Unlike Huntington disease, in which the number of nucleotide repeats in a single gene determine outcome, bipolar disorder appears to be influenced by several hundred genes: 266 in a recent meta-analysis. Some genes are more central to the development of bipolar disorder than others, suggesting that there are several main pathways to the development of this illness, not 266 different routes. For example, one of the most consistently identified genes…codes for a calcium channel subunit that affects amygdala processing of emotional events, which itself has been shown to be one of the central differences in brain function in bipolar disorder.
The search for genes associated with bipolar disorder is complicated because many of the same genes… are also associated with major depression and schizophrenia. This should not be surprising: given the large number of genes involved, the range of potential variations of mood and thought is vast… Although not all these variations would necessarily look different clinically, they are better mapped in continua rather than categories…DSM categories “will remain somewhat arbitrary [italics added] because they will be imposed on fully continuous, smooth distributions.”
The search for genes associated with bipolar disorder is further complicated by the overlap between genes that confer bipolar risk and genes that confer “plasticity.” The latter refers to genes that allow individuals to respond more directly to environmental experience, to mold themselves to their environment and potential future environments based on past experience.
Plasticity-specific genes. Multiple genes appear to confer an increased capacity to mold to or respond to one’s environment (particularly childhood environment). These genes include the serotonin transporter gene (SERT) and the brain-derived neurotrophic factor (BDNF) gene, among others.
Differences in the SERT gene length have been extensively investigated in relation to mood and anxiety disorders. The short version of the SERT gene is associated with an increased risk of depression in the face of life stresses, but only in the context of adverse childhood experiences. Benign childhoods appear to completely mask the gene length difference effects…These findings were recently replicated in bipolar disorder. The frequency of the short allele itself is highly variable across ethnic groups; none were found in one Chinese population. Overall, the findings…have been consistent, particularly if age of adverse events is factored in (early childhood events have more impact…
Similarly, a substantial literature associates the BDNF gene with mood disorders and bipolar disorder in particular (a) variant is associated with increased susceptibility to Alzheimer disease, Parkinson disease, depression, eating disorders—and bipolar disorder. In bipolar disorder, carriers of the methionine-yielding allele have significantly higher suicide attempt rates
Although these alleles confer risk of a potentially lethal disorder, they must confer some benefit, or else they would have been selected out evolutionarily long ago (given that they act in young and middle age)….In some contexts, they are beneficial, or protective. For example, inheriting the Met allele…in the context of family maltreatment, inheriting the BDNF Met allele lowered susceptibility to adult depression…(also) appears to confer a degree of vigilance and capacity to handle rapid changes in stress that is evolutionarily advantageous.
Given that there are multiple “plasticity” genes…the interactions are sure to be extremely complex. Nevertheless, one thing is clear: these genes interact with childhood environment to affect risk of developing mood disorders…In bipolar disorders, childhood trauma is strongly associated with severity of illness, including earlier onset of the illness, a rapid cycling course, more psychotic features, and a higher number of lifetime mood episodes, as well as suicidal ideation and suicide attempts.