Bipolar Disorders and Genetics: Clinical Implications of High Heritability

Basic Genetics and Heritability of Bipolar Disorder

The high heritability of bipolar disorder (BD) has been well documented through familial incidence, twin, and adoption studies.^[1] For example, the concordance rate of BD in monozygotic twins (indicating the chance that if one twin has BD, so will the other) is between 40% and 70%. Despite general acceptance that BD is therefore a disorder with a strong genetic basis, no specific gene has been identified as the one "bipolar gene." Nevertheless, linkage studies have implicated the involvement of several chromosomal regions in BD, including 4p16, 12q23-q24, 16p13, 21q22, and Xq24-q26. Chromosome 18 has also been an area of high focus, with up to 3 possible regions implicated.^[1,2] Recent areas of interest have included chromosome 6q^[3] as well as the G-protein receptor kinase 3 gene, located at 22q12.^[4] There are also data suggesting that relatively common polymorphisms of genes coding for the serotonin transporter protein and brain-derived neurotrophic growth factor may contribute somewhat to the development of BD. Because of these variable findings in very different chromosomal regions, it is likely that BD is caused by the presence of multiple genes conferring susceptibility to BD when combined with psychosocial stressors (see below). Thus, inheritance of a specific set of these genes could lead to one phenotypic presentation of the disorder, whereas a different set of genes would lead to a slightly different clinical presentation within the bipolar spectrum of illness.

Genes may also contribute to the age at onset of BD and a phenomenon called genetic anticipation. Anticipation refers to the phenomenon of an illness occurring in successive generations with earlier ages of onset and/or increasing severity. In a recent study using registry data of bipolar subjects, age at onset of first illness episode was examined in 2 successive cohorts: subjects born from 1900 through 1939 and from 1940 through 1959. The median age at onset of the first episode of bipolar illness was lower by 4.5 years in subjects born during or after 1940. The proportion of subjects with bipolar disorder presenting with a prepubertal onset was also significantly higher in the later birth-year cohort, thus supporting the notion of genetic anticipation.^[5]

Some research results have suggested that unstable trinucleotide repeats (eg, CAG), which are transmitted in greater lengths to successive generations, may be the biological basis of genetic anticipation.^[6] For example, an increase in mean CAG repeat length was associated with a diagnosis of BD^[7,8] and with anticipation of BD in a few studies of families with BD.^[9,10] However, there have been no replications of these studies and several negative reports.^[11-14] Furthermore, these repeat sequences have not been successfully linked to meaningful gene regions.

Methodologic limitations such as the phenotypic heterogeneity of BD and reliance of retrospective reports of onset and severity of bipolar symptoms may be partially responsible for the difficulty in isolating gene regions consistently associated with BD and replicating positive findings. Longitudinal, prospective studies examining parents with BD and the genetics and phenomenology of their high-risk offspring might help address such limitations.

Epidemiologic and phenomenologic studies of bipolar offspring also support the high heritability of BD. A meta-analysis of studies conducted before 1997 found bipolar offspring to be at 2.7 times higher risk for developing any psychiatric disorder, and at 4 times higher risk for developing a mood disorder, than children of parents without psychiatric illness.^[15] Recent cross-sectional studies have reported about 50% of bipolar offspring meet criteria for at least one DSM-IV psychiatric disorder.^[16-18] In these studies, the presence of a bipolar spectrum disorder (bipolar I, II, and cyclothymia) ranged from 14% to 50%. However, one study from The Netherlands found a much lower incidence (2.8%) of BD in bipolar offspring.^[19] The authors suggest that a much lower use of antidepressants and stimulants to treat children in European countries might account for this discrepant finding. Of note, this study still identified a 27% incidence of mood disorders in these offspring, raising the possibility that these symptomatic offspring might still be in early phases of the illness. It therefore seems important to identify which children may truly be in the prodromal stages of BD.