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Bipolar and Genetics

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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.

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