Bipolar disorder is an affective disorder characterized by periods of elevated and depressed mood. The cause and mechanism of bipolar disorder is not yet known, and the study of its biological origins is ongoing. Although no single gene causes the disorder, a number of genes are linked to increase risk of the disorder, and various gene environment interactions may play a role in predisposing individuals to developing bipolar disorder. Neuroimaging and postmortem studies have found abnormalities in a variety of brain regions, and most commonly implicated regions include the ventral prefrontal cortex and amygdala. Dysfunction in emotional circuits located in these regions have been hypothesized as a mechanism for bipolar disorder. A number of lines of evidence suggests abnormalities in neurotransmission, intracellular signalling, and cellular functioning as possibly playing a role in bipolar disorder. Studies of bipolar disorder, particularly neuroimaging studies, are vulnerable to the confounding effects such as medication, comorbidity, and small sample size, leading to underpowered independent studies, and significant heterogeneity.
Etiology
Genetic
The etiology of bipolar disorder is unknown. The overall heritability of bipolar is estimated at 79%-93%, and first degree relatives of bipolar probands have a relative risk of developing bipolar around 7–10. While the heritability is high, no specific genes have been conclusively associated with bipolar, and a number of hypotheses have been posited to explain this fact. "The polygenic common rare variant" hypothesis suggests that a large number of risk conferring genes are carried in a population, and that a disease manifests when a person has a sufficient number of these genes. The "multiple rare variant" model suggests that multiple genes that are rare in the population are capable of causing a disease, and that carrying one or a few can lead to disease. The familial transmission of mania and depression are largely independent of each other. This raises the possibility that bipolar is actually two biologically distinct but highly comorbid conditions.
A number of genome wide associations have been reported, including CACNA1C and ODZ4, and TRANK1. Less consistently reported loci include ANK3 and NCAN, ITIH1, ITIH3 and NEK4. Significant overlaps with schizophrenia have been reported at CACNA1C, ITIH, ANK3, and ZNF804A. This overlap is congruent with the observation that relatives of probands with schizophrenia are at higher risk for bipolar disorder and vice versa.
In light of associations between bipolar and circadian abnormalities (such as decreased need for sleep and increased sleep latency), polymorphisms in the CLOCK gene have been tested for association, although findings have been inconsistent, and one meta analysis has reported no association with either bipolar or major depressive disorder. Other circadian genes associated with bipolar at relaxed significance thresholds include ARTNL, RORB, and DEC1. One meta analysis reported a significant association of the short allele of the serotonin transporter, although the study was specific to European populations. Two polymorphisms in the tryptophan hydroxylase 2 gene have been associated with bipolar disorder. NFIA has been linked with seasonal patterns of mania.
One particular SNP located on CACNA1C that confers risk for bipolar disorder is also associated with elevated CACNA1C mRNA expression in the prefrontal cortex, and increased calcium channel expression in neurons made from patient induced pluripotent stem cells.
No significant association exists for the BDNF Val66Met allele and bipolar disorder, except possibly in a subgroup of bipolar II cases, and suicide.
Due to the inconsistent findings in GWAS, multiple studies have undertaken the approach of analyzing SNPs in biological pathways. Signaling pathways traditionally associated with bipolar disorder that have been supported by these studies include CRH signaling, cardiac β-adrenergic signaling, phospholipase C signaling, glutamate receptor signaling, cardiac hypertrophy signaling, Wnt signaling, notch signaling, and endothelin 1 signaling. Of the 16 genes identified in these pathways, three were found to be dysregulated in the dorsolateral prefrontal cortex portion of the brain in post-mortem studies, CACNA1C, GNG2, and ITPR2.
Advanced paternal age has been linked to a somewhat increased chance of bipolar disorder in offspring, consistent with a hypothesis of increased new genetic mutations.