The phenotypes of bipolar disorder: relevance for genetic investigations

Abstract

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...

Heritability of Strabismus: Genetic Influence Is Specific to Eso-Deviation and Independent of Refractive Error

“…Bipolar disorder has been shown to be highly heritable mental illness (McGuffin et al, 2003), with linkage studies supporting a complex polygenic basis for the condition (Craddock & Jones, 1999). Additionally, phenotypic heterogeneity associated with diaphanous diagnostic boundaries of the bipolar disorder spectrum has been recognized as a major obstacle in the genetic dissection of the illness (Hasler et al, 2006;MacQueen et al, 2005). Consequently, it has been suggested that genetic and clinical work might consider whether all phenotypic variants of the bipolar spectrum are an expression of a continuous underlying genetic liability (Edvardsen et al, 2008).…”

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

“…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. Using Australian allele frequencies for the additional markers, a significant two-point LOD score of 3.38 was identified at marker D15S130.…”

The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1

“…The quoted prevalence for BD is approximately one percent of the population (Spearing, 2001), although several factors probably result in under-or misdiagnosis. First, there are many BD phenotypes, complicating diagnosis (Thomas, 2004;MacQueen et al, 2005). Second, from these multiple phenotypes several variants exist in which one or other phase is extremely mild.…”