| Abstract |
The philosophy of my thesis is relative with the influence of selected polymorphisms of three genes which are associated with psychoses to the phenotype and to a selected endophenotype i.e. affective startle modulation in healthy males, a philosophy that will help us i) to understand schizophrenia and Bipolar Disease which are syndromes, ii) to improve the diagnosis more than just symptomatic categorization of DSM-V and iii) to design more personalized treatments. We selected young men healthy volunteers to construct our sample, because they are ideal study model of the functions of genes consequences because of lack of problematic factors which complicate the studies in patients, such as age and sex, medication, presence of symptoms and the effects of the disease in the brain. We followed the «Candidate gene approach» which is an appropriate and modern research strategy for discovering the mechanisms by which genes affect cerebral and mental functions and increase the risk for disease. In this thesis, the main psychosis we had in mind was the bipolar disorder and related affective disorders, which have the same basic problems with schizophrenia in understanding, diagnose and treat the disease. We know that bipolar disorder is at 80% heritable and that common and rare genetic polymorphisms increase the risk for it. We also know that both diseases i.e. schizophrenia and affective psychoses have significant overlap in the clinical, neuropsychological, epidemiological, pathophysiological and genetic level.
The members of our sample were analyzed with Affective Startle Modulation as regards the experimental control of this candidate endophenotype of affective psychoses. The sample was also analyzed with the Cantab battery for testing cognitive and executive functions, Iowa Gambling Task for testing decision making process in problems with the contribution of emotion and with psychometric scales which test Affective personality traits.
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The three polymorphisms which are associated with the phenotype in this thesis are the sequent: i) CACNA1C rs1006737, ii) FOXP2 rs1358278, iii) COMT rs4680.
The CACNA1C rs1006737 risk A allele has been associated with affective psychoses. Previous functional studies indicate that it is associated with increased hippocampal/amygdala activity during emotional face-processing. Relative to the other genotypes, risk A allele healthy homozygotes males appear to have marked contextual sensitivity, affective reactivity to anxiety, inefficient emotional appraisal and also a deficit in the verbal memory performance, a potential endophenotype for bipolar disorder which theoretically reflect deficient coding ability in hippocampal level. Our findings provide phenotypic detail of the CACNA1C AA genotype in non-symptomatic individuals, which suggest primary effects in emotional circuitry, consistent with previously documented alterations in hippocampal/amygdala processing.
FOXP2 encodes a transcription factor involved in speech and language and in the control of the corticobasal ganglia circuits. There is also evidence supporting a role for the FOXP2 locus in schizophrenia, autism and ADHD. In this thesis we selected the rs1358278A/G FOXP2 non-coding polymorphism which has been associated with schizophrenia. The GG homozygotes had more errors in a Spatial Working Memory task, an abnormal pattern in the Affective Startle paradigm, scored higher in Alexithymia, while they showed an alexithymic profile in the Iowa Gambling Task. Our results suggest that one way for this FOXP2 polymorphism to increase risk for schizophrenia, may be through impairments in working memory and affective processes underlying response to linguistic, pictorial and reward stimuli.
Catechol-O-Methyltransferase (COMT) Val158Met and other dopamine regulating genes and polymorphisms affecting prefrontal cortex (PFC) modulates core cognitive processes and affect. We hypothesize that carriers of Met allele which increase vulnerability for affective disorders carriers present stressful
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emotional profile and impaired decision making process compare to the Val/Val carriers. Although the allele Met leads to advantage in executive functions, our results show that the allele Met is associated with a mixed phenotype of reduced ability to adapt to stress, hyper-response to aversive stimuli and subsequent discomfort. Also showed that the Met allele associated with alexithymia and worst appropriate integration of emotion in decision making.
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