Bipolar disorder (BD) is a complex mental health condition marked by extreme mood swings that alternate between emotional highs and lows. Bipolar I disorder involves at least one episode of mania, while Bipolar II disorder involves hypomania, a less severe elevated mood, alongside at least one major depressive episode. BD is not caused by a single genetic error on one chromosome. Instead, it is a polygenic disorder, meaning it arises from the combined effect of small variations across many different genes throughout the entire genome.
The Polygenic Nature of Bipolar Disorder Risk
Unlike single-gene disorders such as Huntington’s disease, bipolar disorder is a complex trait influenced by thousands of common genetic variants, each contributing only a tiny amount to the overall risk. This type of inheritance, known as polygenic inheritance, means that an individual’s susceptibility is determined by their total “genetic load” of these small-effect risk alleles. The high heritability of bipolar disorder, estimated to be between 70% and 90% based on twin studies, demonstrates that genetics play a substantial role in determining who develops the condition.
The specific genetic markers identified so far only explain a fraction of this high heritability, a concept often referred to as “missing heritability.” This suggests that many more risk genes remain undiscovered, or that the genetic contribution involves rarer variants and complex gene-to-gene interactions. The risk for BD is also highly correlated with the genetic risk for other psychiatric conditions, most notably schizophrenia, underscoring a shared biological basis among several mental illnesses.
Key Chromosomal Regions Associated with Risk
Modern genetic research, primarily through Genome-Wide Association Studies (GWAS), has pinpointed numerous chromosomal regions, or loci, that show an association with bipolar disorder. These studies scan the entire human genome to identify common variations that occur more frequently in people with the disorder compared to healthy individuals. The most recent and largest studies have identified as many as 298 distinct genomic regions that contain DNA variations increasing the risk for BD.
While no single chromosome is the sole source of risk, multiple chromosomes contain genes that are consistently implicated. Chromosomes 3, 10, 13, 18, and 21 were among the earliest regions identified in linkage studies, with more recent GWAS confirming and expanding these findings across the entire genome. The sheer number of identified loci reinforces the idea that the genetic architecture of bipolar disorder is highly distributed, involving small variants scattered across almost all chromosomes.
Genetic Influence on Brain Signaling and Structure
The genes located in these associated chromosomal regions do not cause the disorder directly but rather affect fundamental biological processes in the brain. A primary functional target is the regulation of ion channels, which are proteins that control the flow of ions into and out of brain cells. For instance, a gene called CACNA1C, associated with BD risk, codes for a subunit of a voltage-dependent calcium channel, which is fundamental to a neuron’s ability to fire electrical signals and release neurotransmitters.
Another frequently implicated gene is ANK3 (Ankyrin 3), which plays a role in the structure and function of the axon initial segment, the part of the neuron that decides whether to generate an electrical impulse. These genes highlight a convergence on biological pathways that regulate cellular excitability and communication within the central nervous system. Risk genes also often affect synaptic function, neuroplasticity, and the health of specific brain cells, such as GABAergic interneurons.
The Interplay of Genetic Risk and Environmental Factors
A genetic predisposition alone is typically not enough to cause bipolar disorder; the genetic risk must interact with non-genetic, or environmental, factors to trigger the onset of the condition. This gene-environment interaction model suggests that an individual with a high genetic load may remain healthy until they encounter specific environmental triggers. Examples of environmental factors commonly cited include severe early life stress, such as childhood trauma or abuse, which can alter the expression of certain genes through epigenetic mechanisms.
Other contributing factors include significant sleep-wake cycle disruptions, substance abuse, and major stressful life events. These environmental elements may not cause the disorder in someone without the underlying genetic vulnerability, but they can increase the likelihood of a first mood episode in a genetically susceptible person. This interaction underscores that bipolar disorder is a complex result of both “nature” and “nurture,” where genetics provide the vulnerability and environmental stressors act as the catalyst.