Overview
Mood disorders are the most common chronic psychiatric disorders in the world and are a leading cause of morbidity. In patients with these disorders, mood can range from elation or mania to deep depression. Patients with bipolar I disorder typically demonstrate at least one major manic episode and usually also a major depressive episode, while those with bipolar II disorder typically show a pattern of depressive symptoms and hypomanic episodes.
Etiology of mood disorders is unclear, although a genetic component has been strongly suggested by family and twin studies. However, the mode of inheritance is complex, with no clear Mendelian pattern. Heritability of mood disorders ranges from 50% in major depression to 80% in bipolar disorder.
Bipolar disorder, in particular, is seen in approximately 1% of the population.
Genome-wide association studies (GWAS) have increased the knowledge and understanding of bipolar disorder, identifying genetic markers that may overlap with those of schizophrenia, major depression, and other psychiatric disorders.
Many chromosomal regions have shown linkage to bipolar disorder, but meta-analyses of microsatellite marker–based linkage studies have not provided consistent findings of susceptibility regions.
Nevertheless, mechanisms behind therapeutic agents used in patients with the disorder have lent support to the possible role of a few different genetic pathways and mutations.
A meta-analysis of original data from 11 previous linkage studies in 1067 bipolar disorder families yielded significant findings in chromosomal regions 6q for bipolar I and 8q for bipolar I/II, as well as suggestive findings at chromosomal regions 9p and 20p for bipolar I.
The most significant 6q region harbors the melanin concentrating hormone receptor 2 (MCHR2) gene,
which has been implicated in the phosphoinositol pathway and in intracellular calcium release,
as well as in the kynurenine pathway, all of which are thought to play a role in the mood-stabilizing effect of lithium. A follow-up study also pointed to the SLC22A16 (organic cation/carnitine transporter) gene at 6q21,
the results of which were corroborated by a linkage study with high-density, single-nucleotide polymorphisms.
Association studies of individual candidate genes have yielded largely mixed findings,
but some consistent findings have been reported in a number of genes. For example, the low-functioning variant of a promoter polymorphism (HTTLPR) in the gene coding for the serotonin transporter,
the target for serotonin reuptake inhibitor drugs, was associated with bipolar disorder in a meta-analysis.
A number of genes associated with circadian patterns have been found to be associated with bipolar disorder, including aryl hydrocarbon receptor nuclear translocator-like (ARNTL).
and circadian locomotor output cycles kaput (CLOCK).
These data support the suggestion that disrupted circadian patterns play a role in bipolar disorder.
In addition, lithium has been shown to influence the circadian rhythm.
Indeed, mice carrying a mutant CLOCK gene displayed manialike behaviors that were reversed by lithium treatment.
Findings of circadian rhythm– elated genes support the continued study of these genes in bipolar disorder and lithium response.
Markers within the cadherin (FAT) gene.
were found to be associated with bipolar disorder in multiple samples, and expression analysis in rodents following administration of lithium or valproate indicated a role for FAT in neurodevelopment signaling pathways.
Finally, both lithium and valproate have been shown to inhibit GSK3beta.
Neurotransmitters, including serotonin,
as well as neurotrophins, including BDNF,
are known to inhibit GSK3beta,
and the BDNF gene has been possibly implicated in bipolar disorder,
particularly with regard to its association with rapid mood cycling.
Most studies on the GSK3B gene in bipolar disorder have been negative, but one study reported an increased number of copy-number variations (deletions or duplications) within the gene in a small sample of bipolar disorder patients.
Moreover, the observation that GSK3beta was required for lithium-associated behavioral effects in rodents
encourages the examination of this gene in lithium response.