A genome screen of a large bipolar affective disorder pedigree supports evidence for a susceptibility locus on chromosome 13q

Badenhop, Renee F.; Moses, M. J.; Scimone, Anna; Mitchell, Philip B.; Ewen, Kelly R.; Rosso, A; Donald, Jennifer A.; Adams, Linda J.; Schofield, Peter R.

doi:10.1038/sj.mp.4000887

Cited by 38 publications

(27 citation statements)

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“…54 Region 13q was reportedly linked to schizophrenia in US 55 and Canadian 56 pedigrees, and to BP in US 5,15 and Australian pedigrees. 49 Reports that BP and schizophrenia may have susceptibility genes in common are consistent with the notion of a shared diathesis for the major psychoses. 17,57 They may also provide cross-validation of genetic findings and a basis for a broader view of disease phenotypes.…”

Section: Discussionsupporting

confidence: 49%

“…48 Our finding at 10q21-24 is consistent with similar findings in another series of US pedigrees 15 and in German 9 and UK-Irish 47 families. Support for linkage to 13q was reported in two separate series of US pedigrees 5,15 and in a large Australian pedigree 49 (though at a more proximal site, on 13q14). Modest support for linkage to 17q was observed in a series of UK-Irish families.…”

Section: Discussionmentioning

confidence: 99%

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Evidence for a putative bipolar disorder locus on 2p13–16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21–24, 13q32, 14q21 and 17q11–12

et al. 2003

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Bipolar disorder (BP) is a severe and common psychiatric disorder characterized by extreme mood swings. Family, twin and adoption studies strongly support a genetic component. The mode of inheritance is complex and likely involves multiple, as yet unidentified genes. To identify susceptibility loci, we conducted a genome-wide scan with 343 microsatellite markers in one of the largest, well-characterized pedigree samples assembled to date (373 individuals in 40 pedigrees). To increase power to detect linkage, scan statistics were used to examine the logarithm of odds (lod) scores based on evidence at adjacent chromosomal loci. This analysis yielded significant evidence of linkage (genome-wide Po0.05) for markers on 2p13-16. Standard linkage analysis was also supportive of linkage to 2p13-16 (lod ¼ 3.20), and identified several other interesting regions: 4q31 (lod ¼ 3.16), 7q34 (lod ¼ 2.78), 8q13 (lod ¼ 2.06), 9q31 (lod ¼ 2.07), 10q24 (lod ¼ 2.79), 13q32 (lod ¼ 2.2), 14q21 (lod ¼ 2.36) and 17q11-12 (lod ¼ 2.75). In this systematic, large-scale study, we identified novel putative loci for BP (on 2p13-16, 8q13 and 14q21) and found support for previously proposed loci (on 4q31, 7q34, 9q31, 10q21-24, 13q32 and 17q11-12). Two of the regions implicated in our study, 2p13-14 and 13q32, have also been linked to schizophrenia, suggesting that the two disorders may have susceptibility genes in common.

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Evidence for a putative bipolar disorder locus on 2p13–16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21–24, 13q32, 14q21 and 17q11–12

et al. 2003

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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%

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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“…59 These findings replicate and further clarify previous linkage findings in BD in these two chromosomal regions. 12,13,19,20,[60][61][62] They are especially interesting as the same regions may encompass susceptibility genes for schizophrenia. [63][64][65][66][67][68][69][70] Park et al 71 made similar conclusions in a study of psychotic BD in which most areas of linkage overlapped with those reported in previous investigations of schizophrenia.…”

Section: Psychotic Symptoms In Bdmentioning

confidence: 99%

“…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 genome screen of a large bipolar affective disorder pedigree supports evidence for a susceptibility locus on chromosome 13q

Cited by 38 publications

References 38 publications

Evidence for a putative bipolar disorder locus on 2p13–16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21–24, 13q32, 14q21 and 17q11–12

Evidence for a putative bipolar disorder locus on 2p13–16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21–24, 13q32, 14q21 and 17q11–12

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

The phenotypes of bipolar disorder: relevance for genetic investigations

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