Heterogeneity and the genetics of bipolar disorder

Faraone, Stephen V.; Tsuang, Ming T.

doi:10.1002/ajmg.c.20017

Cited by 24 publications

(16 citation statements)

References 105 publications

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“…Overlap between psychotic BPD and SCZ has been proposed at symptom definition, family, genetic, cytoarchitectural, and neuropsychological levels [Potash et al, 2001;Berrettini, 2003;Sklar et al, 2004;Craddock et al, 2005;Ishiguro et al, 2001;Reyes et al, 2002;Faraone et al, 2003;Babovic et al, 2004;Washizuka et al, 2004]. Our result with BPD specific phenotype model gave a maximum LOD score of 0.77 at y ¼ 0.15 for D18S453.…”

Section: Discussionsupporting

confidence: 53%

Evidence of linkage and association on 18p11.2 for psychosis

Mukherjee

Meera

Ghosh

et al. 2006

American J of Med Genetics Pt B

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The genetic basis of bipolar disorder (BPD) and schizophrenia (SCZ) has been established through numerous clinical and molecular studies. Although often considered separate nosological entities, evidence now suggests that the two syndromes may share some genetic liability. Recent studies have used a composite phenotype (psychosis) that includes BPD, SCZ, psychosis not otherwise specified, and schizoaffective disorder, to identify shared susceptibility loci. Several chromosomal regions are reported to be shared between these syndromes (18p, 6q, 10p, 13q, 22q). As a part of our endeavor to scan these regions, we report a positive linkage and association finding at 18p11.2 for psychosis. Two-point linkage analysis performed on a series of 52 multiplex pedigrees with 23 polymorphic markers yielded a LOD score of 2.02 at D18S37. An independent set of 159 parent offspring trios was used to confirm this suggestive finding. The TDT analysis yielded support for association between the marker D18S453 and the disease allele (chi2 = 4.829, P < 0.028). This region has been implicated by several studies on BPD [Sjoholt et al. (2004); Mol Psychiatry 9(6):621-629; Washizuka et al. (2004); Biol Psychiatry 56(7):483-489; Pickard et al. (2005); Psychiatr Genet 15(1):37-44], SCZ [Kikuchi et al. (2003); J Med Dent Sci 50(3):225-229; Babovic-Vuksanovic et al. (2004); Am J Med Genet 124(3):318-322] and also as a shared region between the two diseases [Ishiguro et al. (2001); J Neural Transm 108(7):849-854; Reyes et al. (2002); Mol Psychiatry 7(4):337-339; Craddock et al. (2005); J Med Genet 42(3):193-204]. Our findings provide an independent validation of the above reports, and suggest the presence of susceptibility loci for psychoses in this region.

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Section: Discussionsupporting

confidence: 53%

Evidence of linkage and association on 18p11.2 for psychosis

Mukherjee

Meera

Ghosh

et al. 2006

American J of Med Genetics Pt B

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“…As for sample 1, we defined a narrow and broad phenotype definition for BP: the BP narrow phenotype was restricted to BP I (48 subjects in sample 1; 72 subjects in sample 2) and the broad definition included BP I, BP II, and recurrent major depression (72 subjects in sample 1; 133 subjects in sample 2). For each of these two BP phenotype definitions (BP narrow and BP broad), the number of informative families (i.e., containing at least 2 affected subjects) was respectively 26 and 28, and the number of affected subjects per family ranged respectively from 2 to 14 and from 2 to 25.Secondary Objective 1-Phenotype Refinement: Recent genetic findings in 16p [Cheng et al, 2006] indicated that psychotic symptoms may identify a specific subgroup of BP linked to this region, which is concordant with the accumulating evidence that such symptoms may identify a more genetically homogeneous BP subtype [Faraone and Tsuang, 2003]. Therefore, we created two new phenotypes by restricting each of our narrow and broad BP phenotype definition to the subjects whose best-estimate diagnosis specified the presence of psychotic symptoms.…”

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confidence: 58%

“…Using this stringent design, the primary objective of the present report was to seek replication of our initial linkage finding with BP at 16p12. The secondary objectives were: (i) to attempt a phenotype refinement by restricting the phenotype definition to the affected BP subjects showing psychotic symptoms, based on accumulating evidence that such symptoms may identify a more genetically homogeneous BP subtype [Faraone and Tsuang, 2003]; (ii) to test whether the 16p12 linkage was specific to BP or rather shared with SZ. Fig.…”

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confidence: 99%

“…Hence, the BP-Psychotic phenotype, either in a narrow or broad definition, was the one that revealed two convincing features of replicated linkage result, that is, a strongest evidence for linkage (NPL of 3.90) and a consistency in maximum peaks across samples. The linkage strength using the BP-Psychotic phenotype was particularly noteworthy since this phenotype yielded the strongest linkage signal despite reduced sample size, probably because this subgroup of subjects may be more genetically homogeneous than the whole BP group [Faraone and Tsuang, 2003]. This suggested that phenotype refinement was warranted and that such refinement may modify inferences both in terms of the true phenotype and the true region being linked.…”

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confidence: 99%

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Replication of linkage with bipolar disorder on chromosome 16p in the eastern Quebec population

Mérette

Roy

Bureau

et al. 2008

American J of Med Genetics Pt B

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In a previous study [Maziade et al. (2005); Mol Psychiatry 10:486-499], we provided evidence for linkage (parametric lod score of 4.05) on chromosome 16p for bipolar affective disorder (BP) in 21 kindreds from Eastern Quebec, a population characterized by a founder effect. Using a stringent design, we performed a replication study in a second sample of 27 kindreds (sample 2) collected from the same population and assessed with the same methodologies as in our original sample (sample 1), that is with the same diagnostic procedure and using a common set of 23 markers studied with model-based (parametric) and model-free (nonparametric) linkage analyses. We replicated our initial finding with P values <0.001. Indeed, maximum NPL(all) scores of 3.7 and 3.52 were found at marker D16S3060 in sample 2 for the narrow and broad BP phenotype definition, respectively. For the latter definition, the nonparametric score reached 3.87 in the combined sample, a value that exceeded the maximum NPL score obtained in each individual sample (NPL(all) = 2.32 in sample 1; NPL(all) = 3.52 in sample 2). Moreover, a refined phenotype restricted to BP associated with psychosis yielded significant evidence for linkage in each individual sample (NPL(all) = 2.38 in sample 1; NPL(all) = 2.72) while yielding the best result (NPL(all) score = 3.90) in the combined sample (samples 1 and 2), despite an important reduction in the number of affected individuals. It is also noteworthy that the use of the refined phenotype provided a location of the maximum linkage peak shared by both samples, that is, at marker D16S668 in 16p13.12, suggesting consistency across samples. Our study provided one of the strongest pieces of evidence for linkage with BP in 16p and illustrated the heuristic potential of a replication study in a second sample ascertained from the same population and using homogeneous methodologies.

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“…Findings have been inconsistent, but when positive have most often identified the “housekeeping” genes involved in cellular metabolic activities, ion exchange, synaptic development and differentiation, as well as genes regulating myelination, neurotransmission, neuronal plasticity, resilience, and apoptosis. It is conceivable that genetic influences may be reflected in an endophenotype (“hidden phenotype”) of bipolar disorder characterized by abnormal circadian and hormonal rhythms, responses to medications, and specific gray- and white-matter changes (42, 68–70). …”

Section: Genetic Findings In Bipolar Disordermentioning

confidence: 99%

Integrated Neurobiology of Bipolar Disorder

2014

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From a neurobiological perspective there is no such thing as bipolar disorder. Rather, it is almost certainly the case that many somewhat similar, but subtly different, pathological conditions produce a disease state that we currently diagnose as bipolarity. This heterogeneity – reflected in the lack of synergy between our current diagnostic schema and our rapidly advancing scientific understanding of the condition – limits attempts to articulate an integrated perspective on bipolar disorder. However, despite these challenges, scientific findings in recent years are beginning to offer a provisional “unified field theory” of the disease. This theory sees bipolar disorder as a suite of related neurodevelopmental conditions with interconnected functional abnormalities that often appear early in life and worsen over time. In addition to accelerated loss of volume in brain areas known to be essential for mood regulation and cognitive function, consistent findings have emerged at a cellular level, providing evidence that bipolar disorder is reliably associated with dysregulation of glial–neuronal interactions. Among these glial elements are microglia – the brain’s primary immune elements, which appear to be overactive in the context of bipolarity. Multiple studies now indicate that inflammation is also increased in the periphery of the body in both the depressive and manic phases of the illness, with at least some return to normality in the euthymic state. These findings are consistent with changes in the hypothalamic–pituitary–adrenal axis, which are known to drive inflammatory activation. In summary, the very fact that no single gene, pathway, or brain abnormality is likely to ever account for the condition is itself an extremely important first step in better articulating an integrated perspective on both its ontological status and pathogenesis. Whether this perspective will translate into the discovery of innumerable more homogeneous forms of bipolarity is one of the great questions facing the field and one that is likely to have profound treatment implications, given that fact that such a discovery would greatly increase our ability to individualize – and by extension, enhance – treatment.

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Heterogeneity and the genetics of bipolar disorder

Cited by 24 publications

References 105 publications

Evidence of linkage and association on 18p11.2 for psychosis

Evidence of linkage and association on 18p11.2 for psychosis

Replication of linkage with bipolar disorder on chromosome 16p in the eastern Quebec population

Integrated Neurobiology of Bipolar Disorder

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