Linkage analysis of psychosis in bipolar pedigrees suggests novel putative loci for bipolar disorder and shared susceptibility with schizophrenia

Park, N; Juo, Sub Hang Hank; Cheng, Rong; Liu, J; Loth, Jo Ellen; Lilliston, B; Nee, John; Grunn, Adina; Kanyas, Kyra; Lerer, Bernard; Endicott, Jean; Gilliam, T. Conrad; Baron, Miron

doi:10.1038/sj.mp.4001541

Cited by 170 publications

(130 citation statements)

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“…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 Bdsupporting

confidence: 77%

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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Section: Psychotic Symptoms In Bdsupporting

confidence: 77%

The phenotypes of bipolar disorder: relevance for genetic investigations

2005

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“…38 Another group reported genome-wide significant linkage to BP with psychosis on chromosomes 9q31 and 8p21. 39 That same group studied a separate sample and found genome-wide significant linkage to BP with psychosis on chromosome 16p12. 17 Several of these loci fall within regions that have been implicated in previous studies of BP and schizophrenia.…”

Section: Discussionmentioning

confidence: 98%

Genome-wide linkage scan of 98 bipolar pedigrees and analysis of clinical covariates

et al. 2007

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Despite compelling evidence that genetic factors contribute to bipolar disorder (BP), attempts to identify susceptibility genes have met with limited success. This may be due to the genetic heterogeneity of the disorder. We sought to identify susceptibility loci for BP in a genome-wide linkage scan with and without clinical covariates that might reflect the underlying heterogeneity of the disorder. We genotyped 428 subjects in 98 BP families at the Center for Inherited Disease Research with 402 microsatellite markers. We first carried out a nonparametric linkage analysis with MERLIN, and then reanalyzed the data with LODPAL to incorporate clinical covariates for age at onset (AAO), psychosis and comorbid anxiety. We sought to further examine the top findings in the covariate analysis in an independent sample of 64 previously collected BP families. In the non-parametric linkage analysis, three loci were nominally significant under a narrow diagnostic model and seven other loci were nominally significant under a broader model. The top findings were on chromosomes 2q24 and 3q28. The covariate analyses yielded additional evidence for linkage on 3q28 with AAO in the primary and independent samples. Although none of the linked loci were genome-wide significant, their congruence with prior results and, for the covariate analyses, their identification in two separate samples increases the likelihood that they are true positives and deserve further investigation. These findings further demonstrate the value of considering clinical features that may reflect the underlying heterogeneity of disease in order to facilitate gene mapping.

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“…3 A total of 36 of these families are included in the 'psychosis' category, as described. 1 Best-estimate consensus diagnoses are based on the Research Diagnostic Criteria (RDC) 4 using all available sources of information. The models used for the broadened affected phenotype, or 'all BP', are the same as those employed in our initial genome scan 3 : BP1 (manic syndromes; mostly BPI disorder), BP2 (BP1 plus BPII disorder), and BP3 (BP2 plus recurrent major depression).…”

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confidence: 99%

“…The corresponding models for psychotic BP are BP-P1, BP-P2, and BP-P3 described elsewhere. 1 They include 68, 72, and 79 affected individuals, respectively. Thus, the broadened psychotic BP sample includes an additional 228 nonpsychotic affected individuals.…”

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confidence: 99%

Psychosis and the genetic spectrum of bipolar disorder: evidence from linkage analysis

et al. 2005

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the present study may not have been large enough to exclude involvement of a polymorphism with weak effect. Furthermore, in our study sample, to detect the difference between 93/196 and 103/196 with power 0.5, the minimum sample size should be 778. Similarly, to detect the difference between 237/461 and 224/461 in the sample from three Chinese studies with power 0.5, the minimum sample size should be 2487. If a higher power is desired, say, 0.8, then the required minimum sample size would be much greater than those two figures above.In this study, we only tested COMT Val108/158Met polymorphism in a family-based association study. There is some evidence that the COMT haplotype has additional predictive power for COMT expression. 8,9 In support of this suggestion, Shifman et al. 10 found schizophrenia linkage only to a Val158-containing haplotype. Thus, further research into genotyping more markers and using a haplotype-based approach is needed to definitively characterise the role of COMT gene in the pathogenesis of schizophrenia.

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Linkage analysis of psychosis in bipolar pedigrees suggests novel putative loci for bipolar disorder and shared susceptibility with schizophrenia

Cited by 170 publications

References 33 publications

The phenotypes of bipolar disorder: relevance for genetic investigations

The phenotypes of bipolar disorder: relevance for genetic investigations

Genome-wide linkage scan of 98 bipolar pedigrees and analysis of clinical covariates

Psychosis and the genetic spectrum of bipolar disorder: evidence from linkage analysis

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