A Susceptibility Locus for Bipolar Affective Disorder on Chromosome 4q35

Adams, Linda J.; Mitchell, Philip B.; Fielder, Sharon L.; Rosso, A; Donald, Jennifer A.; Schofield, Peter R.

doi:10.1086/301826

Cited by 90 publications

(71 citation statements)

References 28 publications

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“…Other chromosomal regions with suggestive linkage peaks in the genome-wide scan showed consistent results with other studies. The suggestive peaks at 4q and 13q are consistent with significant linkage results previously reported by our group in independent Australian BP cohorts, 32,42 while the 6q locus was reported as one of two confirmed BP loci in a genome-wide meta-analysis of 1067 families. 43 The supplementary markers were added to confirm the genome-wide linkage to 15q, and to gain greater location estimates for a BP susceptibility gene around the maximal genome scan marker D15S130.…”

Section: Discussionsupporting

confidence: 91%

“…Four liability classes (class 1, < 20 years; class 2, 20-29 years; class 3, 30-39 years; and class 4, > 40 years) were used in the analyses with maximum age-specific penetrance levels of either 60 or 90%. 32 In the 90% model, liability classes were defined with penetrances of 0.18, 0.45, 0.68 and 0.9; those in the 60% model were defined with penetrances of 0.12, 0.30, 0.45 and 0.6. The data was analysed under both dominant and recessive inheritance models.…”

Section: Genotypingmentioning

confidence: 99%

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A genome screen of 35 bipolar affective disorder pedigrees provides significant evidence for a susceptibility locus on chromosome 15q25-26

et al. 2008

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Bipolar affective disorder is a heritable, relatively common, severe mood disorder with lifetime prevalence up to 4%. We report the results of a genome-wide linkage analysis conducted on a cohort of 35 Australian bipolar disorder families which identified evidence of significant linkage on chromosome 15q25-26 and suggestive evidence of linkage on chromosomes 4q, 6q and 13q. Subsequent fine-mapping of the chromosome 15q markers, using allele frequencies calculated from our cohort, gave significant results with a maximum two-point LOD score of 3.38 and multipoint LOD score of 4.58 for marker D15S130. Haplotype analysis based on pedigree-specific, identical-by-descent allele sharing, supported the location of a bipolar susceptibility gene within the Z maxÀ1 linkage confidence interval of 17 cM, or 6.2 Mb, between markers D15S979 and D15S816. Non-parametric and affecteds-only linkage analysis further verified the linkage signal in this region. A maximum NPL score of 3.38 (P = 0.0008) obtained at 107.16 cM (near D15S130), and a maximum two-point LOD score of 2.97 obtained at marker D15S1004 (affecteds only), support the original genome-wide findings on chromosome 15q. These results are consistent with four independent positive linkage studies of mood and psychotic disorders, and raise the possibility that a common gene for susceptibility to bipolar disorder, and other psychiatric disorders may lie in this chromosome 15q25-26 region. Keywords: bipolar affective disorder; manic depressive illness; susceptibility locus; genetic linkage; chromosome 15q Bipolar (BP) affective disorder (MIM 125480) is a severe mood disorder characterised by alternating periods of mania and depression with reversion to normal behaviour in between these episodes. Bipolar disorder is a relatively common condition with a worldwide prevalence between 0.5 and 1.5% 1 and lifetime prevalence of up to 4%. 2 The disorder has a severe impact on sufferers, being ranked the sixth most debilitating disorder in the World Health Organisation Global Burden of Disease Report, 3 and results in suicide rates 15 times higher than the general population. 4 The aetiology of bipolar disorder remains unknown, with little knowledge of the underlying biological, anatomical or biochemical effects. However, family, twin and adoption studies have provided strong evidence that genetic factors contribute to the disorder with heritability estimates in the range of 60-85%. 5,6 The high heritability, increased relative risks within families, 7 and familial clustering of the disorder provide the opportunity to use genetic approaches to identify predisposing genes. The inheritance pattern of the disorder is complex with non-Mendelian inheritance suggesting the involvement of multiple genes and environmental factors.Many genetic studies have attempted to map BP susceptibility loci and have provided evidence for linkage to a number of chromosomal regions (reviewed by Baron 8 ). One meta-analysis of wholegenome linkage scans did not identify consistent loci across linkage studie...

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Section: Discussionsupporting

confidence: 91%

Section: Genotypingmentioning

confidence: 99%

A genome screen of 35 bipolar affective disorder pedigrees provides significant evidence for a susceptibility locus on chromosome 15q25-26

et al. 2008

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“…25 Subsequent analysis in our cohort of 55 multigenerational bipolar pedigrees significantly strengthened the evidence for linkage to chromosome 4q35, and haplotype analysis allowed us to define a candidate interval of 43 cM extending to the telomere of chromosome 4q35. 26 Other groups have now independently published support for this region.…”

Section: Introductionmentioning

confidence: 59%

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

et al. 2006

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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 b-catenin binding sites. Expression of Fat, Catnb (b-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.

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“…In particular, findings in 4p, 4q, 8q, 10p, 12q24, 13q, 18p, 18q, 21q, and 22q have been supported by more than one study. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] However, these studies have not identified any specific genes, and a recent metaanalysis of available genome scans showed no regions with a conclusive evidence of linkage. 20 The relatively slow progress of gene-mapping efforts is often explained by the 'complex' nature of the illness and of the genotype-phenotype relation.…”

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confidence: 99%

The phenotypes of bipolar disorder: relevance for genetic investigations

2005

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The search for susceptibility genes for bipolar disorder (BD) depends on appropriate definitions of the phenotype. In this paper, we review data on diagnosis and clinical features of BD that could be used in genetic studies to better characterize patients or to define homogeneous subgroups. Clinical symptoms, long-term course, comorbid conditions, and response to prophylactic treatment may define groups associated with more or less specific loci. One such group is characterized by symptoms of psychosis and linkage to 13q and 22q. A second group includes mainly bipolar II patients with comorbid panic disorder, rapid mood switching, and evidence of chromosome 18 linkage. A third group comprises typical BD with an episodic course and favourable response to lithium prophylaxis. Reproducibility of cognitive deficits across studies raises the possibility of using cognitive profiles as endophenotypes of BD, with deficits in verbal explicit memory and executive function commonly reported. Brain imaging provides a more ambiguous data set consistent with heterogeneity of the illness. Keywords: bipolar disorder; genetics; endophenotype; neurocognitive function; brain imaging Bipolar disorder (BD) has a genetic basis with heritability of at least 80%. 1 A number of studies have attempted to map the susceptibility loci giving evidence of linkage in multiple genomic regions. In particular, findings in 4p, 4q, 8q, 10p, 12q24, 13q, 18p, 18q, 21q, and 22q have been supported by more than one study. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] However, these studies have not identified any specific genes, and a recent metaanalysis of available genome scans showed no regions with a conclusive evidence of linkage. 20 The relatively slow progress of gene-mapping efforts is often explained by the 'complex' nature of the illness and of the genotype-phenotype relation. The complexity most likely includes heterogeneity, interactions of multiple loci, incomplete penetrance, as well as phenotypes resulting from environmental effects-either alone or in interaction with the genetic predisposition. The goal of psychiatric genetic research is identification of (heritable) variations in DNA sequence or function that influence behaviour or give rise to mental illness. By definition, in complex (multifactorial) traits, this link is not unique and specific. That is, a particular change in gene sequence does not necessarily lead to a specific behaviour, and similar behaviours (symptoms) may be due to distinct (sets of) genes. Moreover, we must consider the possibility that the path between the genotype and behaviour is not unidirectional. Emerging examples point not only to general effects of environment, for instance stress, on behaviour, but also to specific behaviours influencing gene function that can be transmitted onto the next generation. 21 No single method is considered clearly superior in identifying susceptibility genes for complex traits such as BD. Most researchers agree that a combination of strategies is most lik...

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A Susceptibility Locus for Bipolar Affective Disorder on Chromosome 4q35

Cited by 90 publications

References 28 publications

A genome screen of 35 bipolar affective disorder pedigrees provides significant evidence for a susceptibility locus on chromosome 15q25-26

A genome screen of 35 bipolar affective disorder pedigrees provides significant evidence for a susceptibility locus on chromosome 15q25-26

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

The phenotypes of bipolar disorder: relevance for genetic investigations

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