| Abstract |
Σhe subject of my thesis is the influence of genetic polymorphisms of three different genes, hazardous non emotional disorders, mainly for the schizophrenia syndrome, on specific endophenotypes, such as the Gating function and cognitive function in the general population and in healthy high-risk individuals.
Following an appropriate and modern research strategy, Candidate gene approach, the question was raised in our studies, is whether established schizophrenia risk gene variants affect PPI levels in the general population. This approach would further our understanding of these genes‟ functional mechanisms within the human brain. Association of these gene variants with reduced PPI would validate their role as schizophrenia candidate genes and would inform our understanding of the mechanisms through which genes increase the risk for schizophrenia.
In the present study, we examined three single nucleotide polymorphisms (SNPs): Polymorphism Rs10503253 of CSMD1 gene is implicated in neurodevelopmental disorders. The risk A allele is associated with schizophrenia and low IQ. The aim of this study was to see effects of polymorphism on PPI / Gating function, intellectual quotient (IQ), working memory (WM), and also, memory and executive functions.
The second gene studied is FOXP2. Is implicated in speech and language development. Also, studies conducted in recent years, support the association with autism, ADHD and schizophrenia. The risk G allele of polymorphism
Rs1229761 of FOXP2 gene has been shown to correlate with ADHD. The aim of this study was to see effects on Gating function, IQ, cognitive function and traits of personality.
The third genetic polymorphism studied is rs4680 of COMT gene, which has been implicated in the disease of schizophrenia. The aim of this study was to verify, in a larger sample of individuals, already proven impact of risk Val allele of this polymorphism on the functioning of the prefrontal cortex.
Gene CSMD1: rs10503253A/C
In the first study for the CDMD1 gene, took part 829 young males, who were recruited from the first wave of cohort LOGOS participants. 779 participants had reliable PPI. Participants were grouped according to their genotype at three categories: CC: 772, CA: 291, AA: 36. The frequency of the C allele corresponded to 1835 individuals and the A allele to 363 individuals with minor allele frequency of 16.5%. The genotypic distribution was in accordance with the equation in Hardy- Weinberg (p=0.19). To reduce data in classified variables, submitted cognitive outcome variables of neuropsychological tests on principal component analysis (PCA). In total, they were included in the analysis 22 key cognitive outcome variables and exported nine dimensions that explain the 77.64% of the total variance. For quantified genotype-phenotype correlations used in QTPHASE program of package UNPHASED 3.1.7. In order to lessen the likelihood of Type I error due to multiple tests, the p-values were corrected by Bonferroni post hoc test (0.05/10=0,005). Thus, the effects of genotype groups on 9 PCA dimensions and IQ with p-values <0.005 are considered statistically significant, and with p values <0.05 referred to only as "proposed significance"
for future studies. We also calculated, the power (based on an additive model of inheritance). A sample of 829 subjects and 16.5% frequency of minor allele, we have 80% of the power required for the detection of very small effects on the order of 0.1 (effect size r = 0.1).
The risk A allele was associated with poorer performance on measures of general cognitive ability, strategy formation, spatial and visual working memory, set shifting, target detection and planning for problem solving but not for emotional decision making. Most of these effects were dependent on risk A allele dose, with AA and CC homozygotes being the worse and the best respectively, while CA individuals were intermediate. Potential genotype effects in Stroop and verbal memory performance were also suggested by our dataset. These results underline the relevance of the risk A allele to neurocognitive functioning and suggest that its detrimental effects on cognition, may be part of the mechanism by which the CSMD1 mediates risk for schizophrenia.
Gene FOXP2: rs1229761G/C
In the second study, which was conducted for the FOXP2 gene, also took part 829 young males with full cognitive data. 680 participants had reliable PPI. Participants were grouped according to their genotype at three categories: GG: 276, GC: 404, CC: 149. The frequency of G allele corresponded to 956 individuals and allele C to 702 individuals with minor allele frequency of 42.3%. The genotypic distribution, and in this study, was in accordance with the equation in Hardy-Weinberg (p=0.5). We analyzed five phenotypes: PPI/gating function, working memory/strategy from the field of cognition and three personality traits, such as schizotypy, alexithymia and impulsivity. Realized
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Bonferroni correction, as in the previous study, for controlling Type I error (0.05 /5=0.01). Thus, the effects of genotype groups on the 5 phenotypes with p values <0.01 are considered statistically significant, with p values <0.05 referred to only as "proposed significance."
The G allele carriers performed worse (p<0.05) in Spatial Working Memory [Strategy, Total-, Within- and Between- Errors in the difficult 8-box condition]. They also scored higher (p<0.05) in measures of Schizotypy [STQ_Magical Thinking and STQ_Unusual Experiences (p<0.01)] and Impulsivity [BAS_Fun seeking, TCI_Novelty seeking, low scores in EPQ_lie scale]. Finally, they demonstrated a Gating deficit as evidenced by a significant (p<0.01) 3-way interaction in the ANOVA [reduced PPI at the short (30ms) interval with the 85dB prepulse]. The rs1229761 G allele, which has been associated with ADHD, impacts on important intermediate phenotypes such as short interval gating, working memory, strategic thinking, schizotypy and impulsivity in healthy males. These results elucidate the function of the FOXP2 gene in the human brain and suggest that it may be a “hub” for pathological features (gating, cognition, language/thought, impulsivity) common to ADHD, schizophrenia and autism.
Gene COMT: rs4680Val/Met
In the third study for the COMT gene participated 829 young males from the cohort LOGOS with full cognitive data. 779 participants had reliable PPI. Participants were grouped according to their genotype at three categories: Val / Val: 235, Val/Met: 424, Met/Met: 170. The frequency of allele Val corresponded to 894 individuals and the Met allele to 764 individuals with minor allele frequency of 46.1%. The genotypic distribution was in line with expectations at
Hardy - Weinberg (p=0.1). To reduce data in classified variables, we submitted the measurements of all the cognitive tests in PCA. Done Bonferroni correction, for the control of Type I error, resulting in p-values <0.005 are considered statistically significant, and <0.05 referred to only as "proposed significance" for future studies.
The risk Val allele carriers had significantly lower IQ, worse performance on planning for problem solving without emotional involvement [more time for planning] and increased inattention, before or after the covariance parameters age, education and smoking habits. However, the results did not show dose-dependent effect of the risk Val allele. Regarding PPI, the Val carriers demonstrated lower level of prepulse inhibition only at the intermediate (60ms) interval, in both cases administered prepulses of 75 and 85dB. Remarked repeat of previous findings in PPI/Gating and new findings in IQ, Inattention and Planning of problem solving.
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Η επίδραση των γενετικών πολυμορφισμών rs4680 COMT, rs 10503253 CSMD1 και rs 1229761 FOXP2 στη λειτουργία gating και τη γνωστική λειτουργία στο γενικό πληθυσμό και σε υγιή άτομα υψηλού κινδύνου
