The document discusses the role of genetics in bipolar disorder based on literature. It finds that genetics and heredity play an important role based on family and twin studies showing higher prevalence of bipolar disorder in relatives. The focus has shifted from whether genetics plays a role to identifying specific genes that may contribute to onset or protection against bipolar disorder, such as genes related to glutamate receptors and calcium signaling. Research uses genome-wide association studies and identifies several candidate genes and gene variants, though the mechanisms are not fully understood and likely involve multiple genetic factors.

1. What does the literature suggest regarding the role genetics play in Bi Polar Disorders PSY 492XD: Advance General Psychology Submitted by: Scott Carlisle Argosy University Professor Mary Viventi Submitted: December 13, 2010

2. GENETICS AND HEREDITY The evidence that genetics and heredity play an important role is well established from previous studies and research. The lifetime prevalence of bi polar disorder (BP) is 1.3% - 1.6% . Among the world population 1% are affected by bipolar I and an even greater prevalence of bipolar II. (Zhao et al., 2009).

3. GENETICS AND HEREDITY xy X Y YY Monozygotic Twins xy The life time risk of first degree relatives with monozygotic twins ranges from 40 – 70 percent and 5- 10 percent with siblings and relatives (Zhao et al., 2009)

4. GENETICS AND HEREDITY The question becomes not whether genetics plays a role in the onset of BP disorder the question and the focus becomes how does genetics play a role in the onset or protection against BP disorder.

5. GENETICS AND HEREDITY Within the cell of a human being lies the blue print of that individual ; the embodiment which distinguishes this individual from all other individuals in the world, with perhaps the exception, of this individuals monozygotic twin. The deoxyribonucleic acid (DNA) of an individual is segmented into units known as genes, which give instructions to produce proteins that guide the development of the individual from conception.

6. GENETICS AND HEREDITY Cell Nucleus Segment of DNA Chromosome

7. GENETICS AND HEREDITY We know that genes are segments of DNA that contain instruction for an individuals development (Gerrig, Zimbardo, & Hock). Other elements of interest are focused upon during genetic research these elements are known as alleles and single nucleotide polymorphisms. Alleles are one of the possible many alternative genes occupying the same locus (position on a chromosome) on paired chromosomes that has the possibility of controlling the same inherited characteristic (Wikipedia, 2010). A single nucleotide polymorphism (SNP) is a single difference in the gene where the dual chromosome pair are attached the difference can be expressed either using A, T, C, or G differentiating the nucleotide using this definition and what we understand about alleles we can deduce a difference in a single sequence of nucleotides produces two alleles (Wikipedia, 2010).

8. GENETICS AND HEREDITY Now lets examine how some genes, alleles and SNPs interact in order to possibly bring on the onset or the protection against BP disorders. The Ankyrin 3 (ANK3) encodes Ankyrin-G a large protein on the initial stem of the axon stem and Ranvier nodes. This is believed to increase the cell adhesion properties and preserve the ion channels (Schulze, et al., 2009). ANK3 was implicated; and met the possible criteria, for the possible origin and cause of BP disorder, by a genome-wide association study carried out in the United States and Germany. The single nucleotide polymorphism (SNP) rs9804190 was the focus of the study however; further research indicated rs10994336 also turned out to be a SNP indicating a strong signal and was independent to the previous marker (Schulze, et al., 2009).

9. GENETICS AND HEREDITY The previous example focuses on the point of continued research to identify markers that are possible markers for the etiology of BP disorders. From the standpoint of the researchers each locus on the gene or variation represents a possible clue to the mechanisms and processes involved in the onset or protection against BP disorders

10. GENETICS AND HEREDITY The LIM and PRP4FB were found to be altered in autopsies conducted on fifty patients having schizophrenia, BP, and major depression. It was found that the LIM was down regulated by identifying a reduction in the lymphoblastoid cell lines in patients suffer from BP disorder. Lymphoblastoid cell lines are the result of the Epstein- Barr virus infecting the B-lymphocytes in vitro, which are capable of indefinite growth (Wikipedia, 2010). In addition, the LIM was also down regulated in BP type II disorder and schizophrenia patients (Kato, et al., 2005). This led to the belief that the regulation of LIM may be genetically impaired in BP, schizophrenia and other mental illnesses.

11. GENETICS AND HEREDITY LIM encodes an adopter protein connecting the protein kinase C (PKC) to the N type calcium channel. Altered calcium signaling has been considered an important pathophysiological mechanism of BP disorder. It is possible to hypothesize that genetic abnormalities cause the LIM to become down regulated and calcium-signaling abnormalities in BP disorder (Kato, et al, 2005).

12. GENETICS AND HEREDITY An interesting gene that modulates the hippocampus and protects against the onset of BP is a GRIK4 variation (Whalley, 2010). The GRIK4 gene encodes the kainite glutamate receptor KA1, which is found in high concentrations in the hippocampus. Within the hippocampus the KA1 is concentrated at the CA3 synapses where it forms heteromeric kainite receptor complexes with GLuR6/GLuR7 subunits this modulates the plasticity of the CA3 synapses. Variants of the GRIK4 gene have been shown to modulate the hippocampus and provide protection against BP disorder.

13. GENETICS AND HEREDITY The significance of the work by Whalley and researchers (2009) is that it was the first evidence was given that variations of the GRIK4 gene modulate the hippocampal function (Whalley et al, 2009). Research where variation in the suspect gene either modulate, impede, change, enhance a system need to be considered in order to unlock the mechanism and processes of BP disorder. This research was published in 2009 so it is possible further research along this line and with similar methodology is underway.

14. GENETICS AND HEREDITY The pericentrin (PCNT) gene creates nucleation sites by anchoring the gamma tubulin complex to the centrosome. The interaction between DISC1 and PCNT may have an assumed alleged effect on the centrosomal function and thereby certain pathophysiology of certain mental disorders (Numata et al., 2009). Recently studies have shown that significantly higher concentrations of PCNT were found in individuals with BP and major depressive disorder A (MDD) than in the control group. This led researchers to investigate PCNT gene as a possible candidate gene to recognize MDD.

15. GENETICS AND HEREDITY The onset of BP is not considered only specific to one gene abnormality and may be expressed by a combination of several gene variations or their alleles research continues to identify candidate genes, their alleles, and the single nucleotide polymorphisms associated. Research on identifying the suspect genes uses genetic studies. They are known as genome wide association studies (GWAS). After doing research in the original scientific question it became evident that research has conclusively determined genetic inheritance as well as genetic variations are responsible for the onset of BP disorder disease what still remains is the identification of the different genes and alleles at what role they play in the onset or protection of the disease. It makes sense to refocus my research with this intent to answer what the literature says as to what roles genes play in the BP disorder rather than consider controversial views of researchers. In the literature that I have reviewed thus far a consensus of identification of the genes as possible candidates are at the forefront controversial views do not seem to appear very often and if they do, they appear in the form of an additional SNP marker associated with BP rather a dispute of the previous marker.

16. GENETICS AND HEREDITY When considering the vastness of identification of all the genes and alleles associated with chromosomes of the human cell the task is monumental. In 1990, the United States Government funded a program known, as the Human Genome Project (HGP) the mission of the project was to identify the full sequence of genes found on the chromosome associated with the DNA. In 2003, the HGP completed the project and now have focused their intentions on identifying all 20,000 to 25000 human genes (Gerrig, Zimbardo, & Hock, 2009). With this in mind, I believe researchers have not had the time to consider where they have already been and are more interested in delving into unknown territory. This may give a tentative explanation as to why little debate is found regarding the significance of markers and their role in the onset or prevention of BP disorder.

17. GENETICS AND HEREDITY One thing you notice when going through the literature is the dependence on previous research and the reduplication of the research in order to validate a current marker in question. The validation of a past marker gives more credibility to the idea of similar conditions so that meta-analysis can be conducted with the results (Shaughnessey, Zechmeister, & Zechmeister, 2009).

18. GENETICS AND HEREDITY The genetic studies of identifying specific genes , and variations have been likened to an astronomers who have recently discovered a new star cluster and are anxious to categorize them. It is my conjecture that the lack of debate regarding the identified markers and their supposed processes and mechanisms is the precipitation of the interest of first identifying the full scope of genomes and the possible etiology of BP disorders.

19. GENETICS AND HEREDITY To be critical of the research, many of the roles the suspect genes, alleles and SNP are conjectured to have mechanisms that contribute to the onset or protection against BP. The mechanisms and processes given progresses in a logical form and leads the reader to the same conclusion as the authors. With limited knowledge on the subject, it is difficult to infer possibly different mechanisms or processes however, most of the authors are not ready to confer categorically that a particular mechanism is at work and is ready to show the research behind his proposition.

20. GENETICS AND HEREDITY Much of the literature shows the researchers using two popular methodologies to identify new SNP’s or using previous studies to identify a SNP that is associated with BP. The concept of the methodology is simple however; the actual procedure is very technical and requires the use of extremely specialized software and state of the art equipment. A pool of known individuals is tested against individuals without any sign of the illness in the specific area of the gene of interest. Some confounding variable must be accounted for such as individuals in the pool without any sign or undiagnosed may actually be BP previous studies with similar or grater populations are used to lessen the significance of this possible confounding variable and give more credibility to the findings. By following similar procedures and using similar populations the results of the researcher’s investigation can be an element of a meta analysis (Shaughnessey, Zechmeister, & Zechmeister, 2009).

21. GENETICS AND HEREDITY The methodologies of the research are sound by showing individuals with BP disorder have strong signals associated with genes, their alleles and their associated SNP’s and individuals who do not have any history of mental illness do not have this strong signal. Those sites become strong indicators that they may be associated with BP disorder. Accompany this with the known etiology of the disease and the credibility of site caries even greater association with the disease.

22. GENETICS AND HEREDITY One advantage for the neuropsychiatrist, physiologist, and researchers is the mechanisms of the various suspect functions, such as the modulation of the hippocampal function, are the same in individuals without a history of mental illness, and differ from individuals with BP disorder. This allows the researcher, physiologist, and neuropsychiatrist a conduit to discover the possible underlying causes and better treatment of the disease.

23. GENETICS AND HEREDITY Identifying the various genes and the possible roles they play in the onset or protection of BP assist the reader in categorizing various genes and realizing the complex roles the identifiers play within the various mechanisms and processes. Because of the complexity and the vast scope of the number of genes and identifiers as much as 26 genes in the Welcome Trust Case Control Consortium (WTCC), it is difficult to get an overview of how each variation in a gene functions (Ollila et al., 2009). Still I believe it is important to bring to light what information is known regarding the roles genes their alleles and their associated SNP’s play in the onset or protection against BP disorder.

24. GENETICS AND HEREDITY Considerations we have covered: The onset of BP is not considered to be specific to one gene abnormality. BP is considered to be the combination of several gene abnormalities an may be expressed by several gene variations or their alleles. Research continues to identify candidate genes, their allele’s and SNPs associated. Research depends strongly upon validation of previous work. The validation of a past marker gives more credibility to the idea of similar conditions so that meta-analysis can be conducted with the results.

25. GENETICS AND HEREDITY The lack of debate regarding the mechanisms and processes involved in the onset and protection against BP disorders is presupposed as an indication for the need to continue identifying the genes and their variations to improve the understanding of the etiology of BP disorders The methodologies used is well established the technology is very technical however it can simply be broken down into the logical comparison of the appearance of a genetic marker in an individual diagnosed with BP compared to an individual who does not have the disorder. It is difficult to get an overview of the complexity and the vast scope of the number of genes and identifiers however, I believe it is important to bring to light what information is known regarding the roles genes their alleles and their associated SNP’s play in the onset or protection against BP disorder.

26. REFERENCES Gerrig, R. J., Zimbardo, P. G., & Hock, R. R. (2009). An overview of psychology: Its past and present, your future. Upper Saddle River, NJ: Pearson Custom Publishing. Kato, T., Iwayama, Y., Kakiuchi, C., Iwamoto, K., Yamada, K., Minabe, Y., Nakamura, K., Mori, N., Fujii, K., Nanko, S., & Yoshikawa, T. (2005) Gene expression and association analyses of LIM (PDLIM5) in bipolar disorder and schizophrenia Molecular Psychiatry (10) 1045-1055 Retrieved November 1, 2010 from Research Library doi10.1038/sj.mp.4001719 Numata, S., Iga, J., Nakataki, M., Tayoshi, S., Tanahashi, T., Itakura, M., Ueno, S., & Ohmori, T. (2009). Positive association of the pericentrin (PCNT) gene with major depressive disorder in the Japanese population. Journal of Psychiatry & Neuroscience: JPN, 34(3), 195-8. Retrieved November 1, 2010, from Research Library. (Document ID: 1703812911). Ollila, H., Soronen, P., Silander, K., Palo, O., Kieseppä, T., Kaunisto, M., Lönnqvist, J., Peltonen, L., Partonen, T., & Paunio, T. (2009). Findings from bipolar disorder genome-wide association studies replicate in a Finnish bipolar family-cohort. Molecular Psychiatry, 14(4), 351-3. Retrieved November 1, 2010, from ProQuest Health and Medical Complete. (Document ID: 1665306221).

27. Schulze, T., D, S., Akula, N., Gupta, A., Kassem, L., Steele, J., Pearl, J., Strohmaier, J., Breuer, R., Schwarz, M., Propping, P., Nöthen, M., Cichon, S., Schumacher, J., Rietschel, M., & Mcmahon, F. (2009). Two variants in Ankyrin 3 (ANK3) are independent genetic risk Shaughnessey, J. J., Zechmeister, E. B., & Zechmeister, J. S. (2009). Research methods in psychology. (8th ed.). New York, NY: McGraw-Hill. Wikipedia, (2010) Allele, Retrieved November 29, 2010 from http://en.wikipedia.org/wiki/Allele Wikipedia, (2010) Single nucleotide polymorphism, Retrieved November 29, 2010 from http://en.wikipedia.org/wiki/Single-nucleotide_polymorphism Zhao, T., Liu, Y., Wang, P., Li, S., Zhou, D., Zhang, D., Chen, Z., Wang, T., Xu, H., Fen g, G., He, L., & Yu, L. (2009). Positive association between the PDLIM5 gene and bipolar disorder in the Chinese Han population. Journal of Psychiatry & Neuroscience: JPN, 34(3), 199-204. Retrieved November 1, 2010, from Research Library. (Document ID: 1703812921).