Several observations have been made regarding the heritability of bipolar disorder, two of which are that bipolar disorder tends to aggregate in families, and that affected families generally display a spectrum of psychiatric illness phenotypes (which might include bipolar with or without psychotic symptoms, unipolar depression, schizophrenia, schizoaffective disorder, ADHD, or substance abuse disorders, among other things). However, it has also been documented through monozygotic (identical) twin studies that the heritability of bipolar disorder is far from 100%. Different research articles have estimated that the twin of someone diagnosed with bipolar disorder has between a 45-75% chance of developing bipolar disorder themselves (see the following review article from Craddock and Jones, 2001 for reference citations of these studies). However, the identical twin that does not develop bipolar disorder specifically will probably develop some type of affective symptomology. These observations indicate that the traits of bipolar disorder are probably affected to various degrees by a number of different genes, which, when inherited in different combinations and when acted upon by certain environmental factors, may manifest into the psychiatric syndromes that run in families.

Some authors have proposed an epistatic genetic model for bipolar disorder. Epistasis describes a genetic event in which the expression of one gene inflluences the expression of another. other words, bipolar disorder is probably contributed to by many different genes, all of which interact together to influence the expression of different traits and symptoms.

Below is a table with estimates of the heritability risk of various relations of someone with bipolar disorder. Although there is a significant degree of heritability for first-degree relatives and identical twins, there are clearly other factors at work that influence the expression of bipolar disorder.

Source of the above statistics on genetic susceptibility to bipolar disorder; a NARSAD research newsletter article.

Although no study to date has identified a definitive susceptibility gene for bipolar disorder, there are definitely regions of interest that appear to be more prevalent in individuals and families affected by bipolar disorder and related psychiatric symptoms.

Linkage studies are one way to examine the genetic influences of a particular trait. A linkage study will examine large family pedigrees affected by the trait of interest (in this case, bipolar disorder), and attempt to identify another common trait (a "marker trait") that is highly prevalent in the same family. If the physical gene locus (location on the chromosome) of the marker trait is known, then researchers can hypothesize with relative certainty that a gene or cluster of genes that contribute to the trait of interest is also located near the gene locus of the marker. The closer the genes are that influence the two trait (the trait of interest and the marker trait), the more likely they are to be inherited together in relatives.

Linkage studies of bipolar disorder in families have identified several chromosomal regions of interest, including: 4p16, 12q23-q24, 16p, chromosome 18, 21q22, and Xq24-q26. For more details on these linkage studies, please see Craddock and Jones 2001 (review article), or the CAMH Research Annual Report (2002)

Another way researchers are examining the genetics of bipolar disorder is studying candidate genes. A scientist might suggest a candidate gene based on what disease mechanisms appear to be involved in a certain disorder. The scientist might then examine whether the gene or genes that contribute to that disease mechanism are more prevalent in a given population of affected individuals, as compared to a population of control individuals.

An example of a candidate gene being studied in both bipolar disorder and schizophrenia is the COMT gene. Researchers began looking at this gene because it makes a protein responsible for breaking down neurotransmitters in the brain (specifically, dopamine, norepinephrine, and epinephrine) known to be important to mood regulation and/or psychosis. Because people with both bipolar disorder and schizophrenia have been shown to have signficant over- or under-expression of these neurotransmitters in certain regions of their brains, it seemed logical to study whether a certain variation of the COMT gene might be more prevalent in bipolar and schizophrenia populations. Studies have presented conflicting but suggestive evidence that a certain COMT variation may indeed contribute to the expression of schizophrenia and/or bipolar traits. For example, some authors have shown that a low-activity form of the COMT gene (codes for a protein that is not as active as other forms) is more common in people with rapid-cycling type of bipolar disorder. For more research on the role of COMT in schizophrenia and bipolar disorder, see the following research abstract: "COMT: a common susceptibility gene in bipolar disorder and schizophrenia" (Am J Med Genet B Neuropsychiatr Genet., July 2004).

COMT is not the only gene for which common variants appear in both schizophrenia and bipolar populations. Some studies have looked specifically at the genetic overlap between bipolar disorder with psychotic symptoms (it is estimated that about 50% of people with bipolar disorder will experience at least one psychotic episode during their lifetimes) and schizophrenia. In a review article on psychotic bipolar disorder (Ketter et al, 2004), the authors suggested that these common genes might predispose individuals to "psychosis in general", and that other genes and/or environmental influences might then direct how and to what degree that psychosis might manifest. Right now, some of the shared genes between schizophrenia and bipolar disorder being studied include: 10p13-p12, 13q23, 18p, 22q11-q13. For more details, please see Ketter et al, 2004. In this same article, the author cites various studies showing that relatives of people with schizophrenia have a greater likelihood of developing affective disorders with psychotic symptoms (although not as great a risk as developing schizophrenia), and vice-versa, an observation which lends further evidence to the hypothesis that the trait of psychosis may be more highly heritable than the complete syndromes of either schizophrenia or bipolar disorder.

One way that genes might contribute to psychotic traits is through the expression of dopamine receptors, transporters, or enzymes. Dopamine overacivity has been consistently observed in the brains of schizophrenia patients; likewise, a dopamine metabolite called homovanillic acid (a product of dopamine molecule breakdown) has been shown to be increased in the cerebrospinal fluid of bipolar patients during manic episodes, and decreased in patients during depressive episodes. The gene coding for the D4 dopamine receptor is currently being studied for its role in the psychotic symptoms of bipolar disorder and schizophrenia (Ketter et al 2004).

Our understanding of the genetics of bipolar disorder has progressed remarkably, but there is still much to discover. Hopefully future research will shed further light on how exactly genes contribute to the expression of psychiatric symptoms in certain individuals.

References for the information above:

• Psychotic bipolar disorders: dimensionally similar to or categorically different from schizophrenia? J Psychiatr Res. 2004 Jan;38(1):47-61. Review.
• An overview of the genetics of psychotic mood disorders. J Psychiatr Res. 2004 Jan;38(1):3-15. Review.
• Molecular genetics of bipolar disorder. Br J Psychiatry Suppl. 2001 Jun;41:s128-33. Review.

Recent News Updates on Research into the Causal factors in Bipolar Disorder:

• Families With Severe Form Of Bipolar Disorder Help Scientists Narrow The Search For Disease Genes (April 2003)
• Discovery That Common Mood Disorders Are Inherited Together May Reveal Genetic Underpinnings (Jan 2002)
• Gene Variation Raises Risk Of Bipolar Disorder And Schizophrenia (April 2003)
• UCSD Researchers Identify Gene Involved In Bipolar Disorder (June 2003)
• UCSD Biologists Discover That Nerve Activity, Not Just Genetics Controls Kinds Of Neurotransmitters Produced (June 2004)
  
• Genes Play A Bigger Role In Women's Depression Than In Men's, Twin Study Finds (July 1999)