Bipolar and Genetics

Genetic Research and Bipolar Disorder

Amy Pattishall

  Penn State College of Medicine

2002

 

Bipolar Disorder

• Affective disorder characterized by recurrent manic and depressive episodes.
• High level of psychiatric service use and morbidity.
• About 15% suicide rate among bipolar disorder patients.
• Variable age of onset, mean age of onset is 21.
• A great amount of anatomical, biochemical, genetic and pharmacologic data on the disorder, however no theory unifies this data.

Etiology

• Stress-Diathesis Model
• Environmental Stressors: Death of a loved one

Job/School setback

Relationship problems

Drug Use

• Acquired Vulnerabilities: Medical illnesses that affect well-being/brain function

Psychobiological sequelae of abuse, parental loss, trauma

• Genetic Background

 

Genetics

• Concordance rates: Monozygotic  56-80%

Dizygotic          14-25%

• Lifetime risk of first degree relatives 5-10%
• Lifetime risk of general population: 0.5-1.5%
• Rates are similar in males and females

 

Family Studies

Craddock and Jones

• Compilation of studies which measured lifetime risk of bipolar disorder in first degree relatives of bipolar proband in which DSM IV criteria for bipolar I was used and some of the relatives were interviewed directly.
• Findings: Increased relative risk of Bipolar I in relatives of proband

Odds Ratio of 7

• First degree relatives of bipolar probands have increased risk of unipolar major depression (evidence shows 2/3-3/4 of cases may be bipolar genetically).
• Bipolar II disorder occurs more frequently, as does schizoaffective disorder with manic features.
• Lifetime risk of affective disorder increases with: Early age of onset

Number of affected relatives

• Unknown whether risk varies according to type of relative.

 

Twin Studies

• 6 studies using the DSM IV criteria for Bipolar Disorder were pooled

 

Relationship to Proband            Risk of Bipolar Disorder           Risk of Unipolar Depression

Monozygotic Co-twin               40-70%                                   15-25%

First Degree Relative                5-10%                                     10-20%

General Population                   0.5-1.5%                                 5-10%

 

Adoption Studies

Mendlewicz and Rainer

• 29 bipolar and 22 normal adoptees, 31 bipolar non-adoptees
• Significantly greater risk of affective disorder in biological parents of bipolar adoptees (18%) compared with adoptive parents (7%).
• Risk of biological parents of bipolar adoptees was similar to risk of relatives of bipolar non-adoptees.
• Further evidence for genetic component of bipolar disorder.

 

Wender, et al

• Similar, non-significant results.
• Only 10 probands.

 

Linkage Studies

• Pedigrees showing single gene inheritance are rare.
• In the majority of cases, no single “bipolar gene” exists.
• The recurrent risk data suggest a complex genetic mechanism such as epistasis, imprinting, trinucleotide repeat expansion or allelic/locus heterogeneity.
• Additive effects of susceptibility genes could contribute to a continuous spectrum of phenotypes, or could lead to a threshold for bipolar phenotype.

 

A Few Chromosomes of Interest:

Chromosome 5

• Studies have shown 5p15 to be significant in bipolar disorder, this region also contains the gene for a dopamine transporter.

Chromosome 16

• A region of this chromosome shows linkage to bipolar disorder as well as to alcohol dependence.

Chromosome 12

• There is evidence for linkage at the12q23-24 region.
• This region coincides with the Darier’s disease gene, which was found to co-segregate with bipolar disorder in one family study. Darier’s disease is frequently associated with psychiatric disorders.
• The gene involved is a Ca-ATPase. In patients without mental symptoms, mutations have been shown to occur in many regions of the gene. In patients with coexisting psychiatric disorders, the mutations were localized to a specific exon.
• Search for mutations in this gene in patients with bipolar disorder showing linkage with markers in 12q23-24 region has been inconclusive.

Chromosome 21

• Studies have shown that bipolar disorder, and mania in general to be less common in patients with Trisomy 21.
• Individuals with Down’s Syndrome may be more susceptible to depression.
• Several different theories:
• The chromosome abnormality may confer non-specific effects on expression of affect.
• One or more genes on chromosome 21 may make an individual more susceptible to depression and less susceptible to mania.
• A specific susceptibility locus for bipolar disorder may exist on chromosome 21.

Chromosome 22

• Several regions of chromosome 22 have been associated with bipolar disorder.
• Multiple regions of this chromosome, (most importantly a loci on 22q12) as well as loci on 13q and 10q, have been shown to be near loci involved in schizophrenia.
• Although schizophrenia has not been shown to occur at a higher rate in families with a bipolar proband, the two disorders may share susceptibility genes.

 

Future of Genetic Research

• Greater understanding of pathophysiology.
• Development of new treatments.
• Laboratory tests for diagnosis/treatment?
• Provide information to those at risk.

 

References

Craddock, N., Jones, I. (1999) Genetics of bipolar disorder. Journal of Medical

Genetics 36, 585-594.

Craddock, N., Owen, M. (1994) Is there an inverse relationship between Down’s

Syndrome and bipolar disorder? Literature review and genetic implications. Journal of Intellectual Disability Research 38, 613-620.

Frank, E., Thase, M. (1999) Natural History and Preventative Treatment of Recurrent

Mood Disorders. Annual Review of Medicine 50, 453-648.

Kelsoe, J. et al (2001) A genome survey indicates a possible susceptibility locus for

bipolar disorder on chromosome 22. Procedings of the National Academy of Sciences 98, 585-590.