Shannon Looney – Schizophrenia and Bipolar


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Shannon Looney – Schizophrenia and Bipolar

  1. 1. 1 Shannon Adele Looney Dr. Bert Ely Biology 303—Genetics 8 November 2008 Seeking Similarities between Schizophrenia and Bipolar Disorder: A Portal to Discovery The brain is central to human existence, to personality, and to awareness of and responsiveness to surroundings. Mental functioning is an essential component of quality of life. Thus, cognitive disorders including Schizophrenia, often characterized by paranoia and by altered perceptions of reality, and Bipolar Disorder, characterized by periods of mania alternating with periods of severe depression, are extremely debilitating. Although in modern psychology these disorders are seen as distinct, “it has not escaped attention that the classifications share some pathophysiology, vulnerability and risk factors, genetic loci, clinical manifestations and approximate ages of onset.”3 Separate clinical studies of at-risk individuals for Bipolar Disorder and Schizophrenia have identified the DAOA gene as a potential genetic source for these diseases, and further similarities can be seen in studies on gene causation and expression.
  2. 2. 2 Jeremy Hall and colleagues2 performed a study linking the DAOA gene to hippocampal function in 61 adolescents at high risk for Schizophrenia (controlled by selection of individuals not exhibiting the disease or taking medication for it). The DAOA, or D-amino acid oxidase activator, gene directly affects NMDA (N-methyl-D-aspartic acid) receptors, which are important in learning and memory, so it was hypothesized that changes in the DAOA gene would alter these processes.2 The SNPs (single-nucleotide polymorphisms) M23 of this gene had previously been associated with schizophrenia, so the researchers focused on these markers in their genotypic analysis of the 61 individuals.2 The hippocampus and parahippocampus also play important roles in learning, memory, and the integration of knowledge. The researchers therefore further examined hippocampal and parahippocampal functions in the same high-risk individuals using the Hayling Sentence Completion Test accompanied by functional MRI (fMRI). In the sentence completion test, each individual was asked to provide missing words in a series of sentences, and the researchers found that in individuals homozygous for the T allele at M23, hippocampal and parahippocampal activation was less than in heterozygous individuals (CT) and both genotypes had less activation than individuals homozygous for the C allele. (See figure 1 for images of brain activation during the task as well as a bar graph of the data
  3. 3. 3 resulting from differences in M23.2 )
  4. 4. 4 Figure 1: *Figure 1 (A) shows images of brain activation during the Hayling Sentence Completion test. Statistical mapping indicated significantly decreased activity in the TT genotype compared with the CC genotype in the hippocampal and parahippocampal cluster shown here. (B) shows proportion estimates of hippocampal and parahippocampal activation in the 3 genotype groups at M23 (with error bars showing standard error). The results of this study are significant because decreases in volume and activation of the hippocampus and parahippocampus have been reported in subjects with schizophrenia, so the apparent
  5. 5. 5 relationship between decreased activation of these parts of the brain and variation in the M23 markers on the DAOA gene suggests that the DAOA gene could be a cause for schizophrenia.2 Soronen and his team performed a similar experiment in a family study on individuals both with bipolar disorder and at risk for it.4 Results must be considered carefully, however, because this experiment could have more confounding variables than the Hall et al. 2 experiment as a result of the intermediate levels of psychological conditions present in the former as opposed to the highly uniform “at-risk” and unrelated individuals in the latter. Nevertheless, it is extremely interesting to consider the ramifications of the suggestion that DAOA is a gene involved in both Schizophrenia and Bipolar Disorder. The Soronen study takes this into account, stating: “bipolar disorder and schizophrenia co- segregate in many pedigrees, which suggest a shared genetic etiology of these two disorders at least to some extent.”4 These researchers examined the effects of several genes previously identified as possible contributors to Bipolar Disorder, including but not limited to DAOA and COMT (Catechol-O-methyl transferase) within a sample of test data from 159 individuals from 65 families.4 Their results regarding DAOA were particularly interesting in light of the Hall et al. 2 study. They analyzed the relationship between gene markers in DAOA and both Bipolar Disorder and psychotic disorders
  6. 6. 6 in general, indicating that there seems to be a very strong relationship between the two4:
  7. 7. 7 Table 1: Ratio of DAOA and COMT Markers in Families with Bipolar or other Psychotic Disorders Bipolar Spectrum Disorder Psychotic Disorder Phase I Familial (62 Phase I + II Casesa Phase I Phase I + Familie (154 (99 (57 II (144 s) Families) Families) Families) Families) Familial Casesa (102) DAOA rs39169 .696 .966 .906 .843 .839 .616 66 rs23911 .889 .913 .735 .87 .891 .349 91 rs21536 .072 .353 .095 .066 .700 .233 74 rs70156 .670 .593 .407 .278 .133 .031 7 rs77832 .025 .111 .024 .010 .186 .018 6 rs95458 .040 .107 .052 .049 .565 .252 0
  8. 8. 8 COMT rs4680 .085 .046 .020 .340 .072 .149 rs16559 .003 .829 .035 .015 .396 .103 9 They also used a visuospatial test called the Block Design Test and considered the results in context of variants of the DAOA gene in subjects, most specifically those individuals homozygous for the G allele at SNP rs2391191. These homozygotes generally performed worse on the Block Design Test than others.4 This finding augments the results of the Hall et al. 2 study because it adds (visuospatial in addition to language/processing) to the list of cognitive functions affected by the DAOA gene, indicating its general effect on working memory and strengthening the hypothesis that this gene is involved in psychiatric disorders, specifically in Bipolar Disorder and Schizophrenia. Further research involving shared genetic characteristics of Schizophrenia and Bipolar Disorder includes the study by Lyudmila Georgieva and colleagues1 regarding Neuregulin 1 (NRG1), which was previously identified as a susceptibility gene for psychiatric
  9. 9. 9 disorders. The researchers performed statistical analyses on genetic data from trios of parents and children. Their results indicated that NRG1 seems to be strongly associated with Schizophrenia, and there was some evidence that it is also involved in susceptibility to Bipolar or manic disorder, although this evidence was weaker. NRG1 is thought (like DAOA) to be involved in several important cognitive processes, mainly connective functions like synaptogenesis and neurotransmission.1 The study supports the idea that Bipolar Disorder and Schizophrenia result from similar genetic bases that are associated with physical brain alterations. Furthermore, the researchers found similarities in the association patterns of COMT and NRG1 with physiological processes, which is intriguing because of the relationship already established on the correlation of COMT and Bipolar Disorder.4 Shao and Vawter3 performed a study that integrates the ideas presented by the previous studies into an investigation of shared genes and gene expression patterns in Bipolar Disorder and Schizophrenia. The researchers analyzed RNA samples from a total of 105 subjects, 35 in each category—Bipolar, Schizophrenic, and a control group. They performed this analysis in conjunction with demographic data and concluded that brain pH appeared lower in subjects with Bipolar Disorder or Schizophrenia than the control group and that more
  10. 10. 10 women appeared to have Bipolar Disorder than men. When they took these observations into account in their gene analysis, they narrowed the number of genes shared between Bipolar Disorder and Schizophrenia to 82 (78 unambiguous genes). (See figure 2 for a visual representation of this analysis.3 ) Figure 2: Figure 2 shows a venn diagram for the results of 88 RNA samples from the prefrontal cortex of schizophrenic, bipolar, and control subjects. (A) shows the overlap of 327 genes between Bipolar
  11. 11. 11 Disorder and Schizophrenia in an unrestricted sample. (B) shows the overlap of 280 genes in only subjects with brain pH of greater than 6.57. (C) shows the combination of these two analyses, resulting in 82 shared genes, 78 of which were proven to be unambiguously matched to the probes used. The researchers therefore concluded that there appeared to be 78 shared genes between Bipolar Disorder and Schizophrenia. Many of the shared genes are involved in cell death and immune response.3 This study reinforces the concept that Schizophrenia and Bipolar Disorder share a genetic basis. The researchers concluded that “these results… offer a window into discovery of common pathophysiology that might lead to core treatments.”3 Ultimately, studies on the genetic basis for heritable disorders serve as potential steps toward finding a treatment. Investigation into the genetic basis for Schizophrenia and Bipolar Disorder has led to the exciting conclusion that these two genetic disorders seem to share many common genetic origins, such as the DAOA gene and possibly the NRG1 gene as well as similar alterations of gene expression expression and similar physiological effects on the brain. These findings not only allow scientists to work toward finding a cure or more effective treatment for each of these disorders individually, but also allow them to look for a common treatment
  12. 12. 12 based on similarities in cause and function.
  13. 13. 13 References 1. Georgieva, Lyudmila, Albena Dimitrova, Dobril Ivanov, Ivan Nikolov, Nigel M. Williams, Detelina Grozeva, Irina Zaharieva, Draga Toncheva, Michael J. Owen, George Kirov, and Michael C. O’Donovan. “Support for Neureglin 1 as a Susceptibility Gene for Bipolar disorder and Schizophrenia.” Biological Psychiatry 64.5 (2008): 419-427. 2. Hall, Jeremy, Heather C. Whalley, T. William J. Moorhead, Ben J. Baig, Andrew M. McIntosh, Dominic E. Job, David G. C. Owens, Stephen M. Lawrie, and Eve C. Johnstone. “Genetic Variation in the DAOA (G72) Gene Modulates Hippocampal Function in Subjects at High Risk of Schizophrenia.” Biological Psychiatry 64.5 (2008): 428-433. 3. Shao, Ling and Vawter, Marquis P. “Shared Gene Expression Alterations in Schizophrenia and Bipolar Disorder.” Biological Psychiatry 64.2 (2008): 39-97. 4. Soronen, Pia, Kaisa Silander, Mervi Antila, Outi M. Palo, Annamari Tuulio-Henriksson, Tuula Kieseppa, Pekka Ellonen, Juho Wedenoja, Joni A. Turunen, Olli P. H. Pietilainen, William Hennah, Jouko, Lonnqvist, Leena Peltonen, Timo Partonen, and Tiina Paunio. “Association of a Nonsynonymous Variant of DAOA with Visuospatial Ability in a Bipolar Family Sample.”
  14. 14. 14 Biological Psychiatry 64.5 (2008): 438-442.