The Genetic Cause of Bipolar Disorder - Research Paper Example

The Genetic Cause of Bipolar Disorder Statement of the Topic Bipolar disorder, as defined by the National Institutes of Health, is “a condition in which people go back and forth between periods of a very good or irritable mood and depression” (Bipolar Disorder). Bipolar disorder affects both men and women with almost the same frequency and its onset is as early as 15 to 25 years old. Bipolar disorder may occur either as type I or manic depression, or type II, where the mania is not pronounced. Another type of bipolar disorder is cyclothymia, where the mania and the depression are both mild (Bipolar Disorder). Although the exact cause of bipolar disorder is unknown, the NIH states that “it occurs more often in relatives of people with bipolar disorder” (Bipolar Disorder). This statement alone means that bipolar disorder has a genetic cause and this may explain why its physical causes may not be readily known. Studies have also proven the same, like twin, family and adoption studies that support “the existence of genes that predispose [one] to bipolar disorder” (Grozeva et al.). The percentage of heritability of bipolar disorder, based on scientific studies on the matter, is around 60%, and this was proven by several genome-wide association studies, or GWAS, which try to resolve a disease by studying its genetic causes (Gershon et al.). Nevertheless, some other possible non-genetic causes of bipolar disorder include major life changes especially those that may bring about so much stress, periods of sleeplessness, antidepressant or steroid medications or other similar types, and use of recreational drugs (Bipolar Disorder). Overall, the problem with bipolar disorder and the need to investigate its genetic causes is that bipolar disorder is the reason for the “loss of more disability-adjusted life-years than all forms of cancer or major neurologic conditions such as epilepsy or Alzheimer’s disease” (Merikangas et al. 247). In fact, this claim is usually associated with the fact that bipolar disorder has an “early onset and chronicity across a life span” (Merikangas et al. 248). In short, bipolar disorder is more dangerous and harmful to the mental and physical health of an individual more than anyone could ever imagine. Brief Survey of Related Literature Several recent research studies have pointed out the theory that there is indeed a genetic basis for the occurrence of bipolar disorder. Copy number variants, or CNVs, which naturally occur in the human genome, may play a role in the occurrence of bipolar disorder in an individual and may determine one’s susceptibility to the disease (Grozeva et al. 320). In fact, CNVs have been associated with and implicated in the existence of several neuropsychiatric phenotypes as well as schizophrenia, mental retardation, epilepsy and autism. These CNVs are large, rare deletions that occur in the human genome and may predispose one to the disease. So far, the study of Grozeva et al. in 2010 has found out that the genetic cause of bipolar disorder is “2 genes involved in ion channel function [which are namely] ANK3 and CACNA1C” (Grozeva et al. 322). Aside from these two genes, other genes that may make an individual susceptible to bipolar disorder include PALB2, MYO5B and DGKH. So far, based on this study, there was a natural increase in the number of singleton CNVs in cases of bipolar disorder compared to those who were healthy (Grozeva et al. 325). According to the consortium study of recurrent depression by the Genetic Association Information Network, or GAIN, there is “nominally significant” evidence that the CACNA1C gene is mainly involved in the hereditary nature of bipolar disorder. However, the CACNA1C gene is not specific to bipolar disorder as this particular gene increases the individual’s risk for schizophrenia and recurrent major depression as well (Green et al. 1018). SNPs or single nucleotide polymorphisms are also another possible factor that might explain the genetic basis of bipolar disorder. An SNP is a “variation at a single position in a DNA sequence among individuals” (SNP). If there is a particular arrangement of adenine, cytosine, guanine, and thymine that account for less than 1% of the population, then this is an SNP and this may be associated with a particular disease(SNP). In a particular study of bipolar disorder patients of European and African ancestries, the SNPs involved were SLITRK2 and NTRK2. SLITRK2 is expressed in the neural tissue and produces membrane-bound proteins, and is known as a “logical bipolar risk gene,” while NTRK2 is involved in the regulation of neurite growth and a “high priority bipolar candidate gene” (Smith et al. 759). Although there were significant variations between the genetic make ups of patients with bipolar disorder and of different ancestries, it has been found out by one study that the prevalence rates of bipolar disorder as well as the impact, severity and patterns of comorbidity are “remarkably similar” regardless of which part of the world the individual is in (Merikangas et al. 247). In another study, the role of the previously mentioned genes – ANK3 and CACNA1C – has been emphasized. However, in this particular study, it is stated that non-genetic and external factors may in fact precipitate bipolar disorder such as natural hormone changes, stressors, and steroid medication may actually influence transcription of DNA and may therefore affect the genotype, which in turn affects the phenotype of the affected individual (Holmans et al. 20). According to a study by Scott et al., “There are few, if any, common SNP variants with large effects on bipolar disorder risk” (Scott et al. 7502). These genes include MCTP1, ANKRD32, CACNA1C, and ITIH1. The first three of these occur on chromosome 5. Other suspect genes include CTNNA2, LRRTM1, NEK7, and ATP6V1G3 (Scott et al. 7505). As the genotype expresses itself in the phenotype, one study has proven this fact by concluding that “genetic risk for bipolar disorder was specifically associated with gray matter deficits only in the right anterior cingulate gyrus and ventral striatum” (McDonald et al. 982). This means that bipolar disorder may be physically proven by deficits in gray matter particularly in the right anterior cingulate gyrus and the ventral striatum, which may translate as deficits in emotion, decision-making and and behavior. It is not the gene sometimes that is believed to cause bipolar disorder but the certain chromosomal arrangements especially those of chromosomal regions: “4p,4q,10p,12q, 16p, 18q, 21q, and Xq,” and arrangements concerning these chromosomal regions run similar in families (Blackwood et al. 135). Thus, this somehow explains the genetic basis of bipolar disorder. Critique of the Readings Genome-wide association studies, or GWAS, have been useful in determining the genetic cause of diseases in order to at least identify a particular disease and find out its weaknesses as well as what can be done to prevent or cure it. In the case of bipolar disorder, the initial steps have been taken by GWAS but because of the varying results presented in the previously discussed studies, it is clear that the true genetic cause of bipolar disorder has not been established yet or has not been properly identified. The study of Groveza et al. identified the role of copy number variants or CNVs in the genetic cause of bipolar disorder and has identified it as the CACNA1C. Moreover, the study of Green et al. confirmed the theory that it is the CACNA1C gene that causes bipolar disorder. However, Smith et al. argue that it is NTRK2 and SLITRK2 that cause the disease. The problem is that the two studies that have pointed out the role of CACNA1C have not exactly pointed out whether this particular gene alone determines an individual’s susceptibility to bipolar disorder or the CACNA1C works together with other genes and produces a synergistic effect. The study of Smith et al. confidently describe SLITRK2 as a “logical bipolar risk gene,” while labeling NTRK2 as a “high priority bipolar candidate gene” (Smith et al. 756). The methods used by Smith et al. in ascertaining the roles of these genes are obviously relatively more reliable. Moreover, Smith et al.’s emphasis on the idea that SNPs cause bipolar disorder is very sound considering the fact that many diseases have been identified to be a result of a particular arrangement of the components of the genetic material. Nevertheless, the study of Smith et al. fails to discuss the possible role of the CACNA1C gene. It also fails to emphasize whether SLITRK2 and NTRK2 are the only ones responsible for predisposing an individual to bipolar disorder. Other studies that specified the genes include that of Holmans et al., which specified the roles of ANK3 and still the CACNA1C gene in the occurrence of bipolar disorder. Moreover, Scott et al. pointed out that this role is actually being played by MCTP1, ANKRD32, CACNA1C, ITIH1, CTNNA2, LRRTM1, NEK7, and ATP6V1G3. The results may vary but with the exception of Smith et al., all these studies believe that the CACNA1C gene plays a very significant role in an individual’s susceptibility to bipolar disorder. The study conducted by Smith et al. used several subjects from both European and African ancestries and found out slight variations in their results, which means that there are slight variations in how exactly bipolar disorder affects or manifests in a particular group of people by virtue of their geographical area. However, the findings of Merikangas et al. oppose this as these findings suggest that bipolar disorder occurs in all individuals in a similar way regardless of nationality. This finding alone implies that the environment has nothing to do with the nature of the disease and that most probably, bipolar disorder is largely genetic in nature. It is possible that the environment may trigger the disease as when some previously mentioned factors influence it like serious life changes, sleeplessness, medications or recreational drug use (Bipolar Disorder). However, from the point of view theorized by Merikangas et al., bipolar disorder is still mostly genetic in cause, with or without these probable environmental or external causes. The interaction between the internal or genetic causes of bipolar disorder and the external or environmental factors that trigger it was explained by the study of Holmans et al. Based on the results and conclusions of Holmans et al.’s study, the external factors that are known to trigger bipolar disorder – natural hormone changes, stressors, and steroid medication – may actually play a role in the transcription of some proteins in the internal system of the individual, and thus trigger an abnormal genotypical change that results in bipolar disorder. This is a new theory and a feasible one since the previous studies failed to emphasize the possibility that bipolar disorder is actually originally congenital. The onset of the disease is around the age of 15 to 25, which is the age range where an individual usually experiments with chemicals like nicotine and alcohol as well as recreational drugs. These chemicals may be the ones responsible for altering the transcription process of certain proteins in operation in the individual at that time, thus causing bipolar disorder. Moreover, there is also a possibility that the genetic cause of bipolar disorder is a process whereby certain external chemical factors trigger particular genes in the individual congenitally predisposed to the disease. Thus, in any case, there is a clear and obvious connection between the genes and the environment in bipolar disorder. The study of Scott et al. emphasized that the role of SNPs in the occurrence of bipolar disorder is not that established. If this is true, then it implies that there are actually particular genes that cause bipolar disorder, and that this disease is not due to any arrangement of components of genetic material nor is it due to any particular deletion of a part of a chromosome or an error in transcription. In short, according to Scott et al., there are really actual genes that carry the bipolar disorder trait. Scott et al. enumerated and specified several genes that might be responsible for bipolar disorder. However, Scott et al. failed to emphasize whether these genes were the only ones responsible for bipolar disorder or whether there are probably others. Furthermore, the researchers failed to ascertain whether only one of these genes was enough to trigger bipolar disorder or all these genes had to assist each other in producing the symptoms of the disease. The study of McDonald et al. shows that there deficits in gray matter that either result from or cause bipolar disorder for these deficits occur in conjunction with the disease. Nevertheless, the implication of this result is that it is, according to the authors, similar to schizophrenia and other psychotic illnesses. Thus, the presence of deficits in gray matter, whether it is due to bipolar disorder or not, is an indication of the presence of a mental illness. Furthermore, identifying the fact that such deficits occur in the right anterior cingulate gyrus and ventral striatum somehow specifies such deficits as pertaining only to bipolar disorder and not to schizophrenia or any other mental illness. The right anterior cingulate gyrus is responsible for the regulation of blood pressure as well as heart rate and rational cognitive functions like emotion, empathy and decision-making. The ventral striatum is also responsible for emotion, motivation and behavior. Thus, deficits in these particular areas in bipolar disorder would somehow be equivalent to a deficiency in the functions fulfilled by these areas. Nevertheless, the study by McDonald et al. fails to account how significant these deficits in the gray matter are to the occurrence of bipolar disorder. Moreover, since gray matter deficits occur in many types of mental disorders including schizophrenia, then care should be taken to ensure that such gray matter deficits in bipolar disorder do not occur in conjunction with other diseases that may vary the location of these deficits. According to the study by Blackwood et al., the genetic cause of bipolar disorder is not due to particular genes but to problems with the physical structures of certain chromosomal regions. The method of determining this is relatively easier than determining particular genes responsible for bipolar disorder. Nevertheless, the authors fail to confirm whether the list of chromosomal regions that they presented is actually exhaustive or not. Therefore, there may be other chromosomal regions responsible for triggering bipolar disorder. Moreover, the authors did not make any comment regarding the reliability of the evidence concerning certain genes that are known to cause bipolar disorder, like CACNA1C. Thus, there is still a question of whether bipolar disorder is actually caused by certain genes or it is a rearrangement of certain chromosomal regions. Conclusion There is a genetic cause for bipolar disorder but it is still largely unknown or at least uncertain as the theories are not only varied but also do not establish clear links among themselves. The most common theory is that bipolar disorder is caused by certain genes, especially the CACNA1C gene, which is specifically mentioned by a number of research studies. However, the problem with this theory is that it has not been established whether only one gene causes bipolar disorder or whether several genes combine to produce the manifestations of the disease. Further studies should therefore be conducted and care should be taken to ensure that the results do not overlap with those of schizophrenia or other diseases that are also genetically caused. The other theory is that CNVs and SNPs as well as other rearrangements of components of genetic material may cause bipolar disorder. However, the problem remains the same because there is no complete list of such specific chromosomal changes that can cause bipolar disorder. Moreover, there is no clearly established link between this theory and the first one, or even between the roles of CNVs and SNPs. Thus, there is therefore a need for a comprehensive study that will try to test all these theories in order to determine once and for all which particular genes or chromosomal arrangements exactly trigger bipolar disorder. Another recommendation for further studies is based on the theory of Holmans et al. that certain external factors can actually cause changes in the transcription of genetic material and thus alter the genotype and consequently the phenotype of the individual. Thus, it is recommended that a study should be made in order to ascertain the extent of the role of environmental factors in the genetic origins of bipolar disorder. Top of Form Bottom of Form Works Cited “Bipolar Disorder.” 2012. National Institutes of Health. 7 Jan 2013. Blackwood, Douglas H. R., Visscher, Peter M. & Muir, Walter J. “Genetic studies of bipolar disorder in large families.” 2001. The British Journal of Psychiatry, 178 (134-136). 7 Jan 2013. Gershon, Elliot S., Ney Alliey-Rodriguez & Chunyu Liu. “After GWAS: Searching for Genetic Risk for Schizophrenia and Bipolar Disorder.” 2011. The American Journal of Psychiatry, 168:3 (253-256). 7 Jan 2013. Green, E. K., D. Groveza, I. Jones & G. Kirov. “The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia.” 2010. Molecular Psychiatry, 15:10 (1016-1022). 7 Jan 2013. Grozeva, Detelina, George Kirov, Dobril Ivanov & Ian R. Jones. “Rare Copy Number Variants: A Point of Rarity in Genetic Risk for Bipolar Disorder and Schizophrenia.” 2010. Archives of General Psychiatry, 67:4 (318-327). Web. 7 Jan 2013. Holmans, Peter, Elaine K. Green, Jaspreet Singh Pahwa & Manuel A. R. Ferreira. “Gene Ontology Analysis of GWA Study Data Sets Provides Insights into the Biology of Bipolar Disorder.” 2009. American Journal of Human Genetics, 85:1 (13-24). 8 Jan 2013. McDonald, Colm, Edward T. Bullmore, Pak C. Sham & Xavier Chitnis. “Association of Genetic Risks for Schizophrenia and Bipolar Disorder With Specific and Generic Brain Structural Endophenotypes.” 2004. Archives of General Psychiatry, 61:10 (974-984). 7 Jan 2013. Merikangas, Kathleen R., Robert Jin, Jian-Ping He & Ronald C. Kessler. “Prevalence and Correlates of Bipolar Spectrum Disorder in the World Mental Health Survey Initiative.” 2011. Archives of General Psychiatry, 68:3 (241-251). 6 Jan 2013. Scott, Laura J., Pierandrea Muglia, Xiangyang Q. Kong & Weihua Guan. “Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry.” 2009. Proceedings of the National Academy of Sciences of the United States of America, 106:18 (7501-7506). 7 Jan 2013. Smith, Erin N., Cinnamon S. Bloss, Judith A. Badner, Thomas Barrett & Pamela L. Belmonte. “Genome-Wide Association Study of Bipolar Disorder in European American and African American Individuals.” 2009. Molecular Psychiatry, 14:8 (755-763). 6 Jan 2013. Read More