[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: Recent evidence indicated that the ZNF804A (rs1344706) risk allele A is associated with better cognitive performance in patients with schizophrenia. Moreover, it has been demonstrated that ZNF804A may also be related to relatively intact gray matter volume in patients. To further explore these putatively protective effects, the impact of ZNF804A on cortical thickness and folding was examined in this study. To elucidate potential molecular mechanisms, an allelic-specific gene expression study was also carried out. Magnetic resonance imaging cortical thickness and folding were computed in 55 genotyped patients with schizophrenia and 40 healthy controls. Homozygous risk allele carriers (AA) were compared with AC/CC carriers. ZNF804A gene expression was analyzed in a prefrontal region using postmortem tissue from another cohort of 35 patients. In patients, AA carriers exhibited significantly thicker cortex in prefrontal and temporal regions and less disturbed superior temporal cortical folding, whereas the opposite effect was observed in controls, ie, AA carrier status was associated with thinner cortex and more severe altered cortical folding. Along with this, our expression analysis revealed that the risk allele is associated with lower prefrontal ZNF804A expression in patients, whereas the opposite effect in controls has been observed by prior analyses. In conclusion, our analyses provide convergent support for the hypothesis that the schizophrenia-associated ZNF804A variant mediates protective effects on cortex structure in patients. In particular, the allele-specific expression profile in patients might constitute a molecular mechanism for the observed protective influence of ZNF804A on cortical thickness and folding and potentially other intermediate phenotypes.
[show abstract][hide abstract] ABSTRACT: Probabilistic independent component analysis was applied to identify the default mode network (DMN) in resting state data obtained with functional magnetic resonance imaging from 25 DSM-IV schizophrenia and 25 matched healthy subjects. Power spectrum analysis showed a significant diagnosis×frequency interaction and higher power in one frequency band, indicating an alteration of DMN frequency spectrum in schizophrenia.
[show abstract][hide abstract] ABSTRACT: Schizophrenia has been linked to disturbed connectivity between large-scale brain networks. Altered thalamocortical connectivity might be a major mechanism mediating regionally distributed dysfunction, yet it is only incompletely understood. We analysed functional magnetic resonance imaging data obtained during resting state from 22 DSM-IV schizophrenia patients and 22 matched healthy controls to directly assess the differences in thalamocortical functional connectivity. We identified significantly higher overall thalamocortical functional connectivity in patients, which was mostly accounted for by difference in thalamic connections to right ventrolateral prefrontal and bilateral secondary motor and sensory (superior temporal and lateral occipital) cortical areas. Voxelwise analysis showed group differences at the thalamic level to be mostly in medial and anterior thalamic nuclei and arising thalamocortical changes to be mostly due to higher positive correlations in prefrontal and superior temporal correlations, as well as absent negative correlations to sensory areas in patients. Our findings demonstrate that different types of thalamocortical dysfunction contribute to network alterations, including lack of inhibitory interaction attributed to the lack of significant negative thalamic/sensory cortical connections. These results emphasize the functional importance of the thalamus in the pathophysiology of schizophrenia.
European Archives of Psychiatry and Clinical Neuroscience 07/2013; · 2.75 Impact Factor
[show abstract][hide abstract] ABSTRACT: Structural deficits in the superior temporal cortex and transverse temporal gyri appear to be related to auditory hallucinations in schizophrenia, which are a key symptom of this disorder. However, the cellular and neurochemical underpinnings are poorly understood and hardly studied in vivo. We used (31)P-MRS (magnetic resonance spectroscopy) with chemical shift imaging to assess the association between left superior temporal cortex metabolism and severity of auditory hallucinations in 29 schizophrenia patients off antipsychotics. Hallucinations scores derived from the Scale for the Assessment of Positive Symptoms showed significant positive correlations with both measures of phospholipids (phosphomonoesters and phosphodiesters), and energy (inorganic phosphate and phosphocreatine, but not adenosine tri-phosphate) metabolism in left superior temporal gyrus/Heschl gyrus voxels. There was no correlation of metabolites in these regions with formal thought disorder, a symptom also linked to superior temporal pathology, thus suggesting symptom specificity. Our findings provide a link between established structural deficits and neurochemical pathology related to membrane pathology and markers of general metabolic turnover.
Brain Structure and Function 07/2013; · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recent studies have provided strong evidence that variation in the gene neurocan (NCAN, rs1064 395) is a common risk factor for bipolar disorder (BD) and schizophrenia. However, the possible relevance of NCAN variation to disease mechanisms in the human brain has not yet been explored. Thus, to identify a putative pathomechanism, we tested whether the risk allele has an influence on cortical thickness and folding in a well-characterized sample of patients with schizophrenia and healthy controls. Method Sixty-three patients and 65 controls underwent T1-weighted magnetic resonance imaging (MRI) and were genotyped for the single nucleotide polymorphism (SNP) rs1064 395. Folding and thickness were analysed on a node-by-node basis using a surface-based approach (FreeSurfer).
In patients, NCAN risk status (defined by AA and AG carriers) was found to be associated with higher folding in the right lateral occipital region and at a trend level for the left dorsolateral prefrontal cortex. Controls did not show any association (p > 0.05). For cortical thickness, there was no significant effect in either patients or controls.
This study is the first to describe an effect of the NCAN risk variant on brain structure. Our data show that the NCAN risk allele influences cortical folding in the occipital and prefrontal cortex, which may establish disease susceptibility during neurodevelopment. The findings suggest that NCAN is involved in visual processing and top-down cognitive functioning. Both major cognitive processes are known to be disturbed in schizophrenia. Moreover, our study reveals new evidence for a specific genetic influence on local cortical folding in schizophrenia.
Psychological Medicine 06/2013; · 5.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: The functional variant Val(158)Met in the coding sequence of COMT gene is involved in the modulation of dopamine availability in the prefrontal cortex in both clinical and general population samples. It has been suggested that the interplay between this genotype and early environmental factors could be used to predict the observed variation in cognitive flexibility. However, other genetic variants and environmental factors may confound the association and produce the inconsistent results commonly found in the literature. In the present study we aimed at testing putative interaction mechanisms between childhood maltreatment and COMT genotypic variability that might explain a proportion of the observed variability of cognitive flexibility in the population. Our design was based on a sample of adult monozygotic twins, which allowed us to test these effects free from potential genetic and shared-environmental confounding factors. Results showed that unique environmental effects of childhood maltreatment significantly impacted cognitive performance among Met/Met subjects. Interestingly, the direction of the association indicated that exposure to early stressful experiences was associated with enhanced cognitive flexibility in this genotype group. These results suggest that COMT may operate as a plasticity gene that provides differential cognitive capacity to respond to environmental stressors.
Journal of psychiatric research 03/2013; · 3.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: The identification of an ultra-high risk (UHR) profile for psychosis and a greater understanding of its prodrome have led to increasing interest in early intervention to delay or prevent the onset of psychotic illness. In a randomized placebo-controlled trial, we have identified long-chain ω-3 (ω-3) polyunsaturated fatty acid (PUFA) supplementation as potentially useful, as it reduced the rate of transition to psychosis by 22.6% 1 year after baseline in a cohort of 81 young people at UHR of transition to psychosis. However, the mechanisms whereby the ω-3 PUFAs might be neuroprotective are incompletely understood. Here, we report on the effects of ω-3 PUFA supplementation on intracellular phospholipase A2 (inPLA2) activity, the main enzymes regulating phospholipid metabolism, as well as on peripheral membrane lipid profiles in the individuals who participated in this randomized placebo-controlled trial. Patients were studied cross-sectionally (n=80) and longitudinally (n=65) before and after a 12-week intervention with 1.2 g per day ω-3 PUFAs or placebo, followed by a 40-week observation period to establish the rates of transition to psychosis. We investigated inPLA2 and erythrocyte membrane FAs in the treatment groups (ω-3 PUFAs vs placebo) and the outcome groups (psychotic vs non-psychotic). The levels of membrane ω-3 and ω-6 PUFAs and inPLA2 were significantly related. Some of the significant associations (that is, long-chain ω-6 PUFAs, arachidonic acid) with inPLA2 activity were in opposite directions in individuals who did (a positive correlation) and who did not (a negative correlation) transition to psychosis. Supplementation with ω-3 PUFA resulted in a significant decrease in inPLA2 activity. We conclude that ω-3 PUFA supplementation may act by normalizing inPLA2 activity and δ-6-desaturase-mediated metabolism of ω-3 and ω-6 PUFAs, suggesting their role in neuroprogression of psychosis.Molecular Psychiatry advance online publication, 12 March 2013; doi:10.1038/mp.2013.7.
[show abstract][hide abstract] ABSTRACT: BACKGROUND: The influence of genetic and/or environmental factors on the volumetric brain changes observed in subjects affected by anxiety and depression disorders remains unclear. The current study aimed to investigate whether genetic and environmental liabilities make different contributions to abnormalities in gray matter volume (GMV) in anxiety and depression using a concordant and discordant MZ twin pairs design. METHODS: Fifty-three magnetic resonance imaging (3T) brain scans were obtained from monozygotic (MZ) twins concordant (6 pairs) and discordant (10 pairs) for lifetime anxiety and depression disorders and from healthy twins (21 subjects). We applied voxel-based morphometry to analyse GMV differences. Concordant affected twins were compared to healthy twins and within-pairs comparisons were performed in the discordant group. RESULTS: GMV reductions in bilateral fusiform gyrus and amygdala were observed in concordant affected twins for anxiety and depression compared to healthy twins. No intrapair differences were found in GMV between discordant affected twins and their healthy co-twins. LIMITATIONS: The sample size was modest. This might explain why no intrapair differences were found in the discordant MZ twin group. CONCLUSIONS: As concordant affected MZ twins are believed to have a particularly high genetic liability for the disorder, our findings suggest that fusiform gyrus and amygdala gray matter reductions are related to a genetic risk for anxiety and depression. Discrepancies in regard to brain abnormalities in anxiety and depression may be related to the admixture of patients with GMV abnormalities mainly accounted for by genetic factors with patients presenting GMV mainly accounted for by environmental factors.
Journal of affective disorders 02/2013; · 3.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: Large rare copy number variants (CNVs) have been recognized as significant genetic risk factors for the development of schizophrenia (SCZ). However, due to their low frequency (1∶150 to 1∶1000) among patients, large sample sizes are needed to detect an association between specific CNVs and SCZ. So far, the majority of genome-wide CNV analyses have focused on reporting only CNVs that reached a significant P-value within the study cohort and merely confirmed the frequency of already-established risk-carrying CNVs. As a result, CNVs with a very low frequency that might be relevant for SCZ susceptibility are lost for secondary analyses. In this study, we provide a concise collection of high-quality CNVs in a large German sample consisting of 1,637 patients with SCZ or schizoaffective disorder and 1,627 controls. All individuals were genotyped on Illumina's BeadChips and putative CNVs were identified using QuantiSNP and PennCNV. Only those CNVs that were detected by both programs and spanned ≥30 consecutive SNPs were included in the data collection and downstream analyses (2,366 CNVs, 0.73 CNVs per individual). The genome-wide analysis did not reveal a specific association between a previously unknown CNV and SCZ. However, the group of CNVs previously reported to be associated with SCZ was more frequent in our patients than in the controls. The publication of our dataset will serve as a unique, easily accessible, high-quality CNV data collection for other research groups. The dataset could be useful for the identification of new disease-relevant CNVs that are currently overlooked due to their very low frequency and lack of power for their detection in individual studies.
PLoS ONE 01/2013; 8(7):e64035. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Convergent evidence from pharmacological and animal studies suggests a possible role for the synaptic vesicle glycoprotein 2A gene (SV2A) in schizophrenia susceptibility. To test systematically all common variants in the SV2A gene region for an association with schizophrenia, we used a HapMap-based haplotype tagging approach and tested five SNPs in 794 patients and 843 controls. The SNP rs15931 showed evidence for an association with schizophrenia and was followed-up in an independent sample of 2581 individuals (overall p-value=0.0042, OR=0.779). Our study in the German population provides evidence, at a genetic level, for the involvement of the SV2A gene region in schizophrenia.
Schizophrenia Research 09/2012; 141(2-3):262-5. · 4.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Common genetic variation in the promoter region of the glutamate receptor delta 1 (GRID1) gene has recently been shown to confer increased risk for schizophrenia in several independent large samples. We analysed high-resolution magnetic resonance imaging (MRI) data from 62 patients with schizophrenia and 54 healthy controls using voxel-based morphometry (VBM) to assess the effect of single nucleotide polymorphism rs3814614 (located in the GRID1 promoter region), of which the T allele was identified as a risk factor in a previous association study. There were no effects of genotype or group × genotype interactions on total brain grey matter or white matter, but on regional grey matter. In healthy subjects, we identified a significant effect of rs3814614 genotype in the anterior thalamus (bilaterally), superior prefrontal cortex, and orbitofrontal cortex - in all cases with the homozygous risk genotype TT resulting in higher grey matter density. We did not find this association within the schizophrenia sample, where rs3814614 variation was only associated with grey matter reduction in TT homozygous subjects in medial parietal cortex and increased grey matter in right medial cerebellum. For white matter, we did not find significant genotype effects in healthy controls, and only minor effects within schizophrenia patients in the posterior temporal lobe white matter. Our data indicate that GRID1 rs3814614 genotype is related to grey matter variation in prefrontal and anterior thalamic brain areas in healthy subjects, but not in patients indicating a potential role of this schizophrenia candidate gene in thalamo-cortical functioning.
Journal of psychiatric research 09/2012; · 3.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: There is considerable evidence for specific pathology of lipid metabolism in schizophrenia, affecting polyunsaturated fatty acids and in particular sphingolipids. These deficits are assumed to interfere with neuronal membrane functioning and the development and maintenance of myelin sheaths. Recent studies suggest that some of these lipid pathologies might also be detected in peripheral skin tests. In this study, we examined different skin lipids and their relation to schizophrenia. We assessed epidermal lipid profiles in 22 first-episode antipsychotic-naïve schizophrenia patients and 22 healthy controls matched for age and gender using a hexan/ethanol extraction technique and combined high-performance thin-layer chromatography/gas-chromatography. We found highly significant increase of ceramide AH and NH/AS classes in patients and decrease of EOS and NP ceramide classes. This is the first demonstration of specific peripheral sphingolipid alterations in schizophrenia. The results support recent models of systemic lipid pathology and in particular of specific sphingolipids, which are crucial in neuronal membrane integrity. Given recent findings showing amelioration of psychopathology using fatty acid supplementation, our findings also bear relevance for sphingolipids as potential biomarkers of the disease.
[show abstract][hide abstract] ABSTRACT: Alterations in brain function in schizophrenia and other neuropsychiatric disorders are evident not only during specific cognitive challenges, but also from functional MRI data obtained during a resting state. Here we apply probabilistic independent component analysis (pICA) to resting state fMRI series in 25 schizophrenia patients and 25 matched healthy controls. We use an automated algorithm to extract the ICA component representing the default mode network (DMN) as defined by a DMN-specific set of 14 brain regions, resulting in z-scores for each voxel of the (whole-brain) statistical map. While goodness of fit was found to be similar between the groups, the region of interest (ROI) as well as voxel-wise analysis of the DMN showed significant differences between groups. Healthy controls revealed stronger effects of pICA-derived connectivity measures in right and left dorsolateral prefrontal cortices, bilateral medial frontal cortex, left precuneus and left posterior lateral parietal cortex, while stronger effects in schizophrenia patients were found in the right amygdala, left orbitofrontal cortex, right anterior cingulate and bilateral inferior temporal cortices. In patients, we also found an inverse correlation of negative symptoms with right anterior prefrontal cortex activity at rest and negative symptoms. These findings suggest that aberrant default mode network connectivity contributes to regional functional pathology in schizophrenia and bears significance for core symptoms.
Schizophrenia Research 05/2012; 138(2-3):143-9. · 4.59 Impact Factor