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Bipolar Disorder Genetic Studies


What is Bipolar Disorder?

Bipolar disorder, sometimes called manic depression, is a disorienting condition that causes extreme shifts in mood. Like riding a slow-motion roller coaster, patients may spend weeks feeling like they're on top of the world before plunging into a relentless depression. The length of each high and low varies greatly from person to person. In any given year, bipolar disorder affects more than 2% of American adults.


What are the Causes of Bipolar Disorder?

Doctors aren't exactly sure what causes bipolar disorder. A leading theory is that brain chemicals fluctuate abnormally. When levels of certain chemicals become too high, the patient develops mania. When levels drop too low, depression may result.

Bipolar Disorder Study examined 2 SNPs

Sklar et al in 2002 found that Two SNPs were closely related to Bipolar Disorder they are:

1.Brain-Derived Neurotropic Factor (BDNF)
2.Alpha subunit of the voltage-dependent calcium channel

BUT

Only BDNF in further study was the most potential risk for Bipolar disorder


Sklar, P. P., Gabriel, S. B., McInnis, M. G., Bennet, P. P., Lim, Y. M., Tsan, G. G., & ... Lander, E. S. (2002). Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Molecular Psychiatry, 7(6), 579.

Bipolar Disorder Study examined Markers and LOD Scores

Lambert et al in 2005 using a broad diagnostic model, found two markers gave LOD scores (Method of Estimating Linkage Distances) exceeding 3 with two-point analysis:

1.D4S392 (LOD¼3.30)
2.D10S197 (LOD¼3.18)


Multipoint analysis demonstrated suggestive evidence of linkage between Bipolar Disorder  and chromosomal regions

1.6q16–q21 (MLS¼2.61)
2.4q12–q21 (MLS¼2.38).


6q16–q21 was of particular interest because their data, together with those from two recent genome scans, make this the best supported linkage region for Bipolar Disorder


Lambert, D. D., Middle, F. F., Hamshere, M. L., Segurado, R. R., Raybould, R. R., Corvin, A. A., & ... Holmans, P. P. (2005). Stage 2 of the Wellcome Trust UK–Irish bipolar affective disorder sibling-pair genome screen: Evidence for linkage on chromosomes 6q16–q21, 4q12–q21, 9p21, 10p14–p12 and 18q22. Molecular Psychiatry, 10(9), 831-841. doi:10.1038/sj.mp.4001684

Bipolar Disorder Study examined Possible impact of personality traits

In 2006 Savitz & Ramesar reported that: Progress in identifying the genetic basis of bipolar affective disorder was disappointing, most probably because of the genetic and phenotypic heterogeneity of the condition. These setbacks have led to the adoption of alternative strategies such as the use of endophenotypes or intermediate traits to identify those individuals at genetic risk for developing the disorder


They concluded that A review of the literature suggests that certain personality traits or temperaments are associated with the illness in a state independent manner, that personality is at least partly heritable, and that various temperaments aggregate in the non-affected relatives of bipolar probands.


Savitz, J., & Ramesar, R. (2006). Personality: is it a viable endophenotype for genetic studies of bipolar affective disorder? Bipolar Disorders, 8(4), 322-337. doi:10.1111/j.1399-5618.2006.00309.x

Bipolar Disorder Study examined DGKH & Other Genes

Baum et al in 2008, in their research found that of 37 SNPs selected for individual genotyping, the strongest association signal was detected at a marker within the first intron of diacylglycerol kinase eta (DGKH; P= 1.5108, experiment-wide P < 0.01, OR= 1.59).


This gene encodes DGKH, a key protein in the lithium-sensitive phosphatidyl inositol pathway.

This first genome-wide association study of bipolar disorder shows that several genes, each of modest effect, reproducibly influence disease risk.


They concluded that Bipolar disorder may be a polygenic disease


Baum, A. E., Akula, N. N., Cabanero, M. M., Cardona, I. I., Corona, W. W., Klemens, B. B., & ... McMahon, F. J. (2008). A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Molecular Psychiatry, 13(2), 197-207. doi:10.1038/sj.mp.4002012

Bipolar Disorder Study examined  Co-morbidity with Autism?

Ragunath et al’s (2011) systems biology study of Autism Spectrum Disorders (ASD) and Bipolar Disorder (BP) proved to yield important insight on the genetic basis of comorbidity between the two disorders


1.The networks constructed for the selected 4 pathways leads to a hypothesis that the comorbidity of ASD and BP can be correlated to the genes involved in the pathways common to the two disorders and a further examination can pave way to the identification of the specific genes that contribute to comorbidity

2.Such knowledge would help in devising a novel management technique or developing therapeutics


Ragunath, P. K., Chitra, R. R., Mohammad, S., & Abhinand, P. A. (2011). A systems biological study on the comorbidity of autism spectrum disorders and bipolar disorder. Bioinformation, 7(3), 102-106

Bipolar Disorder Study examined Cognitive Endophenotype
Drysdale et al (2013) found that verbal learning and semantic verbal fluency impairments may represent a cognitive endophenotype for both bipolar disorder & major depression in relatives of bipolar disorder patients, as impairment was also present in high-risk relatives who had not developed any affective disorder symptoms

These findings suggest that impairment in semantic organization may be linked to the genetic etiology of bipolar disorder


Drysdale, E., Knight, H., McIntosh, A., & Blackwood, D. (2013). Cognitive endophenotypes in a family with bipolar disorder with a risk locus on chromosome 4. Bipolar Disorders, 15(2), 215-222. doi:10.1111/bdi.12040

BIPOLAR DISORDER GENETIC STUDY REFERENCES

 

Baum, A. E., Akula, N. N., Cabanero, M. M., Cardona, I. I., Corona, W. W., Klemens, B.

B., & ... McMahon, F. J. (2008). A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Molecular Psychiatry13(2), 197-207. doi:10.1038/sj.mp.4002012

 

Drysdale, E., Knight, H., McIntosh, A., & Blackwood, D. (2013). Cognitive

endophenotypes in a family with bipolar disorder with a risk locus on chromosome 4. Bipolar Disorders15(2), 215-222. doi:10.1111/bdi.12040

 

Lambert, D. D., Middle, F. F., Hamshere, M. L., Segurado, R. R., Raybould, R. R.,

Corvin, A. A., & ... Holmans, P. P. (2005). Stage 2 of the Wellcome Trust UK–Irish bipolar affective disorder sibling-pair genome screen: Evidence for linkage on chromosomes 6q16–q21, 4q12–q21, 9p21, 10p14–p12 and 18q22. Molecular Psychiatry10(9), 831-841. doi:10.1038/sj.mp.4001684

 

Ragunath, P. K., Chitra, R. R., Mohammad, S., & Abhinand, P. A. (2011). A systems

biological study on the comorbidity of autism spectrum disorders and bipolar disorder. Bioinformation7(3), 102-106.

 

Savitz, J., & Ramesar, R. (2006). Personality: is it a viable endophenotype for genetic

studies of bipolar affective disorder?. Bipolar Disorders8(4), 322-337. doi:10.1111/j.1399-5618.2006.00309.x

 

Sklar, P. P., Gabriel, S. B., McInnis, M. G., Bennet, P. P., Lim, Y. M., Tsan, G. G., & ...

Lander, E. S. (2002). Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Molecular Psychiatry7(6), 579.