Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major ...depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases.
We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases.
PRS for both population IQ (P = 4.39 × 10-28) and EA (P = 1.27 × 10-26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS.
Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.
Pharmacogenetics in schizophrenia comprises pharmacokinetical and pharmacodynamical aspects as well as an approach to identify candidate genes associated with therapy response or side effects. ...Firstly focussing on classical drug targets like dopaminergic or serotonergic receptors, currently also developmental and regulatory genes presumably associated with effects of antipsychotic therapy are identified. The aim of this study was to investigate associations between therapy response in schizophrenic patients and different polymorphisms previously been identified within a genome wide array in rodents treated with MK-801 and/or haloperidol combined with some well-known schizophrenia candidate genes. We genotyped for 200 different polymorphisms in 285 schizophrenic patients, who were treated with different antipsychotics within randomized controlled trials. Psychopathology was measured weekly using the PANSS scale. Correlations between psychopathology and genotypes were calculated by using a linear model (ANCOVA). We found significant associations between some well-known candidate genes (e.g. D2 -, 5HT1A -, and α1A -receptors) and different PANSS subscales at baseline and after four weeks of antipsychotic treatment considered as therapy response. Furthermore we also identified several significant associations between some genes introduced from the animal model and psychopathology at baseline and towards therapy response. Some of them were formerly described in the literature (e.g. Homer1, Phospholipase C and Transthyretin), but most of them have not been related to schizophrenia or antipsychotic treatment by now (e.g. PLEKHA6, CLIC6 and SOSTDC1). This indicates an involvement of genes in the pathophysiology of schizophrenia apart from yet known candidate genes and might further help in detecting differential therapy response in individuals with schizophrenia.
Studies of schizophrenia with functional MRI showed hyper- and hypoactivations in various brain regions including the prefrontal cortex. Functional abnormalities have also been reported in ...first-degree relatives of schizophrenic patients. The aim of this study was to examine working memory related brain functions in healthy subjects, schizophrenic patients and unaffected relatives and to determine the influence of psychopathology on these processes. A parametric n-back working memory task and functional MRI were used to examine 61 schizophrenic patients on antipsychotic medication, 11 nonpsychotic relatives of schizophrenic patients and a comparison group of 61 healthy subjects. The task difficulty was incrementally increased using a parametric task (0-back, 1-back, 2-back, and 3-back) to examine the relationship between working memory load, performance, and brain activity. The results indicated that during the attention task (0-back) behavioral responses of patients and healthy subjects hardly differed but BOLD responses were considerably enhanced in schizophrenic patients. With increasing task difficulty differences between groups in BOLD responses diminished whereas behavioral deficits of patients increased. The examination of attention-independent working memory-functions (2- vs. 0-back) produced hypoactivations in patients, especially in frontal, temporal and subcortical brain regions. Behavioral performance and neural responses of unaffected relatives of schizophrenic patients were intermediate between schizophrenic patients and controls indicating slight brain dysfunctions. In addition, compensatory strategies were demonstrated. These findings suggest that the genetic risk for schizophrenia is accompanied by neural inefficiency which is associated with cognitive deficits, especially in difficult tasks.
Introduction Since the introduction of second generation antipsychotics (SGA) extrapyramidal-motor symptoms (EPS) have become a lesser problem in the treatment of schizophrenic patients. Yet, some ...SGAs display these adverse events and first generation antipsychotics are still widely used. Several genetic polymorphisms have been found to be associated with the occurance of EPS. Objectives In this study we tried to identify genes related to EPS from an animal model and then replicated the findings in schizophrenic patients. Aims To identify new genes and show their relevance in the treatment of schizophrenic patients. Methods Rats were treated with haloperidol or saline and differential gene expression was assessed by using microarrays. We genotyped 285 schizophrenic patients for candidate genes and differentially expressed genes derived from the animal model. All patients were treated monotherapeutically with different antipsychotics within randomized controlled trials. EPS were assessed weekly using the ESRS and BAS. We used a linear model (ANCOVA) with PANSS total at baseline, type of medication and premedication as covariates for all investigated SNP's. Results We found several SNPs to be associated with the occurance of EPS. The best results were obtained for SNPs within the genes of Phospholipase C epsilon 1 (PLCe1), Methionine Sulfoxide Reductase B3 (MSRB3), Chloride Intracellular Channel 6 (CLIC6), Prolactin Receptor (PRLR) and Dopamine Receptor D4 (DRD4). Effect sizes were between 1.7 and 4.9. Conclusions We could replicate some findings of the literature and identified four new genes possibly related to EPS. Some of these genes were recently related to schizophrenia.
Family and twin studies point towards a partial heritability of suicidal behavior. We investigated the role of a comprehensive set of genes in this behavior. Their selection was driven by results ...from post mortem and genetic studies. 250 suicide attempters with various psychiatric disorders were compared with 2200 volunteers which were randomly selected from the general population. All subjects were administered standard psychiatric interviews including SCID as well as self-report questionnaires for anger-related traits. Especially, aggressive-impulsive behavior has been studied and associations with these intermediate phenotypes will be presented. Additionally a large-scale gene expression analysis using cDNA-microarrays to identify new candidate-genes for suicide was conducted. We found several genes to be differentially expressed in the orbitofrontal cortex of suicide completers. Cross-validation experiments using quantitative RT-PCR validated a few genes so far. These genes have been genotyped in our patients and controls and associations with suicidal behavior and intermediate phenotypes, like aggression and impulsivity will be presented.
Ethanol-inhibited glutamatergic neurotransmission has been shown to mediate pathophysiological mechanisms in the development of alcoholism, including withdrawal symptoms. NMDA-receptor 2B (NR2B) is a ...subunit that confers a high sensitivity to ethanol-induced inhibition. Previously we had reported a lack of association between the single nucleotide polymorphism (SNP) rs1806201 in the NR2B gene (GRIN2B) and alcoholism. Shortly thereafter, an association between the polymorphism and early-onset alcoholism has been reported. One aim of the present study was to test whether the association between the GRIN2B polymorphism rs1806201 and early-onset alcoholism can be replicated in a larger sample. Moreover, we hypothesized that another genetic variation within GRIN2B (rs1806191) may have an effect in the etiology of alcoholism or withdrawal-related traits.
We extended our original study sample to a size of 377 patients and 464 healthy volunteers and performed a replication study, including the second GRIN2B SNP. Associations between allele, genotype and haplotype frequencies of the two polymorphisms and alcoholism as well as with patients' phenotypes were investigated.
No associations were found between any of the two polymorphisms, tested individually or as haplotypes, and alcoholism, respectively withdrawal-related traits.
Neither the analyzed SNPs nor any of their haplotypes likely modify susceptibility to alcohol dependence or withdrawal-related phenotypes.
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