Einfluss von replizierten Risikogenen auf Kognition und Psychopathologie bei der Schizophrenie

Abstract

Summary: The aim of this thesis consisted in investigating the influence of chosen SNPs of already known and replicated risk genes (TCF4 rs12966547, ZNF804A rs1344706 plus CACNA1C rs1006737, MIR137 rs1625579, MIR137 rs1198588, WWC rs17070145, SCN1A rs10930201 and MHC rs13194053) on single cognitive domains as e.g. executive functions, verbal memory or retentiveness in first-episode patients with only short antipsychotic treatment and chronically affected schizophrenia patients. This study was the first to compare the influence of the genes of interest between these different patient samples. With focus on carriers of the above named risk alleles, we genotyped a cohort of first-episode schizophrenia patients who underwent only short-term treatment with antipsychotics (N=58) plus a second cohort of chronically ill schizophrenia patients (N=130). Both samples in parallel ran through an elected battery of neuropsychological and psychopathological tests. The results were plotted and evaluated with the chosen SNPs of the aforementioned risk genes. By reason of the too small samples in both the HOM and RESIS sample of the respective homozygote non-risk alleles of the investigated risk polymorphisms of the genes MHC, both MIR 137 plus WWC1 (rs17070145 with the non-risk allele T) these were excluded from this study. Within the HOM sample, this also applied to the respective homozygote non-risk alleles of the ZNF804A gene (rs1344706 with the non-risk allele C). Further excluded was the gene SCN1A due to contradictory information on the risk allele of SNP rs10930201. Since, again, the RESIS groups provided relatively sufficient sample sizes, homozygote carriers of the non-risk allele of the investigated risk polymorphisms as to as to the TCF4 and ZNF804A genes were included in this study. Between first-episode and chronically ill schizophrenia patients, regrettably merely one significant difference could be detected with respect to the neuropsychology with a constraint in executive functions in homozygote carriers of the non-risk allele G versus heterozygote and homozygote carriers of the risk allele A of CACNA1C rs1006737. No further significant results could be found in either sample regarding the influence of the investigated risk genes on the neuropsychology or psychopathology, respectively, so that this thesis cannot confirm any prior external studies conducted in this respect. This might possibly be due to our small sample size (especially concerning the HOM group). As to the found deviations in duration of education, age and chlorpromazine equivalent between chronically ill and first episode schizophrenia patients, the above named difference in the neuropsychology in CACNA1C has to be critically questioned. We cannot rule out the influence of the investigated genes on other than the studied neuropsychological and psychopathological variables. Furthermore, this thesis focused only on a small portion of the genes significantly associated with schizophrenia according to GWAS studies. For this reason, an influence of other risk genes on cognition and psychopathology can neither be excluded. Critically to be mentioned has also the missing use of Bonferroni adjustment for multiple testing in a large number of hypothesis tests which might have generated incidental findings. Future studies with considerably larger samples plus prospective studies of the course of disease with an extended neuropsychological test battery should illuminate this topic.