Download Shannon Looney – Schizophrenia and Bipolar

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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 atrisk 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.
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)
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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 resulting from differences in M23.2 )
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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 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
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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 cosegregate 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 in general, indicating that there
seems to be a very strong relationship between the two4:
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Table 1: Ratio of DAOA and COMT Markers in Families with Bipolar or other
Psychotic Disorders
Bipolar Spectrum Disorder
Phase I
Psychotic Disorder
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
rs3916966
.696
.966
.906
.843
.839
.616
rs2391191
.889
.913
.735
.87
.891
.349
rs2153674
.072
.353
.095
.066
.700
.233
rs701567
.670
.593
.407
.278
.133
.031
rs778326
.025
.111
.024
.010
.186
.018
rs954580
.040
.107
.052
.049
.565
.252
rs4680
.085
.046
.020
.340
.072
.149
rs165599
.003
.829
.035
.015
.396
.103
COMT
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.
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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 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 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
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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 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.
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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 based on similarities in cause and function.
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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.” Biological Psychiatry 64.5 (2008): 438-442.