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Introduction: The enzyme steroid sulfatase converts sulfated steroids to their non-sulfated forms. Deficiency for this enzyme is associated with inattention but preserved response control. The polymorphism rs17268988 within the X-linked steroid sulfatase gene (STS) is associated with inattentive, but not other, symptoms in boys with Attention Deficit Hyperactivity Disorder (ADHD). Methods: We initially tested whether rs17268988 genotype was associated with attention, response control and underlying aspects of cognition, using questionnaires and neuropsychological tasks, in two independent cohorts of healthy adult males. In an additional analysis based upon existing data, the performance of mice with genetic or pharmacological manipulations of the steroid sulfatase axis under attentionally-demanding conditions was investigated. Results: G-allele carriers at rs17268988 exhibited reduced reaction time, enhanced attention and reduced reaction time variability relative to C-allele carriers. Mice with genetic or pharmacological manipulations of the steroid sulfatase axis were shown to have perturbed reaction time variability. Discussion: Our findings provide additional support for an association between rs17268988 genotype and attention, which may be partially mediated by reaction time variability; they also indicate that, in contrast to the situation in boys with ADHD, in healthy men, the G allele at rs17268988 is associated with enhanced cognition. As reaction time variability is a predictor of wellbeing, rs17268988 genotype may represent a biomarker for long-term health.

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6; P=1 × 10−4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10−7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies., Relatives of patients with amyotrophic lateral sclerosis have an unexpectedly high incidence of schizophrenia. Here, the authors show a genetic link between the two conditions, suggesting shared neurobiological mechanisms.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P−8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

Several lines of evidence indicate that suicidal behaviour is partly heritable, with multiple genes implicated in its aetiology. We focused on nine genes (S100A13, EFEMP1, PCDHB5, PDGFRB, CDCA7L, SCN2B, PTPRR, MLC1 and ZFP36) which we previously detected as differentially expressed in the cortex of suicide victims compared to controls. We investigated 84 variants within these genes in 495 suicidal subjects (299 completers and 196 attempters) and 1513 controls (109 post-mortem and 1404 healthy). We evaluated associations with: 1) suicidal phenotype; 2) possible endophenotypes for suicidal behaviour. Overall positive results did not survive the correction threshold. However, we found a nominally different distribution of EFEMP1 genotypes, alleles and haplotypes between suicidal subjects and controls, results that were partially replicated when we separately considered the subgroup of suicide completers and post-mortem controls. A weaker association emerged also for PTPRR. Both EFEMP1 and PTPRR genes were also related to possible endophenotypes for suicidal behaviour such as anger, depression-anxiety and fatigue. Because of the large number of analyses performed and the low significance values further replication are mandatory. Nevertheless, neurotrophic gene variants, in particular EFEMP1 and PTPRR, may have a role in the pathogenesis of suicidal behaviour.

Objectives: Disturbances in the gamma-frequency band of electroencephalography (EEG) measures are among the most consistently observed intermediate phenotypes in schizophrenia. We assessed whether genetic variations are associated with gamma-band activity. Methods: We performed a genome-wide association analysis of the early auditory evoked gamma-band response in schizophrenia affected subjects and healthy control individuals (in total N = 315). Results: No marker surpassed the threshold for genome-wide significant association. Several of the markers that were closest to significance mapped to genes involved in neuronal development and the Neuregulin-ErbB signalling network, such as NRG2 and KALRN. Using a gene-set enrichment analysis, we found suggestive evidence for association with genes involved in EEG abnormality (P = .048). Conclusions: We identified no marker genome-wide significantly associating with gamma response; independent replication of the gene-set analysis result and larger sample sizes will be required to provide leads to cellular pathways involved in gamma-band activity.

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case–control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10−7) and PKP4 (P=8.67 × 10−7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10−3]), SCZ (rg=0.34 [P=4.37 × 10−5]) and MDD (rg=0.57 [P=1.04 × 10−3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.

AIM: The aim of the study was to detect the genetic predictors of reseponse to haloperidol.BACKGROUND: Haloperidol is a benchmark drug for the pharmacological treatment of schizophrenia, but the genetics of its efficacy is yet to be elucidated.METHODS: A genome-wide association analysis was carried out in a small sample of patients treated with haloperidol (n=96) and the results were replicated in a larger sample of patients treated with second-generation antipsychotics or perphenazine (final n=169, available from the Clinical Antipsychotic Trials for Intervention Effectiveness study). The Positive and Negative Symptom Scale % score decrease was the outcome in both samples. The period of observation was restricted to 1 month in the replication sample and the most severe cases were included to best balance the replication. The quality control (QC) for the investigation and replication sample included a minor allele frequency at least 0.01, call rate at least 0.95, and Hardy-Weinberg equilibrium P at least 0.0001. The source for imputation was the 1000 Genomes Pilot+HapMap 3 dataset. In total 1 080 870 single nucleotide polymorphisms (SNPs) were available after imputation and QC in the investigation sample. After QC of real genotypes, locus-targeted imputations were restricted to windows of 10 kb on either side of the sentinel SNP in the replication sample. Sentinel SNPs were the most significant findings in the investigation sample. Analysis of variance was the test of choice, PLINK, SNPTEST, and GTOOL were used in the analysis.RESULTS: Two SNPs (rs7912580 and rs2412459) were associated with response in both samples, respectively, located in an intergenic region between the AT-rich interactive domain 5B (ARID5B, MRF1-like) gene and rhotekin 2 (RTKN2) gene, an intronic region located in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene (P=1.358e-06 and 0.015 for the Positive and Negative Symptom Scale % total score decrease in the investigation and replication samples, respectively). The direction of association was opposite in the two samples, a finding that is sometimes reported as a flip-flop association.CONCLUSION: Heterozygosis for the ancestral allele was associated with the best improvement in the investigation sample and with poorer outcome in the replication sample. This discrepancy can be because of differences in the replication and investigation sample including the drugs used and the severity at baseline. Nevertheless, this finding is in line with two relevant hypothesis of schizophrenia, related to alterations in the immunological system (RTKN2) and in the neurodevelopment of the central nervous system (EIF2AK4). More studies are warranted to further investigate these associations.

There is a dearth of information on the association of atopy with schizophrenia. The few available studies used population-based registers to classify the atopy status of the patients but this strategy is not reliable. This study measured seropositivity with a multiallergen screen of allergen specific IgE antibodies in schizophrenia patients versus healthy controls. A subset of 66 schizophrenia patients and 34 healthy controls were randomly selected from a large comparative study of schizophrenia patients and controls. The Phadiatop multi-allergen screen was performed on sera from all the participants to assess their atopic status. Logistic regression was used to calculate the odds ratio for the association of schizophrenia with Phadiatop seropositivity as a measure of atopy. The prevalence of Phadiatop seropositivity was significantly lower (χ2 4.59, p = 0.032) and there was a reduced odds ratio for atopy in schizophrenia patients relative to controls (OR 0.40; 95% CI 0.17 to 0.94, p = 0.036). Though limited by a relatively small sample size and potentially confounded by anti-psychotic medications, this study suggests that the prevalence of atopy is lower in patients with schizophrenia. Replicating these results in larger samples could add to our growing understanding of immunological implications in mental illness.

Introduction The enzyme steroid sulfatase (STS) converts sulfated steroids to their non‐sulfated forms. Deficiency for this enzyme is associated with inattention but preserved response control. The polymorphism rs17268988 within the X‐linked STS gene is associated with inattentive, but not other, symptoms in boys with attention deficit hyperactivity disorder (ADHD). Methods We initially tested whether rs17268988 genotype was associated with attention, response control, and underlying aspects of cognition, using questionnaires and neuropsychological tasks, in two independent cohorts of healthy adult males. In an additional analysis based upon existing data, the performance of mice with genetic or pharmacological manipulations of the STS axis under attentionally demanding conditions was investigated. Results G‐allele carriers at rs17268988 exhibited reduced reaction time, enhanced attention, and reduced reaction time variability relative to C‐allele carriers. Mice with genetic or pharmacological manipulations of the STS axis were shown to have perturbed reaction time variability. Discussion Our findings provide additional support for an association between rs17268988 genotype and attention, which may be partially mediated by reaction time variability; they also indicate that, in contrast to the situation in boys with ADHD, in healthy men, the G‐allele at rs17268988 is associated with enhanced cognition. As reaction time variability is a predictor of well‐being, rs17268988 genotype may represent a biomarker for long‐term health.

The postsynaptic scaffolding protein SHANK3 is essential for the normal function of glutamatergic synapses in the brain. Emerging evidence suggests that impaired plasticity of glutamatergic synapses contributes to the pathology of schizophrenia (SCZ). To investigate whether variants in the SHANK3 gene contribute to the etiology of SCZ, we sequenced SHANK3 in 500 affected individuals (cohort C1). In total, we identified 48 variants and compared them to European controls from the 1000 Genomes Project and the Exome Variant Server. Five variants showed significant differences in frequencies between patients and controls. We were able to follow three of them up in an independent cohort (C2) comprising 993 SCZ patients and 932 German controls. We could not confirm an association for three of these variants (rs140201628, rs1557620, and rs61729471). Two rare variants with predicted functional relevance were identified in further SCZ individuals of cohort C1: c.3032G>T (p.G1011V) and c.*27C>T. The latter variant was found in one additional SCZ individual and the p.G1011V variant was identified in two additional SCZ individuals from cohort C2. The p.G1011V variant was the most interesting variant in our study; together with previous studies this variant has been identified in 4 out of 1,524 SCZ patients and in 4 out of 2,147 individuals with autism spectrum disorder (ASD), but not in 2468 European Sanger-sequenced controls. Therefore, we consider this variant a promising candidate variant for follow-up studies in larger samples and functional investigations. © 2017 Wiley Periodicals, Inc.

Background Alzheimer's Disease (AD) is the most common form of dementia. One characteristic of AD is the accumulation of amyloid-β (Aβ) peptides in different regions of the brain caused by the sequential cleavage of the transmembrane amyloid precursor protein. These extracellular amyloid plaques are a result of a dysregulated Blood-Brain Barrier (BBB) and emerge either due to an augmented production or a decreased excretion through brain barriers. The BBB with its several transporter systems shows age dependent expression levels of unspecific Aβ transporters. Recently, 19 loci including ABCA7, an ABC transporter responsible for Aβ efflux at the BBB, were discovered showing genome-wide significant association with the sporadic, late-onset form of AD (LOAD). Together with other research groups we identified several mutations in ABCA7 in AD patients, which is why an analysis of mutated ABCA7 in AD-related BBB models should be considered. We established patient-specific pluripotent stem cells from AD patients and healthy donors to differentiate endothelial cells and other related BBB cells for the investigation of disease mechanisms related to ABCA7 in AD patients. Methods Episomal vectors were used for the generation of induced Pluripotent Stem (iPS) cell lines from AD-specific B-lymphoblastoid cell lines (B-LCLs) and control B-LCLs of healthy donors. Alkaline phosphatase staining, immunofluorescence analysis, transcript analysis, western blot analysis, and the induction of three germ layers verified pluripotency. Successfully established lines were applied for the generation of BBB cells and neighboring cells. Endothelial cells and astrocytes were characterized by transcript analysis and flow cytometry. The differentiation process was analyzed for the altered expression of ABCA7. Results AD-specific iPS cells were successfully generated from B-LCLs. We could show alkaline phosphatase activity and the nuclear localization of pluripotency-related transcription factors including OCT4, SOX2, and NANOG. Transcript analysis and western blot analysis verified permanent induction of pluripotency marker genes including OCT4. The spontaneous differentiation of iPS cells into derivatives of the three germ layers was demonstrated. The efficient differentiation of high quality endothelial cells was shown by the expression of endothelial marker genes including von Willebrand factor. Astrocyte-specific markers including EAAT1 demonstrated efficient astrocyte differentiation. Discussion Human iPS cells provide a powerful tool for the analysis of AD-associated and patient-specific mutations in ABCA7. We successfully established endothelial cells and astrocytes representing suitable to study disease mechanisms of the BBB. Accordingly, this approach is an excellent opportunity to analyze pathogenic phenotypes of AD in vitro towards the identification of potential therapeutic targets.

Background Late Onset Alzheimer's Disease (LOAD) is a chronic and progressive neurodegenerative disorder affecting elderly people and is accompanied by severe cognitive decline. Genetics is supposed to be one of the key factors for the susceptibility to the disease. Several loci have been associated with an increased risk of developing Alzheimer's disease via Genome-Wide Association Studies (GWAS). The aim of this study was to investigate whether 33 susceptibility loci recently associated with LOAD in a large meta-analysis affect cognition in a healthy population. Methods Therefore, 2147 unrelated healthy subjects of German descent were recruited. The Structured Clinical Interview for DSM-IV (SCID 1 and SCID 2) was conducted to exclude psychotic diseases, a family history was recorded to exclude subjects with a positive family history for psychotic disorders and the Mini Mental Status Examination (MMSE) was conducted for every subject being older than 60 years, to exclude possible cognitive impairments. Cognitive performance was assessed via the German version of the 'Wechsler Adult Intelligence Scale, Revision 1991' (WAIS-R). Genotype data was obtained using chip technology and imputation. After stringent quality controls 31 single nucleotide polymorphisms (SNPs) were analyzed. SNPs having mismatches between reported and estimated gender and callrate differences ≥ 0.02 between cases and controls were not considered. The analysis was calculated through an additive linear regression model. Results Nominal association could be detected for 18 SNPs affecting at least one phenotype. The most significant SNP rs983392 was associated with the subscale digit span. This polymorphism is in linkage disequilibrium with the membrane spanning 4-domains A6A-gene (MS4A6A), belonging to the MS4A gene family on Chromosome 11q12. This gene was associated with a smaller right middle temporal volume, which hosts the hippocampus. A decreasing hippocampus is known to be a symptom in Alzheimer's disease. Another notable finding was the association of rs6733839 with performance, verbal and general IQ. This SNP is located near the bridging integrator 1-gene (BIN1), located on chromosome 2q14.3. It is thought to be involved in synaptic vesicle endocytosis and modulation of tau pathology, one of the key symptoms of Alzheimer's dementia. Discussion Results of this study indicate an influence of LOAD associated variations on cognitive performance in healthy controls. Both verbal and performance subtests show significant associations. These findings could help to improve the knowledge of pathophysiology and genetics of cognitive decline as observed LOAD. However, further research is needed to validate these associations and detect the functional relevance of the affected genes.

Background Suicide is one of the leading causes of death worldwide. A complex interplay between various risk factors is assumed to ultimately trigger a suicide attempt. Among those, genetic variations and personality traits seem to be the most relevant predictors. Results from a genome-wide association study we participated in (Galfalvy et al. 2015) point to several variations associated with the condition. In order to elucidate their underlying function a closer look on the influence on personality traits as one of the main predictors seemed feasible. Among others, stressful life events have been known to increase the risk of suicidal behavior. Therefore, we investigated whether 23 susceptibility markers associated with suicidal behavior also affect obsessive- compulsive behavior (as a personality trait prone to show a high risk of coping problems under stress) in healthy individuals. Methods Unrelated healthy volunteers of German descent were screened for an absence of any psychiatric disorder in themselves or their first degree relatives. Obsessive and compulsive symptoms were elevated using the Maudsley Obsessive Compulsive Inventory (MOCI). Finally, 2104 subjects (52% female) were enrolled in the study. Genotype data was obtained using chip technology and imputation. After stringent quality controls 23 Single Nucleotide Polymorphisms (SNPs) were analyzed using an additive linear regression model. Benjamini-Hochberg procedure was used to correct for multiple testing. Results In females, significant associations with the MOCI total score were identified for two intergenic SNPs, localized near BRINP3 (associated with coronary heart disease and aggressive periodontitis) and LOC647132 (a processed pseudogene which is associated with antibody response to smallpox vaccine), both involved in inflammation processes. In males, significant associations could be detected for seven SNPs localized in the TBX20 gene linked to migration and development of brainstem motor neurons, cardiac development and multiple cardiac functions and pathologies. Discussion These results indicate a sex specific overlap of the genetic make-up between suicidality and obsessive-compulsive behavior, thereby emphasizing the relevance of personality traits for suicidal behavior. Further research approaches are necessary in order to replicate these findings and also to identify the underlying functional relevance of the associated variants.

Background The atypical antipsychotic drug clozapine is the only effective drug for treatment-resistant schizophrenia, but also bears the risk of inducing severe adverse drug responses like neutropenia and agranulocytosis. Agranulocytosis and neutropenia occurs in about 1% and 3% of treated individuals. The aetiology is largely unknown, but there is evidence for contributing genetic factors. Identifying biomarkers could decrease blood monitoring effort and enable a more widespread use of clozapine. Several studies identified HLA variants contributing to the risk of agranulocytosis. The Clozapine-Induced Agranulocytosis Consortium (CIAC) identified two independent loci in the major histocompatibility complex genome-wide associated with clozapine-induced agranulocytosis: A single amino acid in HLA-DQB1 (126Q) (OR=0.19, P=4.7E−14) and an amino acid change in HLA-B (158 T) (OR=3.3, P=6.4E−10). Our study was performed to replicate these interesting findings. Methods The atypical antipsychotic drug clozapine is the only effective drug for treatment-resistant schizophrenia, but also bears the risk of inducing severe adverse drug responses like neutropenia and agranulocytosis. Agranulocytosis and neutropenia occurs in about 1% and 3% of treated individuals. The aetiology is largely unknown, but there is evidence for contributing genetic factors. Identifying biomarkers could decrease blood monitoring effort and enable a more widespread use of clozapine. Several studies identified HLA variants contributing to the risk of agranulocytosis. The Clozapine-Induced Agranulocytosis Consortium (CIAC) identified two independent loci in the major histocompatibility complex genome-wide associated with clozapine-induced agranulocytosis: A single amino acid in HLA-DQB1 (126Q) (OR=0.19, P=4.7E−14) and an amino acid change in HLA-B (158 T) (OR=3.3, P=6.4E−10). Our study was performed to replicate these interesting findings. Results HLA-DQB1 (126Q) was associated with agranulocytosis (OR=0.12, P=5.25E-05) and neutropenia (OR=0.18, P=7.34E-06), whereas HLA-B (158 T) was associated with neutropenia only (OR=2.45, P=1.32E-02). The HLA-DQB1 signal was mainly driven by agranulocytosis cases. Discussion We were able to replicate previous findings. Our study gives further evidence for the implication of immunological pathways and especially HLA-DQB1 in agranulocytosis and neutropenia.

Background Schizophrenia is a neurodevelopmental disease. Causes include environmental and genetic factors. Characteristics of schizophrenia include a deregulation of the glutamatergic and the GABAergic neurotransmission and the degeneration of predominantly inhibitory interneurons. Recently, 108 loci referring to Single Nucleotide Polymorphisms (SNPs) and 8 loci containing Copy Number Variations (CNVs) have been associated with schizophrenia suggesting a strong impact of genetic factors on the embryonic development of human brain. Together with other research teams, we identified CNVs in the Neurexin 1 gene (NRXN1) in patients suffering from schizophrenia, which highly recommends the detailed analysis of NRXN1-related disease mechanisms. Neurexins are presynaptic transmembrane proteins. We established patient-specific induced Pluripotent Stem (iPS) cells from schizophrenia patients and healthy donors to differentiate neurons for the investigation of disease mechanisms related to NRXN1 in schizophrenia patients. Patient-specific iPS cells carry the disease-associated genetic background of a patient, which is a CNVs affecting NRXN1. Methods Human iPS cells were generated from B-Lymphoblastoid Cell Lines (B-LCLs) using episomal vectors. B-LCLs were obtained from patients carrying CNVs in NRXN1 and healthy donors. The pluripotency of stem cells was verified by alkaline phosphatase staining, immunofluorescence analysis, transcript analysis, western blot analysis, and the induction of three germ layers. A neuronal screening protocol was applied to select iPS cell clones with a high differentiation potential towards neuronal cell lineages. Established lines were differentiated into Neural Stem Cells (NSCs) and further differentiated into functional and mature neurons. Terminal differentiated neurons were characterized by morphology, transcript analysis, western blot analysis, immunofluorescence analysis, electrophysiology, and mitochondrial respiration. Results Transcript analysis and western blot analysis of iPS cells verified permanent induction of pluripotency marker genes including OCT4. The spontaneous differentiation of iPS cells into derivatives of the three germ layers was demonstrated. The induction of neural stem cells was characterized by mRNA and protein analysis of neural stem cells markers including SOX2 and PAX6. Neural induction towards cortical neurons was monitored by a set of neurodevelopmental marker genes including NESTIN, GFAP, and NGN3. The efficient differentiation of mature neurons was shown by the expression of marker genes including glutamate and GABA receptors. Mitochondrial respiration was elevated in differentiated neurons. Patch clamp analysis verified the differentiation of functional GABAergic and glutamatergic neurons. Discussion Human iPS cells provide a powerful tool for the analysis of schizophrenia-associated and patient-specific DNA variations including CNVs. We successfully established mature and functional neuronal cultures suitable to study disease mechanisms related to NRXN1. Accordingly, this approach is an excellent opportunity for the identification of potential therapeutic targets.

Background Schizophrenia is a serious psychiatric disorder of multifactorial genesis, which can be associated with serious limitations in everyday life. In addition to environmental factors, genetic factors play a crucial etiological role. In 2014, the Psychiatric Genomics Consortium (PGC) carried out the largest GWAS to date. Significant associations between schizophrenia and 128 linkage-disequilibrium-independent Single-Nucleotide Polymorphisms (SNP) were found in 108 conservatively defined loci (Ripke et al. 2014). A neuropsychological deficit of schizophrenia, which has been widely described in the literature, is a disturbance of verbal fluency. The aim of this study was to examine schizophrenia-associated SNPs for their association with verbal fluency. Methods The PAGES sample includes 1000 schizophrenia patients who were diagnosed according to DSM IV, and 3000 randomly selected psychiatrically healthy controls that performed a multi-stage selection procedure. Verbal fluency was assessed by Regensburg word fluency test (RWT) in a subset of 361 cases and 559 controls. Association analysis was performed applying linear regression using an additive model corrected for affection status, age, education and gender. Results Several SNPs showed nominal significant association with verbal fluency measured with RWT. rs11191419 (BLOC-1 related complex subunit 7, BORCS7) was associated with all tested domains (words, words switch, categories, categories switch), association of rs111294930 (LINC01470) was restricted to categories and categories switch, for both SNPs association was reflected in the same direction of effect in cases and controls. Association in cases only could be detected for rs7523273 (MIR29B2) (all domains) and rs9636107 (transcription factor 4, TCF4) (categories, categories switch), whereas association of rs3849046 (eukaryotic translation termination factor 1, ETF1) (all domains) and rs12826178 (mitochondrial serine hydroxymethyltransferase, SHMT2) (categories and word switch) were restricted to controls. Discussion Though no association survived multiple testing, the nominal associated variations are localized in or near genes showing interesting features. Most genes are involved in regulatory processes either on the transcriptional or translational level: Long non coding RNAs (i.e. LINC01470) and micro RNAs (i.e. MIR29B2) are known to be involved in transcriptional and post-transcriptional regulation of gene expression, ETF1 is involved in termination of mRNA translation and nonsense mediated RNA decay. TCF4 activates transcription. This gene also plays a role in the initiation of neuronal differentiation. Another hit, BORCS7 has been shown to be upregulated during human stem cell differentiation toward neuronal fates in early brain development. The results indicate an influence of schizophrenia risk variants on verbal fluency performance in healthy subjects, thereby implicating an underlying mechanism which might be involved in such deficits in schizophrenia. Functional relevance of the associated SNPs as well as replication in independent samples remains to be determined.

Background The atypical antipsychotic drug clozapine is the only effective drug for treatment-resistant schizophrenia, but also bears the risk of inducing severe adverse drug responses including neutropenia and agranulocytosis. Agranulocytosis and neutropenia occurs in about 1% and 3% of treated individuals. The aetiology is largely unknown, but there is evidence for contributing genetic factors. Identifying biomarkers could decrease blood monitoring effort and enable a more widespread use of clozapine. Several studies identified HLA variants (e.g. Athanasiou et al. 2011) and especially a polymorphism located in HLA-DBQ1 (6672 G>C, rs113332494) as associated with clozapine-induced agranulocytosis or neutropenia. Our study was conducted to replicate previous findings on HLA-DBQ1 6672 G>C. Methods The sample was comprised of individuals from sites of Finland, Germany, the Netherlands and the UK and was collected in the course of the CRESTAR project, which aimed at the development of pharmacogenetic biomarkers for schizophrenia. We analysed the risk allele distribution of rs113332494 in individuals of different ethnic background including 180 clozapine-induced neutropenia cases of which 61 developed agranulocytosis and 1396 controls treated with clozapine but not affected by this severe adverse drug response. We also performed association analyses in subsamples using logistic regression with an additive model seeking replication of previous findings on rs113332494. This CRESTAR project was funded by the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement #279227. Results rs113332494 was associated with neutropenia (OR=6.34, P=2.13E-06) and agranulocytosis (OR=9.59, P=1.11E-05) in individuals of European ancestry. The association signal was mainly driven by agranulocytosis cases. Discussion Our study gives further evidence of an implication of HLA-DQB1 in agranulocytosis. We were able to replicate previous findings. This implicates immune function as contributing process to this severe adverse drug response.

Converging evidence suggests that frontostriatal abnormalities underlie OCD symptoms. The event-related potential P300 is generated along a widely distributed network involving several of the areas implicated in OCD. P300 abnormalities reported in patients with OCD suggest increased activity in these areas. The aim of the present study was to investigate this assumption in unmedicated patients with OCD, and to assess the effects of OCD treatment on P300 brain activity patterns. Seventy-one unmedicated patients with a DSM-IV diagnosis of OCD and 71 age- and gender-matched healthy control subjects participated in the study. The P300 was obtained through 32-channel EEG during an auditory oddball paradigm. Forty-three patients underwent a second EEG assessment after treatment with sertraline and behavioural therapy. Low-resolution electromagnetic tomography (LORETA) was used to localize the sources of brain electrical activity. Results: Increased P300-related activity was observed predominantly in the left orbitofrontal cortex, but also in left prefrontal, parietal and temporal areas, in patients compared to controls at baseline. After treatment, reduction of left middle frontal cortex hyperactivity was observed in patients. Conclusions: Findings of increased activity in frontoparietal areas in patients are consistent with several previous studies. Importantly, OCD treatment led to reduction of hyperactivity in the left middle frontal cortex, an area associated with context processing and uncertainty that might be important for the emergence of OCD symptoms. Thus, the present study is the first to show an association between P300 abnormalities and activity in brain regions postulated to be involved in the pathophysiology of OCD.

We previously investigated a sample of psychotic patients acutely ill and acutely treated with haloperidol in the search for genetic predictors of response at PANSS scores during the first month of treatment. In the present work we extend the analysis to a wider panel of genetic variations including SNPs harbored by genes whose products are involved in molecular pathways consistent with the latest results of genome-wide association studies (GWAS) of antipsychotic efficacy. 96 Patients were investigated. The results were replicated in an independent sample of bipolar manic patients treated with antipsychotics (n tot=470, the sample was retrieved from the STEP-BD). Outcomes were the PANSS variation through time in the first sample, and changes of mania symptomatology at any two consecutive observations in the public available STEP-BD replication sample. A list of variations harbored by AKAP13, CACNA1, GRIK4 and GRIA1 were found to be significantly associated with outcome in both samples (different set of variations for each sample). Results did not survived multiple testing in the original sample but were replicated in both samples. This finding stresses the relevance of the glutamatergic system and regulatory molecular cascades in antipsychotic response. Nonetheless, the level of significance and the indirect and incomplete replication mandate cautiousness and further replication.

The single-nucleotide polymorphism (SNP) rs10503253, located within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2, was recently identified as genome-wide significant for schizophrenia (SZ), but is of unknown function. We investigated the neurocognitive effects of this CSMD1 variant in vivo in patients and healthy participants using behavioral and imaging measures of brain structure and function. We compared carriers and non-carriers of the risk ‘A’ allele on measures of neuropsychological performance typically impaired in SZ (general cognitive ability, episodic and working memory and attentional control) in independent samples of Irish patients (n = 387) and controls (n = 171) and German patients (205) and controls (n = 533). Across these groups, the risk ‘A’ allele at CSMD1 was associated with deleterious effects across a number of neurocognitive phenotypes. Specifically, the risk allele was associated with poorer performance on neuropsychological measures of general cognitive ability and memory function but not attentional control. These effects, while significant, were subtle, and varied between samples. Consistent with previous evidence suggesting that CSMD1 may be involved in brain mechanisms related to memory and learning, these data appear to reflect the deleterious effects of the identified ‘A’ risk allele on neurocognitive function, possibly as part of the mechanism by which CSMD1 is associated with SZ risk.

We aimed to replicate, in a larger sample and in a different geographical location, the previously reported elevation of anti-gliadin IgG antibodies in schizophrenia.A total of 950 adults with schizophrenia (severity assessed by PANSS) and 1000 healthy controls were recruited in the Munich metropolitan area. Anti-gliadin IgG antibodies were analyzed with ELISA. χ(2)-tests and logistic regression were used to analyze the association of schizophrenia with elevated anti-gliadin IgG. A multivariable general linear model was used to compare anti-gliadin IgG levels between patients and controls.The odds ratio of having elevated anti-gliadin IgG antibodies in the schizophrenia group was 2.13 (95% CI 1.57 to 2.91, p0.0001). Mean anti-gliadin IgG levels were higher in schizophrenia patients (0.81 ± 0.79 vs. 0.52 ± 0.56, t = 9.529, df = 1,697, p0.0001) and the difference persisted after adjusting for potential confounders.Our study, limited by its cross sectional design, confirmed an association between anti-gliadin IgG antibodies and schizophrenia. Replication in longitudinal studies, clinical trials of gluten free diet and mechanistic investigation could lead to novel treatment targets, preventive and therapeutic considerations in schizophrenia.

To access publisher's full text version of this article click on the hyperlink at the bottom of the page Clozapine is a uniquely efficacious antipsychotic drug in treatment-resistant schizophrenia. Its use is restricted due to adverse effects including a rare but dangerous reduction in neutrophils (agranulocytosis) and the mandatory hematological monitoring this entails in many countries. We review the statistical, ethical and legal issues arising from a hypothetical pharmacogenetic test for clozapine, using the UK as an exemplary case for consideration. Our key findings include: a consideration of the probabilistic results that a pharmacogenetic test may return; the impact on drug licensing; and the potential for pharmacogenetic tests for clozapine being used without consent under the UK's legal framework. We make recommendations regarding regulatory changes applicable to the special case of pharmacogenetic testing in clozapine treatment. National Institute for Health Research info:eu-repo/grantAgreement/EC/FP7/279227

Background Recent studies demonstrated benefits of cognitive intervention in mild cognitive impairment (MCI), but few studies have determined long-term effects on cognition, conversion rate to Alzheimer's disease, and the role of early intervention. Method A 6-month multicomponent cognitive group intervention was applied in participants with single- or multiple-domain amnestic MCI (defined according to Petersen's criteria). One group (n = 12) received the intervention at the beginning of the study period and was compared with an active control group (n = 12) who received it after an 8-month time lag. Follow-up assessments were conducted at 15 and 28 months (study period was August 2007-December 2009). The primary outcome was change in cognitive function as determined by changes in scores on the Mini-Mental State Examination and the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), and the secondary outcomes were change in specific cognitive and noncognitive functions and conversion to Alzheimer's disease (according to DSM-IV/NINCDS-ADRDA criteria and NAI-AA criteria for probable Alzheimer's dementia with increased level of certainty). Results Eighteen participants completed the study after 28 months. Long-term data revealed a stable intervention effect on the primary outcome ADAS-cog in the early-intervention group (P = .024). The participants in the later-intervention (control) group appeared to benefit to a lesser extent from the cognitive intervention compared to those who received it earlier. Only participants in the later-intervention group (6 of 12) converted to Alzheimer's disease during the 28-month study period. Conclusions Benefits of our 6-month cognitive intervention on global cognitive status appear to be preserved over extended follow-up periods. Early cognitive intervention may delay conversion to Alzheimer's disease. Findings in a small sample encourage the use of the intervention in larger-scale studies. Trial registration ClinicalTrials.gov identifier: NCT00544856.

MAOA and, to a lesser extent, MAOB poly- morphisms have been related to aggression traits and suicidality. We aimed to investigate the role of MAOA and MAOB in suicidal versus non-suicidal participants and interactions between genetic variation and suicidal status on aggression and anger-related traits. The sample was com- posed of three groups: one group of suicide attempters (n = 171, males 35.1 %), one group of suicide completers (n = 90, males 57.8 %) and a healthy control group (n = 317, males 43.8 %). We examined the following markers: MAOA rs909525, rs6323, and rs2064070, and MAOB rs1799836. Anger traits were measured with the state-trait anger expression inventory (STAXI) and aggression traits with the questionnaire for measuring fac- tors of aggression (FAF). Associations were separately examined for males and females. Variation in the three MAOA variants was associated with higher levels of anger expressed outwards (STAXI ''anger-out'' subscale) in male suicidal patients compared to controls (p \ 0.001). In females, the C allele of rs6323 showed higher scores on the same subscale (''anger out'') (p = 0.002). Allele frequen- cies of the MAOA rs909525 were associated with suici- dality (p \ 0.007). Our findings show an association between genetic variation in three polymorphisms of the MAOA and anger traits in suicidal males and one replication for the functional variant rs6323 in females. This relation- ship was stronger than a direct genetic association with suicide status. Future studies incorporating endophenotypic measures of anger and aggression in suicidal participants are warranted.

Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype. © 2013 WILEY PERIODICALS, INC.

Only a few common variants in the sequence of the genome have been shown to impact cognitive traits. Here we demonstrate that polygenic scores of educational attainment predict specific aspects of childhood cognition, as measured with IQ. Recently, three sequence variants were shown to associate with educational attainment, a confluence phenotype of genetic and environmental factors contributing to academic success. We show that one of these variants associating with educational attainment, rs4851266-T, also associates with Verbal IQ in dyslexic children (P = 4.3 × 10−4, β = 0.16 s.d.). The effect of 0.16 s.d. corresponds to 1.4 IQ points for heterozygotes and 2.8 IQ points for homozygotes. We verified this association in independent samples consisting of adults (P = 8.3 × 10−5, β = 0.12 s.d., combined P = 2.2 x 10−7, β = 0.14 s.d.). Childhood cognition is unlikely to be affected by education attained later in life, and the variant explains a greater fraction of the variance in verbal IQ than in educational attainment (0.7% vs 0.12%,. P = 1.0 × 10−5).

Genomic copy number variants (CNVs) have been strongly implicated in the etiology of schizophrenia (SCZ). However, apart from a small number of risk variants, elucidation of the CNV contribution to risk has been difficult due to the rarity of risk alleles, all occurring in less than 1% of cases. We sought to address this obstacle through a collaborative effort in which we applied a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. We observed a global enrichment of CNV burden in cases (OR=1.11, P=5.7e −15 ), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7e −6 ). CNV burden is also enriched for genes associated with synaptic function (OR = 1.68, P = 2.8e −11 ) and neurobehavioral phenotypes in mouse (OR = 1.18, P=7.3e −5 ). We identified genome-wide significant support for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. We find support at a suggestive level for nine additional candidate susceptibility and protective loci, which consist predominantly of CNVs mediated by non-allelic homologous recombination (NAHR).

Die genetische Forschung hat in der Psychiatrie seit uber 100 Jahren eine sehr wechselhafte Geschichte. So wurde uber viele Jahrzehnte des 20. Jahrhunderts in Psychologie und Psychiatrie eine heftige, teilweise verbitterte Diskussion uber „Gene oder Umwelt“ („nature vs. nurture“) gefuhrt. Sind psychische Eigenschaften und Storungen auf genetisch-konstitutionelle Faktoren oder auf Umwelteinflusse wie z. B. psychosoziale Belastungen zuruckfuhrbar? Heute ist allgemein anerkannt, dass die Wahrheit in der Mitte liegt. Es ist unstreitig: Psychische Eigenschaften und v. a. psychische Storungen werden sowohl von genetischen Anlagen als auch von Umweltbedingungen beeinflusst, noch wenig bekannt sind die Mechanismen der Interaktion beider Ebenen. Das gesamte Feld der psychiatrischen Genetik hat sich im Rahmen der sich rapide entwickelnden technischen Moglichkeiten von der Analyse familiarer Ahnlichkeitsmuster in Familien-, Zwillings- und Adoptionsstudien auf die molekulargenetische Analyse psychischer Eigenschaften und Storungen verschoben. Der vollzogene methodische „Paradigmenwechsel“ hat das Interesse an dem klinischen Forschungsfeld der psychiatrischen Genetik massiv gesteigert. Die molekulargenetische Analyse ist mittlerweile zur wichtigsten Erkenntnisquelle der Pathophysiologie und Neurobiologie psychischer Storungen geworden. Sie stellt auch die Nosologie psychischer Krankheiten zunehmend in Frage. Die heutige klinische Nutzlichkeit liegt in der Fruherkennung („diagnostische und pradikative Marker“) und Entwicklung neuer, molekularer Wirkprinzipien fur Therapie und Pravention. Bisher sind jedoch in der Umsetzung der genetischen Erkenntnisfortschritte in die klinische Basis noch keine durchschlagenden, nachhaltigen Erfolge erzielt worden. Dieser Ertrag ist erst langfristig zu erwarten.

Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity-multiple homozygous SNPs in a row-to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003-0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.Molecular Psychiatry advance online publication, 22 September 2015; doi:10.1038/mp.2015.120.

Duplications in 16p11.2 are a risk factor for schizophrenia (SCZ). Using genetically modified zebrafish, Golzio and colleagues identified KCTD13 within 16p11.2 as a major driver of the neuropsychiatric phenotype observed in humans. The aims of the present study were to explore the role of KCTD13 in the development of SCZ and to provide a more complete picture of the allelic architecture at this risk locus. The exons of KCTD13 were sequenced in 576 patients. The mutations c.6G>T and c.598G>A were identified in one patient each. Both mutations were predicted to be functionally relevant and were absent from the 1000 Genomes Project data and the Exome Variant Server. The mutation c.6G>T was predicted to abolish a potential transcription factor-binding site for specifity protein 1. Altered specifity protein 1 expression has been reported in SCZ patients compared with controls. Further studies in large cohorts are warranted to determine the relevance of the two identified mutations.

Schizophrenia is a devastating brain disease. The mode of inheritance is complex and non-Mendelian with a high heritability of ca. 65-80%. Given this complexity, until most recently it was notoriously difficult to identify disease genes. Due to new technologies the last few years have brought an explosion of interest in human genetics of complex diseases. The knowledge resulting from the availability of the complete sequence of the human genome, the systematic identification of single nucleotide polymorphisms (SNPs) throughout the genome, and the development of parallel genotyping technology (microarrays) established the conditions that brought about the current revolution in our ability to probe the genome for identifying disease genes. All these studies have opened a window into the biology of common complex diseases and have provided proof of principle and yielded a multitude of genes showing strong association with complex diseases. New findings in schizophrenia will be summarized in this review and discussed in the light of a possible translation into the development of better treatment.

Growing evidence implicates that abnormal stem cell proliferation and neurodegenerative mechanisms may be involved in the pathogenesis of neuropsychiatric disorders including schizophrenia. Here, we studied the underlying pathomechanisms of psychosis. We are employing a translational approach combining in vivo data with supplementary data from an adult neuronal stem cell-derived cell culture model by generating a large number of analytes in our specimens following a multiplexing strategy. In the animal model the NMDA receptor was chronically antagonized by MK-801 at ultralow doses. As a result of this, we were able to demonstrate a roughly twofold increased density of PCNA positive cells in the germinal zone of the dentate gyrus indicating enhanced neuroproliferative activity. In vitro stem cell experiments additionally pointed to this direction showing an increase both in proliferation and neuronal differentiation after MK-801 treatment. These alterations were partially prevented by coapplication of the dopamine receptor antagonist haloperidol. In addition, apoptotic activity assessed by immunohistochemical demonstration of cleaved caspase-3 stainings was unaffected by MK-801 treatment. These observations were largely supported by microarray gene expression analysis, which permits high-throughput multiplexed assessment of expression data from a comprehensive set of genes and showed parallels with data from human post mortem studies. In conclusion, our data support the notion, that abnormal proliferation due to anti-apoptotic mechanisms may represent a factor in the pathogenesis of psychosis. Thus, research on the exact interplay between glutamatergic neurotransmission and neuronal proliferation deserves more attention. This dual in vivo and in vitro strategy described here may prove as a suitable model for addressing complex neuropsychiatric diseases especially when taking advantage of the potential of multiplex technologies not only in diagnostics but also in basic research.

The serotonin type 3 (5-HT(3) ) receptor (R) belongs to the family of ligand-gated ion channels. It is supposed to play an important role in the pathogenesis of schizophrenia and might also represent an interesting target for the pharmacological treatment of this disorder. In this study, we searched for variations within the 5-HT(3A) receptor gene which might be specifically associated to schizophrenia. Twenty-nine single nucleotide polymorphisms (SNPs) of 943 schizophrenic patients compared to 2,343 healthy individuals were analyzed. SNPs were selected taking into account previous results on a 5-HT(3A) receptor domain involved in neuroleptic binding. Dominant logistic and linear regression models were calculated for the phenotypes number of hospitalizations, duration of hospitalization, age at onset and case-control. The data did not show significant associations of any SNP under investigation specific for schizophrenic patients. In conclusion, our study does not support the hypothesis that the 5-HT(3A) receptor plays a major role in the pathogenesis of schizophrenia.

Item does not contain fulltext Measures of personality and psychological distress are correlated and exhibit genetic covariance. We conducted univariate genome-wide SNP ( approximately 2.5 million) and gene-based association analyses of these traits and examined the overlap in results across traits, including a prediction analysis of mood states using genetic polygenic scores for personality. Measures of neuroticism, extraversion, and symptoms of anxiety, depression, and general psychological distress were collected in eight European cohorts (n ranged 546-1,338; maximum total n = 6,268) whose mean age ranged from 55 to 79 years. Meta-analysis of the cohort results was performed, with follow-up associations of the top SNPs and genes investigated in independent cohorts (n = 527-6,032). Suggestive association (P = 8 x 10(-8) ) of rs1079196 in the FHIT gene was observed with symptoms of anxiety. Other notable associations (P < 6.09 x 10(-6) ) included SNPs in five genes for neuroticism (LCE3C, POLR3A, LMAN1L, ULK3, SCAMP2), KIAA0802 for extraversion, and NOS1 for general psychological distress. An association between symptoms of depression and rs7582472 (near to MGAT5 and NCKAP5) was replicated in two independent samples, but other replication findings were less consistent. Gene-based tests identified a significant locus on chromosome 15 (spanning five genes) associated with neuroticism which replicated (P < 0.05) in an independent cohort. Support for common genetic effects among personality and mood (particularly neuroticism and depressive symptoms) was found in terms of SNP association overlap and polygenic score prediction. The variance explained by individual SNPs was very small (up to 1%) confirming that there are no moderate/large effects of common SNPs on personality and related traits. (c) 2012 Wiley Periodicals, Inc. 01 september 2012

Serotonergic neurotransmission dysfunctions have been well documented in patients with suicidal behaviour. We investigated monoamine oxidase A (MAOA: rs2064070, rs6323, rs909525) and B (MAOB: rs1799836, rs2311013, rs2205655) genetic modulation of personality traits (Temperament and Character Inventory, TCI) as endophenotype for suicidal behaviour. 108 suicide attempters and 286 healthy controls of German origin were screened. Among females, allelic analyses revealed associations between MAOA rs6323 A allele and higher Harm Avoidance in suicide attempters and MAOB rs2205655 A allele and higher Cooperativeness scores in healthy controls. Among males, MAOA rs909525 A allele was associated with higher Reward Dependence in suicide attempters. Multivariate analyses controlling for age and educational level mainly confirmed results. Case -control analyses in this subsample do not differ from our previously reported one. Despite of the small sample size, a possible involvement of these genes in the modulation of personality traits closely related to suicidal behaviour cannot be excluded.

Suicidal behavior is multidimensional. As well as medical, psychological, psychosocial, social, cultural, and socioeconomic parameters, it also includes biological, especially genetic, risk factors. T

Correction to: Molecular Psychiatry (2017) 22, 336–345; doi:10.1038/mp.2016.244;published online 17 January 2017 Data access for several cohorts used in this study was provided by the National Center for Biotechnology Information (NCBI) database of Genotypes and Phenotypes (dbGaP). dbGaP accession numbers for these cohorts were as follows

Toxoplasma gondii (T. gondii) a widespread neurotropic parasite, has been previously associated with schizophrenia and more recently with suicidal behavior. However, no previous study has examined the association of T. gondii with suicidal behavior in schizophrenia patients. 950 individuals diagnosed with schizophrenia by SCID were recruited from the Munich area of Germany. Solid-enzyme immunoassay methods were used to measure IgG plasma antibodies to T. gondii, other neurotropic pathogens and gliadin. Logistic regression models were developed to analyze the association of T. gondii seropositivity or serointensity with history of suicidal behavior. In those younger than the median age of the sample, 38, T. gondii serointensity was associated with history of suicidal behavior (p = 0.02), while in the older patients the relationship was not significant (p = 0.21). Seropositivity was also associated with history of suicide attempt in younger patients, odds ratio 1.59 (95% CI 1.06 to 2.40), p = 0.03. Seropositivity for CMV (p = 0.22), HSV-1 (p = 0.36) and gliadin (p = 0.92) was not related to history of suicide attempt in the entire sample or any age subgroup. T. gondii serology might become, with interaction with vulnerability genes, a candidate biomarker for a subgroup of schizophrenia patients prone to attempting suicide.

Smooth pursuit and visual scanpath deficits are candidate trait markers for schizophrenia. It is not clear whether eye tracking dysfunction (ETD) and atypical scanpath behaviour are the product of the same underlying neurobiological processes. We have examined co-occurrence of ETD and scanpath disturbance in individuals with schizophrenia and healthy volunteers.Eye movements of individuals with schizophrenia (N = 96) and non-clinical age-matched comparison participants (N = 100) were recorded using non-invasive infrared oculography during smooth pursuit in both predictable (horizontal sinusoid) and less predictable (Lissajous sinusoid) conditions and a free viewing scanpath task.Individuals with schizophrenia demonstrated scanning deficits in both tasks. There was no association between performance measures of smooth pursuit and scene scanpaths in patient or control groups. Odds ratios comparing the likelihood of scanpath dysfunction when ETD was present, and the likelihood of finding scanpath dysfunction when ETD was absent were not significant in patients or controls in either pursuit variant, suggesting that ETD and scanpath dysfunction are independent anomalies in schizophrenia.ETD and scanpath disturbance appear to reflect independent oculomotor or neurocognitive deficits in schizophrenia. Each task may confer unique information about the pathophysiology of psychosis.

Background 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 gamma-band was shown to be critically related to a glutamatergic and GABAergic microcircuit which is also known to be involved in the pathophysiology of schizophrenia. Recently, a reduction of the early auditory evoked gamma-band response (eGBR) in schizophrenic patients was reported. In order to investigate the possible applicability of this neurophysiological marker as an intermediate phenotype for schizophrenia, this is the main question of our investigation: Is the early eGBR decreased regarding evoked power and phase locking in first-degree relatives of patients with schizophrenia? Methods We investigated the early eGBR in 17 unaffected first-degree relatives of patients with schizophrenia and in age-, gender- and education-matched groups of schizophrenic patients and healthy controls using an auditory reaction task. Results First-degree relatives of patients with schizophrenia and schizophrenic patients showed a significant reduction of evoked power and phase locking of the early eGBR compared to healthy controls. Conclusion This study shows significantly reduced evoked power and phase locking of the early auditory eGBR in first-degree relatives of patients with schizophrenia pointing to the applicability of this marker as a heritable intermediate phenotype for schizophrenia. 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 HOMER 1 protein plays a crucial role in mediating glutamatergic neurotransmission. It has previously shown to be a candidate gene for etiology and pathophysiology of different psychiatric diseases such as schizophrenia. To identify genes involved in response to antipsychotics, subgroups of animals were treated with haloperidol (1 mg/kg, n = 11) or saline (n = 12) for one week. By analyzing microarray data, we replicated the observed increase of Homer 1 gene expression. Furthermore, we genotyped 267 schizophrenic patients, who were treated monotherapeutically with different antipsychotics within randomized-controlled trials. Psychopathology was measured weekly using the PANSS for a minimum of four and a maximum of twelve weeks. Correlations between PANSS subscale scores at baseline and PANSS improvement scores after four weeks of treatment and genotypes were calculated by using a linear model for all investigated SNP’s. We found an association between two HOMER 1 polymorphisms (rs2290639 and rs4704560) and different PANSS subscales at baseline. Furthermore all seven investigated polymorphisms were found to be associated with therapy response in terms of a significant correlation with different PANSS improvement subscores after four weeks of antipsychotic treatment. Most significant associations have been shown between the rs2290639 HOMER 1 polymorphism and PANSS subscales both at baseline conditions and after four weeks of antipsychotic treatment. This is the first study which shows an association between HOMER 1 polymorphisms and psychopathology data at baseline and therapy response in a clinical sample of schizophrenic patients. Thus, these data might further help in detecting differential therapy response in individuals with schizophrenia.

Age, haloperidol plasma levels and sex are associated with haloperidol induced motor side effects according to some lines of evidence, even though some conflicting findings mandate further research. We here report that age and sex were associated with dystonia during the early phases of treatment (p = 0.0006 and p = 0.008 respectively), but are overall poor predictors of the Extrapyramidal Symptom Rating Scale scores' variation over time (first month of treatment) in a sample of 60 acutely ill haloperidol treated psychotic patients. We conclude that age, sex and haloperidol plasma levels are not robust predictors of haloperidol induced motor side effects. Nonetheless, some limits of the study including the small sample size and the imputation of missing data could have diminished the power of detecting minor impacts of the investigated clinical predictors of the haloperidol induced motor side effects.

Deletions encompassing the X-linked STS gene (encoding steroid sulfatase) have been observed in subjects with neurodevelopmental disorders, including attention deficit hyperactivity disorder (ADHD). Recently, two single nucleotide polymorphisms (SNPs) within STS (rs12861247 and rs17268988) have been reported to be associated with ADHD risk and inattentive symptoms in ADHD, respectively. Using a UK sample of ADHD subjects (aged 5-18 years), we tested the hypothesis that rs12861247 is associated with ADHD risk using a case-control approach (comparing 327 ADHD cases with 358 male controls from the Wellcome Trust Case Control Consortium). Using a subset of males from the ADHD sample, we also examined whether variation within STS is associated with symptomatology/cognitive function in ADHD. We then tested whether SNPs associated with cognitive function in ADHD were also associated with cognitive function in healthy male subjects using a German sample (n = 143, aged 18-30 years), and whether STS was expressed in brain regions pertinent to ADHD pathology during development. We did not replicate the previously identified association with rs12861247. However, in ADHD males, variation at rs17268988 was associated with inattentive symptoms, while variation within STS was significantly associated with performance on three cognitive measures. Three SNPs associated with cognitive function in ADHD males were not associated with cognitive function in healthy males. STS was highly expressed in the developing cerebellar neuroepithelium, basal ganglia, thalamus, pituitary gland, hypothalamus and choroid plexus. These data suggest that genetic variants affecting STS expression and/or activity could influence the function of brain regions perturbed in ADHD.

Background The Human Natural Killer-1 carbohydrate (HNK-1) is involved in neurodevelopment and synaptic plasticity. Extracellular matrix structures called perineuronal nets, condensed around subsets of neurons and proximal dendrites during brain maturation, regulate synaptic transmission and plasticity. Methods Ten genes of importance for HNK-1 biosynthesis ( B3GAT1 , B3GAT2 , and CHST10 ) or for the formation of perineuronal nets ( TNR , BCAN , NCAN , HAPLN1 , HAPLN2 , HAPLN3 , and HAPLN4 ) were investigated for potential involvement in schizophrenia (SCZ) susceptibility, by genotyping 104 tagSNPs in the Scandinavian Collaboration on Psychiatric Etiology sample (849 cases; 1602 control subjects). Genome-wide association study imputation data from the European SGENE-plus sample (2663 cases; 13,498 control subjects) were used for comparison. The effect of SCZ risk alleles on brain structure was investigated in a Norwegian subset (98 cases; 177 control subjects) with structural magnetic resonance imaging data. Results Five single nucleotide polymorphisms (SNPs), located in two adjacent estimated linkage disequilibrium blocks in the first intron of β-1,3-glucuronyltransferase 2 ( B3GAT2 ), were nominally associated with SCZ (.004 ≤ P empirical ≤ .05). The rs2460691 was significantly associated in the comparison sample and in the meta-analysis after correction for all 121 SNP/haplotype tests ( P raw = 1 × 10 −4 ; P corrected = .018). Increased dosage of the rs2460691 SCZ risk allele was associated with decreased cortical area ( p = .002) but not thickness or hippocampal volume. A second SNP ( r 2 = .24 with rs10945275), which conferred the highest SCZ risk effect in the Norwegian subset, was also associated with cortical area. Conclusions The present results suggest that effects on biosynthesis of the neuronal epitope HNK-1, through common B3GAT2 variation, could increase the risk of SCZ, possibly by decreasing cortical area.