Is Bipolar Disorder Genetic?

Bipolar disorder has a strong genetic basis, with multiple genes involved. Family and twin studies reveal a significantly higher risk among relatives. Environmental factors like trauma and stress also play a crucial role by interacting with genetic predispositions. Treatment involves mood stabilisers like Lithium, Carbamazepine, and Valproate, alongside psychotherapies such as Interpersonal and Social Rhythm Therapy (IPSRT) for managing mood swings and improving daily functioning.

Bipolar disorder or BPAD (Bipolar Affective Disorder) is a type of affective disorder, which includes alternate episodes of mania and depression. Often regarded as one of the most challenging illnesses to manage, it causes significant impairment in one’s occupational, interpersonal and daily functioning, and often clients whose episodes are left untreated are at high risk of harm to themselves and others.

The Global Burden of Disease Study (GBDS) estimated the prevalence of bipolar disorder to be 0.7% overall, 0.6% among males, and 0.8% among females worldwide. The prevalence of BPAD as per GBDS in India is 0.6% (for both males and females). (Ferrari et al, 2013). As per the National Mental Health Survey conducted by NIMHANS (2016), the overall prevalence of bipolar disorder was found to be 0.3%. 

How much do genes matter in bipolar disorder?

For a long time, affective disorders have been thought to have a strong genetic component and research heritability of bipolar disorder suggests the same. bipolar disorder has a strong genetic basis, with heritability estimates suggesting a significant genetic contribution.

• Many Genes Involved: Bipolar disorder is likely caused by changes in many different genes working together, rather than just one. Some of the genes that scientists have identified as potentially contributing include DISC1, ANK3, and CACNA1C.
• New Discoveries: Owing to the advanced ways of studying DNA, researchers have found specific areas in our genetic code that seem to be linked to bipolar disorder.
• Past Findings: Older studies that looked at families with bipolar disorder pointed to specific regions on chromosomes 18 and 22 as potentially important.
• Different Types, Different Genes: Some studies suggest that certain genes might be involved in specific types or features of bipolar disorder. Genes on chromosomes 1, 4, 6, 10, 11, 12, 13, 15, 18, 21, and 22 have been highlighted.
• The cAMP Connection: A chemical messenger in the body called cyclic adenosine monophosphate (cAMP) is important for many processes in the brain. Problems with how cAMP signals inside cells might increase the risk of bipolar disorder. Specific gene variations, like in PDE10A (linked to Bipolar I) and DISC1 and GNAS (linked to Bipolar II), affect this pathway. Different gene changes in the cAMP pathway working together may increase the risk of bipolar disorder.
• BDNF's Role: A common variation in the BDNF gene, called Val66met, might also play a role in bipolar disorder. People with a specific version of this variation ('Met' allele) seem to be more likely to experience rapid mood swings and have difficulties with thinking.
• BDNF Levels and Mood: The levels of a substance called BDNF in the blood seem to be lower during intense mood episodes (both high and low) in people with BPAD. This suggests that how the body regulates BDNF might be important for keeping mood stable. People with the 'Met' version of the BDNF gene variation tend to have lower BDNF levels in their blood compared to those with a different version ('Val' genotype). Because of these findings, BDNF is considered an important marker to study in understanding bipolar disorder.

How common is BPAD among family members?

The impact of genetics in the development of mental disorders is studied through family and twin studies. Family studies tend to find out if an illness tends to aggregate in families. These studies typically compare the prevalence of the disorder among first-degree relatives of affected probands (cases) to the prevalence in the population or among relatives of unaffected probands (controls). 

• Research over the years has indicated that first-degree relatives of probands with bipolar I disorder had a higher risk of developing the illness compared to relatives of controls. 
• There is also an increased chance of developing unipolar depression among them compared to controls. Gershon et al (1982) also estimated the risk of affective illness (including bipolar, unipolar, or schizoaffective disorder) among offspring and found a significantly higher risk if two parents have affective illness (74%) than if only one parent is affected (27%). For early-onset bipolar disorder, the risk in probands has been found to be even higher, as it indicates stronger genetic loading. 

Twin studies

Family studies cannot establish the role of genes or estimate the magnitude of their influence. Twin studies compare groups of twin pairs matched for shared environment but differing in degree of genetic relatedness, which helps to separate genetic and environmental contributions. Twin studies typically compare the concordance rates of a disorder between monozygotic (MZ) twins and dizygotic (DZ) twins.

• Identical twins of persons with a bipolar disorder have a 40% likelihood of developing the same disorder, and fraternal twins, siblings, and other close relatives of such persons have a 5% to 10% likelihood, compared to the 1% to 2.6% prevalence rate in the general population. 
• Tsuang & Faraone (1990) report a proband-wise concordance rate of 78% for MZ twins and 29% for DZ pairs. The summary estimate of heritability was 63%. Kendler et al (1993) found a concordance rate of 38.5% for MZ twins and 4.5% for DZ twins. 

Adoption studies

Adoption studies can help distinguish genetic and environmental influences by comparing rates of a disorder in biological family members to those in adoptive family members. Unfortunately, because they are logistically difficult to conduct and subject to a number of potential confounds, the availability of adoption studies of mood disorders has been limited. 

The frequency of affective illness (comprising bipolar, unipolar, schizoaffective, and cyclothymic disorders) was significantly greater in the biological parents (31%) than in the adoptive parents (12%) of bipolar probands. The risk of affective illness was high in the biological parents of adopted and nonadopted bipolar probands and low among those in the adoptive parents of bipolar probands. 

Does the environment play a role in the development of bipolar disorder?

While it has been seen that most mental disorders have a strong genetic basis, studies have failed to accurately detect the same magnitude of heritability in the form of common genetic variants, also called the ‘heritability gap’, which suggests that additional mechanisms are operative. Thus, the current model for bipolar disorder views the disease as the result of the interaction between genetic susceptibility and environmental stimuli (Kerner, 2015). 

Accordingly, several environmental events have been reported to be associated with a higher incidence of BPAD, including childhood trauma and chronic stress (Brietzke et al, 2012). These external stimuli interact with a susceptible genotype in the pathogenesis of BPAD, which has been empirically shown by a few studies. 

For instance, patients who carry the Met allele at the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism have been shown to be more likely to develop depressive episodes following stressful life events than those with the Val allele. Pathogen exposure interacts with polymorphism in the TLR2 gene, and the same polymorphism has also been suggested to amplify the negative effects of childhood sexual abuse on age at onset of BPAD (Oliveira et al., 2015). 

Finally, interactions between early trauma and polymorphisms in genes coding for calcium channel activity-related proteins have also been suggested to have a potential effect on the development and manifestation of BPAD (Anand et al., 2015). Such interactions suggest the action of ‘epigenetic mechanisms’, which modulate gene expression in response to the environment, and therefore might partly underlie the multifactorial heritability of bipolar disorder.

How is bipolar disorder treated?

BPAD is one of the most challenging disorders to treat and requires early identification, assessment and diagnosis to prevent deterioration.

Until the 1970s, researchers observed that the disorder did not respond much to medicines used to treat unipolar depression and the approval of Lithium was found to be a game-changer in the management of BPAD. A class of drugs known as mood stabilisers, including Carbamazepine and Valproate, have been found to be highly effective in managing manic episodes. 

Along with medications, psychotherapy is also required to ensure remission of symptoms. Interpersonal and Social Rhythm Therapy (IPSRT) is frequently suggested for clients with BPAD, which helps people improve their mood and overall mental health by building a regular routine and improving their interpersonal relationships.