The presence of genetic influences on cognitive performance and brain volume is well established. However, specific genetic determinants of the variance of these quantitative traits are not yet ...known. Plexins act as receptors for semaphorins and are implicated in axon guidance, which is a key process in brain development. We have previously shown that plexin B3 is a highly potent stimulator of neurite outgrowth, which makes its gene PLXNB3 an intriguing candidate gene for traits related to human brain development and cerebral connectivity. We identified several polymorphisms in PLXNB3 predicting changes of amino acids (V598I, E1156D and V1596E) conserved at the corresponding positions of the orthologs in mouse and chimpanzee. PLXNB3 was genotyped in 303 healthy volunteers and 42 male patients with schizophrenia. Cognitive performance was measured with the vocabulary test (Wortschatztest (WST)), a method to estimate roughly general intelligence (g). Brain morphology was characterized by magnetic resonance imaging. Compared to subjects not carrying the modern, human-specific haplotype A, carriers of A scored higher in vocabulary test (WST) irrespective of diagnosis (P=0.0004). This effect could be observed in three independent groups (healthy males: P=0.048; schizophrenic males: P=0.034 and healthy females: P=0.037). Additionally, the haplotype A was associated with increased volume of brain white matter that in turn correlated with performance in the vocabulary test. These findings suggest that plexin B3 may influence cognitive performance, and the development of white matter in vivo in a way similar to its known stimulating effect on neurite outgrowth in vitro. These novel observations warrant further replication in independent samples.
There is growing evidence of abnormalities of high-frequency oscillations in the gamma range of the electroencephalography in schizophrenia. The generation of neural activity in the gammaband was ...shown to be critically related to a glutamatergic and GABAergic microcircuit which is also known to be involved in the pathophysiology of schizophrenia. One example of such gamma oscillations is the early auditory evoked gamma band response (aeGBR). We aimed to investigate whether there are altered aeGBR and activity of its sources in the anterior cingulate cortex and/or the auditory cortex (identified as sources of the GBR previously) in schizophrenic patients and in first-degree relatives of schizophrenia patients. We investigated the early aeGBR and its sources (LORETA source localisation) in 90 medicated patients with schizophrenia and in 17 unaffected first-degree relatives of patients with schizophrenia using an auditory reaction task (comparison with age-, gender- and educational-level-matched control groups). Evoked power and phase locking of the aeGBR was reduced in schizophrenia patients and healthy first-degree relatives of patients with schizophrenia. This effect was due to a reduced activity in the auditory cortex and the anterior cingulate cortex. The findings are in line with the hypothesis of a disturbed GABAergic interneural modulation of pyramidal cells in schizophrenia and findings of different schizophrenia risk genes associated with transmission at glutamatergic and GABAergic synapses. The results regarding the first-degree relatives of patients with schizophrenia point to the applicability of this marker as a heritable intermediate phenotype for schizophrenia.
Schizophrenia (SCZ) is a severe and debilitating neuropsychiatric disorder with an estimated heritability of ~80%. Recently, de novo mutations, identified by next-generation sequencing (NGS) ...technology, have been suggested to contribute to the risk of developing SCZ. Although these studies show an overall excess of de novo mutations among patients compared with controls, it is not easy to pinpoint specific genes hit by de novo mutations as actually involved in the disease process. Importantly, support for a specific gene can be provided by the identification of additional alterations in several independent patients. We took advantage of existing genome-wide single-nucleotide polymorphism data sets to screen for deletions or duplications (copy number variations, CNVs) in genes previously implicated by NGS studies. Our approach was based on the observation that CNVs constitute part of the mutational spectrum in many human disease-associated genes. In a discovery step, we investigated whether CNVs in 55 candidate genes, suggested from NGS studies, were more frequent among 1637 patients compared with 1627 controls. Duplications in RB1CC1 were overrepresented among patients. This finding was followed-up in large, independent European sample sets. In the combined analysis, totaling 8461 patients and 112 871 controls, duplications in RB1CC1 were found to be associated with SCZ (P=1.29 × 10(-5); odds ratio=8.58). Our study provides evidence for rare duplications in RB1CC1 as a risk factor for SCZ.
There is evidence for a strong genetic component in the etiology of schizophrenia, as demonstrated by family, twin and adoption studies suggesting a heritability of about 80%. There are several ...approaches in the search for genetic risk factors such as linkage or association studies. Additionally, much effort was done in refining the phenotype including neuropsychology, neurophysiology, imaging or the generation of animal models. Genes becoming associated with schizophrenia have to be tested for functionality including e.g. metabolomics, transcriptomics, proteomics, generation of transgenic mice, analysis of protein-protein interactions, allele-specific RNA expression analysis, analysis of neuronal and stem cell cultures, as well as post mortem studies and behavioral studies in rodents. This amount of data requires complex data analysis. A system's perspective can help in the analysis of the structural and functional complexity of the brain. New tools will be needed for a more complex and systemic view. The systems biology approach could be a pivotal tool in understanding of complex behavior and diseases in future.
Methods 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.
Correlations between general intelligence (g) and brain volume are about 0.40, and the correlation between g and white matter volume has been reported to be largely due to genetic factors. ...Establishing that the correlation between brain volumes and cognitive abilities is mediated by shared genetic factors is only the first step in unveiling the relation between them. We have recently shown that methionine at codon 129 in the prion protein is associated with white matter reduction in a group of healthy volunteers and schizophrenic patients. The present study examines the influence of the same genetic variation on psychometric cognitive performance measurements in 335 community-based healthy volunteers. The polymorphism was associated with Full Scale IQ (genotype: F=4.38, df=2/317, P=0.013; allele: F=8.04, df=1/658, P=0.005), as measured by HAWIE-R (German version of the Wechsler Adult Intelligence Scale, Revised). Genotype accounted for 2.7% of the total variability in Full Scale IQ (partial eta2=0.027). An exploratory analysis revealed association with several HAWIE-R subscales; the association with the Digit Symbol subtest remained significant after correction for multiple testing. In summary, we deliver evidence for an association of a common genetic variation in the prion protein gene with cognitive performance. However, independent replications are needed before firm conclusions can be drawn.
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