuals from seven bipolar pedigrees that we previously reported as showing evidence for linkage to chromosome 4q35. Analysis of these SNPs was then extended to our unrelated bipolar case-control cohort to test for association with the disorder. Our data suggests that all genes analyzed can be excluded from direct involvement in the disorder. We have therefore, excluded approximately half the genes within the chromosome 4q35 candidate interval from playing a direct pathogenic role in bipolar disorder.
    No preview · Article · Apr 2005 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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    ABSTRACT: Bipolar affective disorder is a severe mood disorder that afflicts approximately 1% of the population worldwide. Twin and adoption studies have indicated that genetic factors contribute to the disorder and while many chromosomal regions have been implicated, no susceptibility genes have been identified. We undertook a combined analysis of 10 cM genome screen data from a single large bipolar affective disorder pedigree, for which we have previously reported linkage to chromosome 13q14 (Badenhop et al, 2001) and 12 pedigrees independently screened using the same 400 microsatellite markers. This 13-pedigree cohort consisted of 231 individuals, including 69 affected members. Two-point LOD score analysis was carried out under heterogeneity for three diagnostic and four genetic models. Non-parametric multipoint analysis was carried out on regions of interest. Two-point heterogeneity LOD scores (HLODs) greater than 1.5 were obtained for 11 markers across the genome, with HLODs greater than 2.0 obtained for four of these markers. The strongest evidence for linkage was at 3q25-26 with a genome-wide maximum score of 2.49 at D3S1279. Six markers across a 50 cM region at 3q25-26 gave HLODs greater than 1.5, with three of these markers producing scores greater than 2.0. Multipoint analysis indicated a 20 cM peak between markers D3S1569 and D3S1614 with a maximum NPL of 2.8 (P= 0.004). Three other chromosomal regions yielded evidence for linkage: 9q31-q33, 13q14 and 19q12-q13. The regions on chromosomes 3q and 13q have previously been implicated in other bipolar and schizophrenia studies. In addition, several individual pedigrees gave LOD scores greater than 1.5 for previously reported bipolar susceptibility loci on chromosomes 18p11, 18q12, 22q11 and 8p22-23.
    No preview · Article · May 2004 · Molecular Psychiatry
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    ABSTRACT: A susceptibility locus for bipolar affective disorder has been mapped to chromosome 4q35 in a large multigenerational pedigree. We have expanded this analysis to include 55 pedigrees (674 individuals, 214 affecteds). The evidence for linkage to 4q35 was strengthened in this larger cohort, with a maximum two-point LOD score of 3.2 for marker D4S1652. Several other markers in the region gave LOD scores greater than 1.5. Non-parametric analysis provided additional support for linkage to the 4q35 region. To further refine this region, haplotype analysis was carried out in 16 of the 55 pedigrees that showed evidence of linkage. As there is no evidence for an ancestral haplotype, nor a one-to-one correspondence between the disease and putative disease haplotype, we undertook an analysis based on pedigree-specific, identical-by-descent allele-sharing in order to define a probable disease region. This analysis indicated that the percentage sharing of alleles, identical-by-descent, in affecteds of all linked pedigrees increases from 60% at the centromeric markers to 75% for markers at the telomere. Maximal allele sharing occurred between markers D4S3051 and 4qTEL13 with this 24 cM region defining a probable disease region. We have constructed a physical map of the 4q35 interval consisting of a YAC contig and BAC clones. Based on this map the probable disease region between D4S3051 and 4qTEL13 corresponds to only 2.3 Mb. This region is very gene poor with only three known genes indicated from the YAC/BAC map. The small number of genes will facilitate systematic screening for variations associated with bipolar disorder.
    No preview · Article · Feb 2003 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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    ABSTRACT: Bipolar affective disorder is a severe mood disorder that afflicts approximately 1% of the population worldwide. Twin and adoption studies have indicated that genetic factors contribute to the disorder and while many chromosomal regions have been implicated, no susceptibility genes have been identified. We undertook a combined analysis of 10 cM genome screen data from a single large bipolar affective disorder pedigree, for which we have previously reported linkage to chromosome 13q14 (Badenhop et al, 2001) and 12 pedigrees independently screened using the same 400 microsatellite markers. This 13 pedigree cohort consisted of 231 individuals, including 69 affected members. Two-point LOD score analysis was carried out under heterogeneity for three diagnostic and four genetic models. Non-parametric multipoint analysis was carried out on regions of interest. Two-point heterogeneity LOD scores (HLODs) greater than 1.5 were obtained for 11 markers across the genome, with HLODs greater than 2.0 obtained for four of these markers. The strongest evidence for linkage was at 3q25-26 with a genome-wide maximum score of 2.49 at D3S1279. Six markers across a 50 cM region at 3q25-26 gave HLODs greater than 1.5, with three of these markers producing scores greater than 2.0. Multipoint analysis indicated a 20 cM peak between markers D3S1569 and D3S1614 with a maximum NPL of 2.8 (P = 0.004). Three other chromosomal regions yielded evidence for linkage: 9q31-q33, 13q14 and 19q12-q13. The regions on chromosomes 3q and 13q have previously been implicated in other bipolar and schizophrenia studies. In addition, several individual pedigrees gave LOD scores greater than 1.5 for previously reported bipolar susceptibility loci on chromosomes 18p11, 18q12, 22q11 and 8p22-23.
    Full-text · Article · Feb 2002 · Molecular Psychiatry
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    ABSTRACT: Bipolar affective disorder is one of the most common mental illnesses with a population prevalence of approximately 1%. The disorder is genetically complex, with an increasing number of loci being implicated through genetic linkage studies. However, the specific genetic variations and molecules involved in bipolar susceptibility and pathogenesis are yet to be identified. Genetic linkage analysis has identified a bipolar disorder susceptibility locus on chromosome 4q35, and the interval harbouring this susceptibility gene has been narrowed to a size that is amenable to positional cloning. We have used the resources of the Human Genome Project (HGP) and Celera Genomics to identify overlapping sequenced BAC clones and sequence contigs that represent the region implicated by linkage analysis. A combination of bioinformatic tools and laboratory techniques have been applied to annotate this DNA sequence data and establish a comprehensive transcript map that spans approximately 5.5 Mb. This map encompasses the chromosome 4q35 bipolar susceptibility locus, which localises to a "most probable" candidate interval of approximately 2.3 Mb, within a more conservative candidate interval of approximately 5 Mb. Localised within this map are 11 characterised genes and eight novel genes of unknown function, which together provide a collection of candidate transcripts that may be investigated for association with bipolar disorder. Overall, this region was shown to be very gene-poor, with a high incidence of pseudogenes, and redundant and novel repetitive elements. Our analysis of the interval has demonstrated a significant difference in the extent to which the current HGP and Celera sequence data sets represent this region.
    Full-text · Article · Feb 2002 · Molecular Psychiatry
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    Full-text · Article · Feb 2002 · Molecular Psychiatry
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    ABSTRACT: We have developed a novel haplotype-based approach to define a 4q35 bipolar susceptibility region. Linkage analysis in 55 pedigrees gave a maximum two-point LOD score of 3.01 for D4S1652 and scores between 1.5 and 2.44 for several other markers. 24 linked pedigrees were selected for haplotype analysis based on having LOD scores greater than their maximum expected LOD score for multiple markers. There was no ancestral disease haplotype and no one-to-one correspondence between disease and disease haplotype. Therefore we determined a probable disease region based on the percentage of affected individuals within each pedigree sharing the same portion of the disease haplotype and pooled this data across all linked pedigrees. In each pedigree, for each 4q35 marker we calculated the number of affecteds who share the marker allele that forms part of the disease haplotype, identical-by-descent (IBD). The number of affected individuals sharing alleles IBD at each marker was pooled to generate a map of percentage of sharing. A probable disease region of 4.7Mb from D4S1540 to the telomere was defined by maximum allele sharing of affected pedigree members. Using this pedigree specific IBD allele sharing approach provides a means for focusing the candidate gene search for this complex trait.
    No preview · Article · Oct 2001
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    ABSTRACT: Bipolar affective disorder is a severe mood disorder that afflicts approximately 1% of the population worldwide. Twin and adoption studies have indicated that genetic factors contribute to the disorder and while many chromosomal regions have been implicated, no susceptibility genes have been identified. In this present study, we undertook a 10 cM genome screen using 400 microsatellite markers in a large multigenerational bipolar pedigree consisting of 40 individuals, including six affecteds. We found strongest evidence for linkage to chromosome 13q14. A maximum NPL score of 4.09 (P = 0.008) was obtained between markers D13S1272 and D13S153 using GENEHUNTER. A maximum two-point LOD score of 2.91 (theta = 0.0) was found for marker D13S153 and a maximum three-point LOD score of 3.0 was obtained between markers D13S291 and D13S153 under a recessive model with 90% maximum age-specific penetrance and including bipolar I and unipolar individuals as affected. Several other markers in the region, D13S175, D13S218, D13S263, and D13S156 had two-point LOD scores greater than 1.5. These results meet the criteria for evidence of suggestive linkage. Haplotype analysis enabled us to narrow the likely disease region to a 6 cM region between markers D13S1272 and D13S1319, which contains the serotonin 2A receptor candidate gene. Two single nucleotide polymorphisms were identified in this gene but we did not detect any significant differences in allele frequency in a case-control sample. The region on chromosome 13q14-32 has previously been implicated in other bipolar and schizophrenia cohorts. Our results provide further support for the existence of a susceptibility locus on chromosome 13q14.
    Full-text · Article · Aug 2001 · Molecular Psychiatry
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    ABSTRACT: Classical family, twin and adoption studies have indicated a genetic component to bipolar affective disorder (BAD), and a disease prevalence of 1-2% in the population. In order to identify susceptibility loci we have undertaken a 10 cM genomewide screen of 231 individuals from 13 new Australian families. The pedigrees include 33 individuals with bipolar I (BPI), 7 with schizoaffective/mania (SZ/MA) 4 with bipolar II (BPII) and 25 with recurrent unipolar depression (UP), as deter-mined using the Research Diagnostic Criteria diagnostic categories based on the Diagnostic Interview for Genetic Studies (DIGS). All individuals were genotyped for 400 microsatellite markers from the ABI PRISM Linkage Mapping Set Version 2.0 (PE Applied Biosystems) by the Australian Genomic Research Facility, Melbourne, Australia. Analysis of the genotyping data was undertaken using the ANALYZE package. Two different diagnostic models were used in the analysis: Model 1 in which all BPI, BPII and SZ/MA individuals are considered affected and all other family members are considered unaffected; and Model 2 in which all affected individuals from Model 1 and all UP individuals are affected, and all other members are considered unaffected. Data was analyzed using both dominant and recessive models and with two penetrance groups with maximum age-specific penetrance levels of either 60% or 90%. Over all families the maximum lod score obtained was 2.39 (p = 0.0004) for D3S1279 (3q25-q26) from a sibpair analysis on nuclear families using diagnostic model 1. Other two-point lod scores greater than 1.5 were obtained for D9S1776 (9q33) and D19S216 (19p13). Several individual families gave lod scores greater than 2.0. These included lod scores of 2.91 at D13S153 (13q14) in Family 04, 2.38 at D3S1614 (3q25-26) in Family 05, 2.18 at D3S3681 (3p11) in Family 20 and 2.0 at D22S420 (22q11) in Family 03. In addition there was some support for 18p11 in two families, one giving a two-point lod score of 1.8 at D18S53 (Family 17) and another giving a lod score of 1.68 for D18S1102 (Family 22). In conclusion, the results of this genome scan have failed to identify a single major locus. However evidence for potential susceptibility loci has been obtained for chromosomes 3, 13, 18, 22,9 and 19. It is of interest that the loci we have identified on chromosomes 13q14, 18p11 and 22q11 have been implicated by other bipolar disorder genome scans.
    No preview · Article · Aug 2000
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    ABSTRACT: Bipolar affective disorder (BAD) has a lifetime prevalence of 1-2%, and strong heritability is highly suggestive of a genetic component. A 15 cM genome-wide screen of microsatellite markers on 35 individuals from a large and informative Australian pedigree has identified a potential susceptibility locus on chromosome 4q35 (1). Analysis of five markers at 4q35 in a total of 545 individuals (including 158 affecteds) from 41 pedigrees results in a maximum two-point LOD score of 2.56 for D4S1652. A disease haplotype has been found in six of these pedigrees and recombinations within these families narrow the susceptibility region to approximately 4 Mb near the telomeric end of chromosome 4q35. Analysis of the 97 pedigree NIMH cohort (2) also showed six pedigrees with suggestive linkage to chromosome 4q35 and carrying a potential disease haplotype. Using the known EST and STS markers in the region, a YAC/BAC contig has been constructed in order to facilitate the examination of candidate genes. BACs have been identified for 31 markers and 24 ESTs and genes in this region. Candidate genes located within the probable critical region include melatonin receptor 1A (MTNR1A), adenine nucleotide translocator 1 (ANT1) and FSHD region 1 (FRG1), amongst others. Direct sequence analysis of these candidate genes is being used to identify SNP variation. The SNPs are being examined over a population cohort to determine their importance as potential susceptibility alleles.
    No preview · Article · Aug 2000
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    ABSTRACT: Bipolar affective disorder is characterised by severe mood swings (mania and depression) and affects 1-2% of the population. Its complex genetic nature, variable age of onset, and age-specific penetrance confounds linkage studies. No predisposing genes have been identified although a number of groups have mapped susceptibility loci with linkage having been reported to several chromosomes. We have undertaken a two-stage genome screen using 214 microsatellite markers on 87 individuals from the most powerful pedigree in our cohort. The data were analysed by two-point linkage analysis and nonparametric methods under several diagnostic models. Initial lod scores greater than 2 were obtained for four markers although after completion of the second stage, only one marker D4S1652 (θ = 0.15) remained with a lod score of 2.2. Multipoint analysis using additional markers gave a maximum lod score of z = 3.19 between D4S408 and D4S2924. Nonparametric analyses supported our conclusions with a maximum score of 2.61 (P = 0.01) between D4S1652 and D4S171 using Genehunter. Initial analysis of a further 10 pedigrees indicates the presence of the 4q35 locus in at least one additional pedigree. A high density, 1-2 cM map is being constructed using 25 pedigrees (491 individuals, including 115 affected members) to establish a minimal disease haplotype. In summary, our results suggest the presence of an additional susceptibility locus for bipolar disorder on chromosome 4q35.
    No preview · Article · Nov 1998