Bipolar disorder (BD) is a complex mood disorder defined by pronounced shifts in mood and energy levels that cycle between episodes of elevated or irritable states (mania/hypomania) and periods of low mood (depression). The disorder is highly heritable, but the underlying cause is multifactorial, meaning genetic vulnerabilities interact with external life events to trigger the onset and course of the condition. Understanding the genetic component involves recognizing the collective influence of many small genetic variations rather than searching for a single defective gene.
Understanding the Search for Genetic Loci
The question of which chromosome carries the genetic mutation for bipolar disorder does not have a simple answer because the disorder is polygenic, involving the contributions of many genes across the entire human genome. Genome-Wide Association Studies (GWAS) are the primary tool used by researchers to scan the DNA of thousands of individuals to find small, common genetic variations that occur more frequently in people with BD. These variations, known as Single Nucleotide Polymorphisms (SNPs), are tiny changes in a single DNA building block. Risk for BD comes from the cumulative effect of hundreds of these common SNPs, each contributing a very small amount of risk. Recent large-scale studies have identified nearly 300 risk regions, or loci, across various chromosomes. The collective genetic risk explains a substantial portion of the heritability, which is estimated to be between 60 to 80%.
How Identified Genes Affect Brain Function
The genes identified through large genetic studies point toward several specific biological pathways that are disrupted in bipolar disorder, shifting the focus from where the genes are to what they do.
One consistently reproduced finding is the association with the CACNA1C gene, which codes for a subunit of the L-type voltage-gated calcium channel. This channel plays an important role in controlling the influx of calcium ions into neurons, a process that is fundamental for neurotransmission and synaptic plasticity. Genetic variation in CACNA1C affects brain circuitries involved in emotional processing, such as the amygdala and hippocampus, which show altered activity in people with BD.
The genetic findings also implicate genes that affect various neurotransmitter systems, including those that influence dopamine and serotonin signaling. These chemical messengers regulate mood, motivation, and reward pathways, and disruptions in their signaling contribute to the extreme mood states characteristic of BD. The cumulative effect of variations in genes across these systems collectively increases a person’s vulnerability.
A third major area of involvement is the regulation of the body’s internal clock, known as the circadian rhythm, which controls the 24-hour cycle of sleep and wakefulness. Genes such as PER3 and CRY2 are core components of this clock machinery and have been linked to bipolar disorder. Abnormalities in the expression of these clock genes are observed in individuals with the disorder, suggesting that the genetic predisposition interferes with the brain’s ability to maintain stable daily biological rhythms.
The Role of Gene-Environment Interaction
Genetic susceptibility for bipolar disorder is not deterministic; instead, it creates a vulnerability that must often be activated or modified by external factors. This concept is described using the diathesis-stress framework, where a person’s genetic predisposition (diathesis) interacts with environmental stressors to increase the risk of developing the disorder. Environmental factors act as triggers or modifiers for individuals who are already genetically predisposed to BD.
Specific environmental factors shown to interact with genetic vulnerabilities include chronic stress, early life trauma, and disrupted sleep patterns, which can destabilize mood. Substance use, particularly cannabis use during adolescence, is also identified as a factor that may interact with certain risk genes to increase susceptibility to psychiatric conditions. The interplay between these external factors and an individual’s genetic profile highlights why life events are so important in the clinical course of BD.
Current Clinical Utility of Genetic Findings
Despite the remarkable progress in identifying hundreds of risk loci, genetic testing is currently not used for the primary diagnosis of bipolar disorder. Due to the polygenic nature of the disorder, no single gene or set of genes can definitively confirm or rule out a diagnosis, which remains a clinical assessment based on symptoms and history. The small effect size of each individual genetic variant means that a test for susceptibility risk would have low predictive power for the average person.
However, the field of pharmacogenomics is beginning to translate these genetic findings into practical applications for treatment optimization. Pharmacogenomics involves using genetic markers to predict a patient’s response to specific medications or their likelihood of experiencing adverse side effects. A significant area of research focuses on predicting an individual’s response to lithium, the most established mood stabilizer for BD.
Studies have identified genetic variants related to the glutamate system that are associated with a more favorable response to lithium treatment. While genetic markers are beginning to be included in drug labels to screen for safety concerns with medications like carbamazepine and valproate, no pharmacogenomic test for mood stabilizer efficacy has yet been approved by major regulatory bodies. This research holds promise for guiding treatment decisions and moving beyond the current trial-and-error approach to medication selection.