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Background: Schizophrenia is a highly heritable disorder characterized by increased cortical thinning throughout the life span. Studies have reported a shared genetic basis between schizophrenia and cortical thickness. However, no genes whose expression is related to abnormal cortical thinning in schizophrenia have been identified., Methods: We conducted linear mixed models to estimate the rates of accelerated cortical thinning across 68 regions from the Desikan-Killiany atlas in individuals with schizophrenia compared with healthy control participants from a large longitudinal sample (n cases  = 169 and n controls  = 298, ages 16-70 years). We studied the correlation between gene expression data from the Allen Human Brain Atlas and accelerated thinning estimates across cortical regions. Finally, we explored the functional and genetic underpinnings of the genes that contribute most to accelerated thinning., Results: We found a global pattern of accelerated cortical thinning in individuals with schizophrenia compared with healthy control participants. Genes underexpressed in cortical regions that exhibit this accelerated thinning were downregulated in several psychiatric disorders and were enriched for both common and rare disrupting variation for schizophrenia and neurodevelopmental disorders. In contrast, none of these enrichments were observed for baseline cross-sectional cortical thickness differences., Conclusions: Our findings suggest that accelerated cortical thinning, rather than cortical thickness alone, serves as an informative phenotype for neurodevelopmental disruptions in schizophrenia. We highlight the genetic and transcriptomic correlates of this accelerated cortical thinning, emphasizing the need for future longitudinal studies to elucidate the role of genetic variation and the temporal-spatial dynamics of gene expression in brain development and aging in schizophrenia., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Genes that encode synaptic proteins or messenger RNA targets of the RNA-binding protein FMRP (fragile X messenger ribonucleoprotein) have been linked to schizophrenia and autism spectrum disorder (ASD) through the enrichment of genetic variants that confer risk for these disorders. FMRP binds many transcripts with synaptic functions and is thought to regulate their local translation, a process that enables rapid and compartmentalized protein synthesis required for development and plasticity., Methods: We used summary statistics from large-scale genome-wide association studies of schizophrenia (74,776 cases, 101,023 controls) and ASD (18,381 cases, 27,969 controls) to test the hypothesis that the subset of synaptic genes that encode localized transcripts is more strongly associated with each disorder than nonlocalized transcripts. We also postulated that this subset of synaptic genes is responsible for associations attributed to FMRP targets., Results: Schizophrenia associations were enriched in genes encoding localized synaptic transcripts compared to the remaining synaptic genes or to the remaining localized transcripts; this also applied to ASD associations, although only for transcripts observed after stimulation by fear conditioning. The genetic associations with either disorder captured by these gene sets were independent of those derived from FMRP targets. Schizophrenia association was related to FMRP interactions with messenger RNAs in somata, but not in dendrites, while ASD association was related to FMRP binding in either compartment., Conclusions: Our data suggest that synaptic transcripts capable of local translation are particularly relevant to the pathogenesis of schizophrenia and ASD, but they do not characterize the associations attributed to current sets of FMRP targets., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Clozapine is the only licensed medication for treatment-resistant schizophrenia (TRS). Few predictors for variation in response to clozapine have been identified, but clozapine metabolism is known to influence therapeutic response and adverse side effects. Here, we expand on genome-wide studies of clozapine metabolism, previously focused on common genetic variation, by analysing whole-exome sequencing data from 2062 individuals with schizophrenia taking clozapine in the UK. We investigated whether rare genomic variation in genes and gene sets involved in the clozapine metabolism pathway influences plasma concentrations of clozapine metabolites, assessed through the longitudinal analysis of 6585 pharmacokinetic assays. We observed a statistically significant association between the burden of rare damaging coding variants (MAF ≤ 1 %) in gene sets broadly related to drug pharmacokinetics and lower clozapine (β = -0.054, SE = 0.019, P-value = 0.005) concentrations in plasma. We estimate that the effects in clozapine plasma concentrations of a single damaging allele in this gene set are akin to reducing the clozapine dose by about 35 mg/day. The gene-based analysis identified rare variants in CYP1A2, which encodes the enzyme responsible for converting clozapine to norclozapine, as having the strongest effects of any gene on clozapine metabolism (β = 0.324, SE = 0.124, P = 0.009). Our findings support the hypothesis that rare genetic variants in known drug-metabolising enzymes and transporters can markedly influence clozapine plasma concentrations; these results suggest that pharmacogenomic efforts trying to predict clozapine metabolism and personalise drug therapy could benefit from the inclusion of rare damaging variants in pharmacogenes beyond those already identified and catalogued as PGx star alleles., Competing Interests: Declaration of competing interest AK is a full-time employee of Magna Laboratories Ltd. MH and JJ are full-time employees of Leyden Delta B.V. MJO, MCOD, and JTRW are supported by a collaborative research grant from Takeda Pharmaceuticals Ltd. for a project unrelated to the work presented here. ER, AFP, MJO, MCOD, and JTRW also reported receiving grants from Akrivia Health for a project unrelated to this submission. Takeda and Akrivia played no part in this study's conception, design, implementation, or interpretation., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Precision medicine has the ambition to improve treatment response and clinical outcomes through patient stratification and holds great potential for the treatment of mental disorders. However, several important factors are needed to transform current practice into a precision psychiatry framework. Most important are 1) the generation of accessible large real-world training and test data including genomic data integrated from multiple sources, 2) the development and validation of advanced analytical tools for stratification and prediction, and 3) the development of clinically useful management platforms for patient monitoring that can be integrated into health care systems in real-life settings. This narrative review summarizes strategies for obtaining the key elements-well-powered samples from large biobanks integrated with electronic health records and health registry data using novel artificial intelligence algorithms-to predict outcomes in severe mental disorders and translate these models into clinical management and treatment approaches. Key elements are massive mental health data and novel artificial intelligence algorithms. For the clinical translation of these strategies, we discuss a precision medicine platform for improved management of mental disorders. We use cases to illustrate how precision medicine interventions could be brought into psychiatry to improve the clinical outcomes of mental disorders., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Schizophrenia (SCZ) is caused by an interplay of polygenic risk and environmental factors, which may alter regulators of gene expression leading to pathogenic misexpression of SCZ risk genes. The CPEB family of RNA-binding proteins (CPEB1-4) regulates translation of target RNAs (approximately 40% of overall genes). We previously identified CPEB4 as a key dysregulated translational regulator in autism spectrum disorder (ASD) because its neuronal-specific microexon (exon 4) is mis-spliced in ASD brains, causing underexpression of numerous ASD risk genes. The genetic factors and pathogenic mechanisms shared between SCZ and ASD led us to hypothesize CPEB4 mis-splicing in SCZ leading to underexpression of multiple SCZ-related genes., Methods: We performed MAGMA-enrichment analysis on Psychiatric Genomics Consortium genome-wide association study data and analyzed RNA sequencing data from the PsychENCODE Consortium. Reverse transcriptase polymerase chain reaction and Western blot were performed on postmortem brain tissue, and the presence/absence of antipsychotics was assessed through toxicological analysis. Finally, mice with mild overexpression of exon 4-lacking CPEB4 (CPEB4Δ4) were generated and analyzed biochemically and behaviorally., Results: First, we found enrichment of SCZ-associated genes for CPEB4-binder transcripts. We also found decreased usage of CPEB4 microexon in SCZ probands, which was correlated with decreased protein levels of CPEB4-target SCZ-associated genes only in antipsychotic-free individuals. Interestingly, differentially expressed genes fit those reported for SCZ, specifically in the SCZ probands with decreased CPEB4-microexon inclusion. Finally, we demonstrated that mice with mild overexpression of CPEB4Δ4 showed decreased protein levels of CPEB4-target SCZ genes and SCZ-linked behaviors., Conclusions: We identified aberrant CPEB4 splicing and downstream misexpression of SCZ risk genes as a novel etiological mechanism in SCZ., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Current definitions and clinical heterogeneity in bipolar disorder are major concerns as they obstruct aetiological research and impede drug development. Therefore, stratification of bipolar disorder is a high priority. To inform stratification, our analysis aimed to examine the patterns and relationships between polygenic liability for bipolar disorder, major depressive disorder (MDD), and schizophrenia with multidimensional symptom representations of bipolar disorder., Methods: In this analysis, data from the UK Bipolar Disorder Research Network (BDRN) were assessed with the Operational Checklist for Psychotic Disorders. Individuals with bipolar disorder as defined in DSM-IV, of European ancestry (self-reported), aged 18 years or older at time of interview, living in the UK, and registered with the BDRN were eligible for inclusion. Psychopathological variables obtained via interview by trained research psychologists or psychiatrists and psychiatric case notes were used to identify statistically distinct symptom dimensions, calibrated with exploratory factor analysis and validated with confirmatory factor analysis (CFA). CFA was extended to include three polygenic risk scores (PRSs) indexing liability for bipolar disorder, MDD, and schizophrenia in a multiple indicator multiple cause (MIMIC) structural equation model to estimate PRS relationships with symptom dimensions., Findings: Of 4198 individuals potentially eligible for inclusion, 4148 (2804 [67·6%] female individuals and 1344 [32·4%] male individuals) with a mean age at interview of 45 years (SD 12·03) were available for analysis. Three reliable dimensions (mania, depression, and psychosis) were identified. The MIMIC model fitted the data well (root mean square error of approximation 0·021, 90% CI 0·019-0·023; comparative fit index 0·99) and suggests statistically distinct symptom dimensions also have distinct polygenic profiles. The PRS for MDD was strongly associated with the depression dimension (standardised β 0·125, 95% CI 0·080-0·171) and the PRS for schizophrenia was strongly associated with the psychosis dimension (0·108, 0·082-0·175). For the mania dimension, the PRS for bipolar disorder was weakly associated (0·050, 0·002-0·097)., Interpretation: Our findings support the hypothesis that genetic heterogeneity underpins clinical heterogeneity, suggesting that different symptom dimensions within bipolar disorder have partly distinct causes. Furthermore, our results suggest that a specific symptom dimension has a similar cause regardless of the primary psychiatric diagnosis, supporting the use of symptom dimensions in precision psychiatry., Funding: Wellcome Trust and UK Medical Research Council., Competing Interests: Declaration of interests We declare no competing interests., (Crown Copyright © 2023 Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

Background: The antipsychotic, clozapine, is the only licensed drug against the treatment-resistant symptoms that affect 20-30% of people with schizophrenia. Clozapine is markedly underprescribed, partly because of concerns about its narrow therapeutic range and adverse drug reaction profile. Both concerns are linked to drug metabolism, which varies across populations globally and is partly genetically determined. Our study aimed to use a cross-ancestry genome-wide association study (GWAS) design to investigate variations in clozapine metabolism within and between genetically inferred ancestral backgrounds, to discover genomic associations to clozapine plasma concentrations, and to assess the effects of pharmacogenomic predictors across different ancestries., Methods: In this GWAS, we analysed data from the UK Zaponex Treatment Access System clozapine monitoring service as part of the CLOZUK study. We included all available individuals with clozapine pharmacokinetic assays requested by their clinicians. We excluded people younger than 18 years, or whose records contained clerical errors, or with blood drawn 6-24 h after dose, a clozapine or norclozapine concentration less than 50 ng/mL, a clozapine concentration of more than 2000 ng/mL, a clozapine-to-norclozapine ratio outside of the 0·5-3·0 interval, or a clozapine dose of more than 900 mg/day. Using genomic information, we identified five biogeographical ancestries: European, sub-Saharan African, north African, southwest Asian, and east Asian. We did pharmacokinetic modelling, a GWAS, and a polygenic risk score association analysis using longitudinal regression analysis with three primary outcome variables: two metabolite plasma concentrations (clozapine and norclozapine) and the clozapine-to-norclozapine ratio., Findings: 19 096 pharmacokinetic assays were available for 4760 individuals in the CLOZUK study. After data quality control, 4495 individuals (3268 [72·7%] male and 1227 [27·3%] female; mean age 42·19 years [range 18-85]) linked to 16 068 assays were included in this study. We found a faster average clozapine metabolism in people of sub-Saharan African ancestry than in those of European ancestry. By contrast, individuals with east Asian or southwest Asian ancestry were more likely to be slow clozapine metabolisers than those with European ancestry. Eight pharmacogenomic loci were identified in the GWAS, seven with significant effects in non-European groups. Polygenic scores generated from these loci were associated with clozapine outcome variables in the whole sample and within individual ancestries; the maximum variance explained was 7·26% for the metabolic ratio., Interpretation: Longitudinal cross-ancestry GWAS can discover pharmacogenomic markers of clozapine metabolism that, individually or as polygenic scores, have consistent effects across ancestries. Our findings suggest that ancestral differences in clozapine metabolism could be considered for optimising clozapine prescription protocols for diverse populations., Funding: UK Academy of Medical Sciences, UK Medical Research Council, and European Commission., Competing Interests: Declaration of interests AK is a full-time employee of Magna Laboratories. MH and JJ are full-time employees of Leyden Delta. MJO, MCOD, and JTRW are supported by a collaborative research grant from Takeda Pharmaceuticals outside the submitted work. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: While a variety of evidence supports a prenatal component in schizophrenia, there are few data regarding the cell populations involved. We sought to identify cells of the human prenatal brain mediating genetic risk for schizophrenia by integrating cell-specific gene expression measures generated through single-nuclei RNA sequencing with recent large-scale genome-wide association study (GWAS) and exome sequencing data for the condition., Methods: Single-nuclei RNA sequencing was performed on 5 brain regions (frontal cortex, ganglionic eminence, hippocampus, thalamus, and cerebellum) from 3 fetuses from the second trimester of gestation. Enrichment of schizophrenia common variant genetic liability and rare damaging coding variation was assessed in relation to gene expression specificity within each identified cell population., Results: Common risk variants were prominently enriched within genes with high expression specificity for developing neuron populations within the frontal cortex, ganglionic eminence, and hippocampus. Enrichments were largely independent of genes expressed in neuronal populations of the adult brain that have been implicated in schizophrenia through the same methods. Genes containing an excess of rare damaging variants in schizophrenia had higher expression specificity for developing glutamatergic neurons of the frontal cortex and hippocampus that were also enriched for common variant liability., Conclusions: We found evidence for a distinct contribution of prenatal neuronal development to genetic risk for schizophrenia, involving specific populations of developing neurons within the second-trimester fetal brain. Our study significantly advances the understanding of the neurodevelopmental origins of schizophrenia and provides a resource with which to investigate the prenatal antecedents of other psychiatric and neurologic disorders., (Copyright © 2022 Society of Biological Psychiatry. All rights reserved.)

Background: Treatment-resistant schizophrenia affects approximately 30% of individuals with the disorder. Clozapine is the medication of choice in treatment-resistant schizophrenia, but optimizing administration and dose titration is complex. The identification of factors influencing clozapine prescription and response, including genetics, is of interest in a precision psychiatry framework., Methods: We used linear regression models accounting for demographic, pharmacological, and clinical covariates to determine whether a polygenic risk score (PRS) for schizophrenia would be associated with the highest dose recorded during clozapine treatment. Analyses were performed across 2 independent multiancestry samples of individuals from a UK patient monitoring system, CLOZUK2 (n = 3133) and CLOZUK3 (n = 909), and a European sample from a Norwegian therapeutic drug monitoring service (n = 417). In a secondary analysis merging both UK cohorts, logistic regression models were used to estimate the relationship between schizophrenia PRSs and clozapine doses classified as low, standard, or high., Results: After controlling for relevant covariates, the schizophrenia PRS was correlated with the highest clozapine dose on record for each individual across all samples: CLOZUK2 (β = 12.22, SE = 3.78, p = .001), CLOZUK3 (β = 12.73, SE = 5.99, p = .034), and the Norwegian cohort (β = 46.45, SE = 18.83, p = .014). In a secondary analysis, the schizophrenia PRS was associated with taking clozapine doses >600 mg/day (odds ratio = 1.279, p = .006)., Conclusions: The schizophrenia PRS was associated with the highest clozapine dose prescribed for an individual in records from 3 independent samples, suggesting that the genetic liability for schizophrenia might index factors associated with therapeutic decisions in cohorts of patients with treatment-resistant schizophrenia., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Attention-deficit/hyperactivity disorder (ADHD) is highly heritable, but little is known about the relative effects of transmitted (i.e., direct) and nontransmitted (i.e., indirect) common variant risks. Using parent-offspring trios, we tested whether polygenic liability for neurodevelopmental and psychiatric disorders and lower cognitive ability is overtransmitted to ADHD probands. We also tested for indirect or genetic nurture effects by examining whether nontransmitted ADHD polygenic liability is elevated. Finally, we examined whether complete trios are representative of the clinical ADHD population., Methods: Polygenic risk scores (PRSs) for ADHD, anxiety, autism, bipolar disorder, depression, obsessive-compulsive disorder, schizophrenia, Tourette syndrome, and cognitive ability were calculated in UK control subjects (n = 5081), UK probands with ADHD (n = 857), their biological parents (n = 328 trios), and also a replication sample of 844 ADHD trios., Results: ADHD PRSs were overtransmitted and cognitive ability and obsessive-compulsive disorder PRSs were undertransmitted. These results were independently replicated. Overtransmission of polygenic liability was not observed for other disorders. Nontransmitted alleles were not enriched for ADHD liability compared with control subjects. Probands from incomplete trios had more hyperactive-impulsive and conduct disorder symptoms, lower IQ, and lower socioeconomic status than complete trios. PRS did not vary by trio status., Conclusions: The results support direct transmission of polygenic liability for ADHD and cognitive ability from parents to offspring, but not for other neurodevelopmental/psychiatric disorders. They also suggest that nontransmitted neurodevelopmental/psychiatric parental alleles do not contribute indirectly to ADHD via genetic nurture. Furthermore, ascertainment of complete ADHD trios may be nonrandom, in terms of demographic and clinical factors., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders., Methods: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors., Results: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged., Conclusions: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

Background: For more than 150 years, controversy over the status of post-partum psychosis has hindered research and caused considerable confusion for clinicians and women, with potentially negative consequences. We aimed to explore the hypothesis that genetic vulnerability differs between women with first-onset post-partum psychosis and those with bipolar disorder more generally., Methods: In this case-control study on first-onset post-partum psychosis and bipolar disorder in the UK, we included 203 women with first-onset post-partum psychosis (defined as a manic, mixed, or psychotic depression episode within 6 weeks of delivery without a psychiatric history) and 1225 parous women with a history of bipolar disorder. Information on women with bipolar disorder was obtained from the Bipolar Disorder Research Network database, and participants were recruited through screening community mental health teams across the UK and via the media and patient support organisations. All were assessed using a semistructured face-to-face psychiatric interview and psychiatric case note review. 2809 women from the general population were recruited via the national UK Blood Services and the 1958 Birth Cohort (UK National Child Development Study) as controls and matched to cases according to genetic ancestry. All self-reported their ethnicity as White and were recruited from across the UK. Polygenic risk scores (PRSs) were generated from discovery genome-wide association studies of schizophrenia, bipolar disorder, and major depression. Logistic regression was used to model the effect of each PRS on diagnosis, and the RRs and ORs presented were adjusted for ten principal components of genetic variation to account for population stratification., Findings: 203 women with first-onset post-partum psychosis (median age at interview: 46 years [IQR 37-55]) and 1225 women with bipolar disorder (49 years [41-58]) were recruited between September, 1991, and May, 2013, as well as 2809 controls. Women with first-onset post-partum psychosis had similar bipolar disorder and schizophrenia PRSs to women with bipolar disorder, which were significantly higher than those of controls. When compared with controls, women with first-onset post-partum psychosis had an adjusted relative risk ratio (RR) for bipolar disorder PRSs of 1·71 (95% CI 1·56-1·86, p<0·0001) and for schizophrenia PRSs of 1·82 (1·66-1·97, p<0·0001). The effect sizes were similar when comparing women with bipolar disorder to controls (adjusted RR 1·77 [1·69-1·84], p<0·0001 for bipolar disorder PRSs; 2·00 (1·92-2·08), p<0·0001 for schizophrenia PRSs). Although women with bipolar disorder also had higher major depression PRSs than did controls (1·24 [1·17-1·31], p<0·0001), women with first-onset post-partum psychosis did not differ from controls in their polygenic liability to major depression (0·97 (0·82-1·11), p=0·63)., Interpretation: Our study supports the recognition of first-onset post-partum psychosis as a separate nosological entity within the bipolar disorder spectrum both in research and clinical settings., Funding: Wellcome Trust and Medical Research Council., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Recent breakthroughs in psychiatric genetics have implicated biological pathways onto which genetic risk for psychiatric disorders converges. However, these studies do not reveal the developmental time point(s) at which these pathways are relevant., Methods: We aimed to determine the relationship between psychiatric risk and developmental gene expression relating to discrete biological pathways. We used postmortem RNA sequencing data (BrainSeq and BrainSpan) from brain tissue at multiple prenatal and postnatal time points, with summary statistics from recent genome-wide association studies of schizophrenia, bipolar disorder, and major depressive disorder. We prioritized gene sets for overall enrichment of association with each disorder and then tested the relationship between the association of their constituent genes with their relative expression at each developmental stage., Results: We observed relationships between the expression of genes involved in voltage-gated cation channel activity during early midfetal, adolescence, and early adulthood time points and association with schizophrenia and bipolar disorder, such that genes more strongly associated with these disorders had relatively low expression during early midfetal development and higher expression during adolescence and early adulthood. The relationship with schizophrenia was strongest for the subset of genes related to calcium channel activity, while for bipolar disorder, the relationship was distributed between calcium and potassium channel activity genes., Conclusions: Our results indicate periods during development when biological pathways related to the activity of calcium and potassium channels may be most vulnerable to the effects of genetic variants conferring risk for psychiatric disorders. Furthermore, they indicate key time points and potential targets for disorder-specific therapeutic interventions., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Cognitive impairment in schizophrenia is a major contributor to poor outcomes, yet its causes are poorly understood. Some rare copy number variants (CNVs) are associated with schizophrenia risk and affect cognition in healthy populations, but their contribution to cognitive impairment in schizophrenia has not been investigated. We examined the effect of 12 schizophrenia CNVs on cognition in those with schizophrenia., Methods: General cognitive ability was measured using the Measurement and Treatment Research to Improve Cognition in Schizophrenia composite z score in 875 patients with schizophrenia and in a replication sample of 519 patients with schizophrenia using Wechsler Adult Intelligence Scale Full Scale IQ. Using linear regression, we tested for association between cognition and schizophrenia CNV status, covarying for age and sex. In addition, we tested whether CNVs hitting genes in schizophrenia-enriched gene sets (loss-of-function intolerant and synaptic gene sets) were associated with cognitive impairment., Results: A total of 23 schizophrenia CNV carriers were identified. Schizophrenia CNV carriers had lower general cognitive ability than nonschizophrenia CNV carriers in discovery (β = -0.66, 95% confidence interval [CI] = -1.31 to -0.01) and replication samples (β = -0.91, 95% CI = -1.71 to -0.11) and after meta-analysis (β = -0.76, 95% CI = -1.26 to -0.25, p = .003). CNVs hitting loss-of-function intolerant genes were associated with lower cognition (β = -0.15, 95% CI = -0.29 to -0.001, p = .048)., Conclusions: In those with schizophrenia, cognitive ability in schizophrenia CNV carriers is 0.5-1.0 standard deviations below non-CNV carriers, which may have implications for clinical assessment and management. We also demonstrate that rare CNVs hitting genes intolerant to loss-of-function variation lead to more severe cognitive impairment, above and beyond the effect of known schizophrenia CNVs., (Copyright © 2021. Published by Elsevier Inc.)

Background: Parkinson's disease (PD) and schizophrenia (SCZ) are heritable brain disorders that involve dysregulation of the dopaminergic system. Epidemiological studies have reported potential comorbidity between the disorders, and movement disturbances are common in patients with SCZ before treatment with antipsychotic drugs. Despite this, little is known about shared genetic etiology between the disorders., Methods: We analyzed recent large genome-wide association studies on patients with SCZ (N = 77,096) and PD (N = 417,508) using a conditional/conjunctional false discovery rate (FDR) approach to evaluate overlap in common genetic variants and improve statistical power for genetic discovery. Using a variety of biological resources, we functionally characterized the identified genomic loci., Results: We observed genetic enrichment in PD conditional on associations with SCZ and vice versa, indicating polygenic overlap. We then leveraged this cross-trait enrichment using conditional FDR analysis and identified 9 novel PD risk loci and 1 novel SCZ locus at conditional FDR < .01. Furthermore, we identified 9 genomic loci jointly associated with PD and SCZ at conjunctional FDR < .05. There was an even distribution of antagonistic and agonistic effect directions among the shared loci, in line with the insignificant genetic correlation between the disorders. Of 67 genes mapped to the shared loci, 65 are expressed in the human brain and show cell type-specific expression profiles., Conclusions: Altogether, the study increases understanding of the genetic architectures underlying SCZ and PD, indicating that common molecular genetic mechanisms may contribute to overlapping pathophysiological and clinical features between the disorders., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Diffusion exchange spectroscopy (DEXSY) provides a means to isolate the signal attenuation associated with exchange from other sources of signal loss. With the total diffusion weighting b 1 +b 2 =b s held constant, DEXSY signals acquired with b 1 =0 or b 2 =0 have no exchange weighting, while a DEXSY signal acquired with b 1 =b 2 has maximal exchange weighting. The exchange rate can be estimated by fitting a diffusion exchange model to signals acquired with variable mixing times. Conventionally, acquired signals are normalized by a signal with b 1 =0 and b 2 =0 to remove the decay due to spin-lattice relaxation. Instead, division by a signal with equal b s but b 1 =0 or b 2 =0 reduces spin-lattice relaxation weighting of the apparent exchange rate (AXR). Furthermore, apparent diffusion-weighted R 1 relaxation rates can be estimated from non-exchange-weighted DEXSY signals. Estimated R 1 values are utilized to remove signal decay due to spin-lattice relaxation from exchange-weighted signals, permitting a more precise estimate of AXR with less data. Data reduction methods are proposed and tested with regards to statistical accuracy and precision of AXR estimates on simulated and experimental data. Simulations show that the methods are capable of accurately measuring the ground-truth exchange rate. The methods remain accurate even when the assumption that DEXSY signals attenuate with b is violated, as occurs for restricted diffusion. Experimental data was collected from fixed neonatal mouse spinal cord samples at 25 and 7°C using the strong static magnetic field gradient produced by a single-sided permanent magnet (i.e., an NMR MOUSE). The most rapid method for exchange measurements requires only five data points (an 80 s experiment as implemented) and achieves a similar level of accuracy and precision to the baseline method using 44 data points. This represents a significant improvement in acquisition speed, overcoming a barrier which has limited the use of DEXSY on living specimen., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Background: Genetic studies of schizophrenia have implicated numerous risk loci including several copy number variants (CNVs) of large effect and hundreds of loci of small effect. In only a few cases has a specific gene been clearly identified. Rare CNVs affecting a single gene offer a potential avenue to discovering schizophrenia risk genes., Methods: CNVs were generated from exome sequencing of 4913 schizophrenia cases and 6188 control subjects from Sweden. We integrated two CNV calling methods (XHMM and ExomeDepth) to expand our set of single-gene CNVs and leveraged two different approaches for validating these variants (quantitative polymerase chain reaction and NanoString)., Results: We found a significant excess of all rare CNVs (deletions: p = .0004, duplications: p = .0006) and single-gene CNVs (deletions: p = .04, duplications: p = .03) in schizophrenia cases compared with control subjects. An expanded set of CNVs generated from integrating multiple approaches showed a significant burden of deletions in 11 of 21 gene sets previously implicated in schizophrenia and across all genes in those sets (p = .008), although no tests survived correction. We performed an extensive validation of all deletions in the significant set of voltage-gated calcium channels among CNVs called from both exome sequencing and genotyping arrays. In total, 4 exonic, single-gene deletions were validated in schizophrenia cases and none in control subjects (p = .039), of which all were identified by exome sequencing., Conclusions: These results point to the potential contribution of single-gene CNVs to schizophrenia, indicate that the utility of exome sequencing for CNV calling has yet to be maximized, and note that single-gene CNVs should be included in gene-focused studies using other classes of variation., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: A recent genome-wide association study (GWAS) of autism spectrum disorder (ASD) (n cases  = 18,381, n controls  = 27,969) has provided novel opportunities for investigating the etiology of ASD. Here, we integrate the ASD GWAS summary statistics with summary-level gene expression data to infer differential gene expression in ASD, an approach called transcriptome-wide association study (TWAS)., Methods: Using FUSION software, ASD GWAS summary statistics were integrated with predictors of gene expression from 16 human datasets, including adult and fetal brains. A novel adaptation of established statistical methods was then used to test for enrichment within candidate pathways and specific tissues and at different stages of brain development. The proportion of ASD heritability explained by predicted expression of genes in the TWAS was estimated using stratified linkage disequilibrium score regression., Results: This study identified 14 genes as significantly differentially expressed in ASD, 13 of which were outside of known genome-wide significant loci (±500 kb). XRN2, a gene proximal to an ASD GWAS locus, was inferred to be significantly upregulated in ASD, providing insight into the functional consequence of this associated locus. One novel transcriptome-wide significant association from this study is the downregulation of PDIA6, which showed minimal evidence of association in the GWAS, and in gene-based analysis using MAGMA. Predicted gene expression in this study accounted for 13.0% of the total ASD single nucleotide polymorphism heritability., Conclusions: This study has implicated several genes as significantly up/downregulated in ASD, providing novel and useful information for subsequent functional studies. This study also explores the utility of TWAS-based enrichment analysis and compares TWAS results with a functionally agnostic approach., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Sequencing studies have pointed to the involvement in schizophrenia of rare coding variants in neuronally expressed genes, including activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-D-aspartate receptor (NMDAR) complexes; however, larger samples are required to reveal novel genes and specific biological mechanisms., Methods: We sequenced 187 genes, selected for prior evidence of association with schizophrenia, in a new dataset of 5207 cases and 4991 controls. Included among these genes were members of ARC and NMDAR postsynaptic protein complexes, as well as voltage-gated sodium and calcium channels. We performed a rare variant meta-analysis with published sequencing data for a total of 11,319 cases, 15,854 controls, and 1136 trios., Results: While no individual gene was significantly associated with schizophrenia after genome-wide correction for multiple testing, we strengthen the evidence that rare exonic variants in the ARC (p = 4.0 × 10 -4 ) and NMDAR (p = 1.7 × 10 -5 ) synaptic complexes are risk factors for schizophrenia. In addition, we found that loss-of-function variants and missense variants at paralog-conserved sites were enriched in voltage-gated sodium channels, particularly the alpha subunits (p = 8.6 × 10 -4 )., Conclusions: In one of the largest sequencing studies of schizophrenia to date, we provide novel evidence that multiple voltage-gated sodium channels are involved in schizophrenia pathogenesis and confirm the involvement of ARC and NMDAR postsynaptic complexes., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Cytochrome (CYP) P450 enzymes have a primary role in antidepressant metabolism and variants in these polymorphic genes are targets for pharmacogenetic investigation. This is the first meta-analysis to investigate how CYP2C19 polymorphisms predict citalopram/escitalopram efficacy and side effects. CYP2C19 metabolic phenotypes comprise poor metabolizers (PM), intermediate and intermediate+ metabolizers (IM; IM+), extensive and extensive+ metabolizers (EM [wild type]; EM+) and ultra-rapid metabolizers (UM) defined by the two most common CYP2C19 functional polymorphisms (rs4244285 and rs12248560) in Caucasians. These polymorphisms were genotyped or imputed from genome-wide data in four samples treated with citalopram or escitalopram (GENDEP, STAR*D, GenPod, PGRN-AMPS). Treatment efficacy was assessed by standardized percentage symptom improvement and by remission. Side effect data were available at weeks 2-4, 6 and 9 in three samples. A fixed-effects meta-analysis was performed using EM as the reference group. Analysis of 2558 patients for efficacy and 2037 patients for side effects showed that PMs had higher symptom improvement (SMD = 0.43, CI = 0.19-0.66) and higher remission rates (OR = 1.55, CI = 1.23-1.96) compared to EMs. At weeks 2-4, PMs showed higher risk of gastro-intestinal (OR = 1.26, CI = 1.08-1.47), neurological (OR = 1.28, CI = 1.07-1.53) and sexual side effects (OR = 1.52, CI = 1.23-1.87; week 6 values were similar). No difference was seen at week 9 or in total side effect burden. PMs did not have higher risk of dropout at week 4 compared to EMs. Antidepressant dose was not different among CYP2C19 groups. CYP2C19 polymorphisms may provide helpful information for guiding citalopram/escitalopram treatment, despite PMs being relatively rare among Caucasians (∼2%)., (Copyright © 2018 Elsevier B.V. and ECNP. All rights reserved.)

Background: Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is two to seven times more common in male individuals than in female individuals. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases., Methods: We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (n = 20,183 cases, n = 35,191 controls) and Swedish population register data (n = 77,905 cases, n = 1,874,637 population controls)., Results: Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with r g estimates close to 1. Analyses of population data, however, indicated that female individuals with ADHD may be at especially high risk for certain comorbid developmental conditions (i.e., autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score analysis did not support a higher burden of ADHD common risk variants in female cases (odds ratio [confidence interval] = 1.02 [0.98-1.06], p = .28). In contrast, epidemiological sibling analyses revealed that the siblings of female individuals with ADHD are at higher familial risk for ADHD than the siblings of affected male individuals (odds ratio [confidence interval] = 1.14 [1.11-1.18], p = 1.5E-15)., Conclusions: Overall, this study supports a greater familial burden of risk in female individuals with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence., (Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder., Methods: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures., Results: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10 -9 ) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10 -9 )., Conclusions: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The UK Biobank is a unique resource for biomedical research, with extensive phenotypic and genetic data on half a million adults from the general population. We aimed to examine the effect of neurodevelopmental copy number variants (CNVs) on the cognitive performance of participants., Methods: We used Affymetrix Power Tools and PennCNV-Affy software to analyze Affymetrix microarrays of the first 152,728 genotyped individuals. We annotated a list of 93 CNVs and compared their frequencies with control datasets. We analyzed the performance on seven cognitive tests of carriers of 12 CNVs associated with schizophrenia (n = 1087) and of carriers of another 41 neurodevelopmental CNVs (n = 484)., Results: The frequencies of the 93 CNVs in the Biobank subjects were remarkably similar to those among 26,628 control subjects from other datasets. Carriers of schizophrenia-associated CNVs and of the group of 41 other neurodevelopmental CNVs had impaired performance on the cognitive tests, with nine of 14 comparisons remaining statistically significant after correction for multiple testing. They also had lower educational and occupational attainment (p values between 10 -7 and 10 -18 ). The deficits in cognitive performance were modest (Z score reductions between 0.01 and 0.51), compared with individuals with schizophrenia in the Biobank (Z score reductions between 0.35 and 0.90)., Conclusions: This is the largest study on the cognitive phenotypes of CNVs to date. Adult carriers of neurodevelopmental CNVs from the general population have significant cognitive deficits. The UK Biobank will allow unprecedented opportunities for analysis of further phenotypic consequences of CNVs., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Schizophrenia typically onsets after puberty but is often preceded by observable childhood neurodevelopmental impairments. Whether these childhood antecedents index genetic liability is unknown. We used polygenic risk scores derived from a patient discovery sample as indicators of the genetic liability of schizophrenia. Our aim was to identify the early childhood manifestations of this liability in a UK population-based cohort., Methods: The study sample was the Avon Longitudinal Study of Parents and Children, a prospective population-based cohort study of 14701 children. Data were primarily analysed with regression-based analyses. Polygenic risk score were generated from a published Psychiatric Genomics Consortium genome-wide association study. Outcomes were childhood (age 4-9 years) dimensional measures in four developmental domains with 12 indicators: cognition and learning, social and communication, emotion and mood regulation, and behaviour (n=5100-6952)., Findings: At age 7-9 years, schizophrenia polygenic risk scores showed associations with lower performance intelligence quotient (β -0·056, OR 1·13 [95% CI 1·04-1·23]), poorer social understanding (β -0·032, OR 1·08 [1·00-1·17]), worse language intelligibility and fluency (β -0·032, OR 1·10 [1·02-1·20]), more irritability (β 0·032, OR 1·07 [1·01-1·14]), and more headstrong behaviour (β 0·031, OR 1·08 [1·02-1·15]). The schizophrenia polygenic risk scores also predicted social and behavioural impairments as early as age 4 years., Interpretation: Childhood cognitive, social, behavioural, and emotional impairments, implicated as antecedents to schizophrenia in high-risk, developmental studies, might represent early manifestations of genetic liability., Funding: Medical Research Council., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Psychotic disorders are currently grouped under broad phenomenological diagnostic rubrics. Researchers hope that progress in identifying aetiological mechanisms will ultimately enable more precise division of heterogeneous diagnoses into specific and valid subgroups. This goal has been an aim of psychiatry since the 19th century, when patients with general paresis were thought to have "insanity" similar to dementia praecox and manic depressive illness. Nowadays, the constructs of organic-induced and substance-induced psychotic disorder show that our diagnostic classification system already reflects, in part, aetiological factors. Most recently, gene copy number variation and autoimmunity have been associated with schizophrenia. We suggest how, on the basis of recent scientific advances, we can progress the identification of further putative subgroups and make the most of currently available interventions. Prompt diagnosis and treatment, and a more routine search for causes, could preserve function and improve outcome, and therefore be more acceptable to patients and carers., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Psychosis has been recognised as an abnormal state in need of care throughout history and by diverse cultures. Present classifications of psychotic disorder remain based on the presence of specific psychotic symptoms, relative to affective and other symptoms, and their sequence and duration. Although extant diagnostic classifications have restricted validity, they have proven reliability and most clinicians and some patients find them useful. Moreover, these classifications have yet to be replaced by anything better. We propose that an expansion of the subgrouping approach inherent to classification will provide incremental improvement to present diagnostic constructs-as has worked in the rest of medicine. We also propose that subgroups could be created both within and across present diagnostic classifications, taking into consideration the potential value of continuous measures (eg, duration of psychotic symptoms and intelligence quotient). Health-care workers also need to work with service users and carers to develop and adapt approaches to diagnosis that are seen as helpful., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

As a part of the Japanese Center for the Validation of Alternative Methods (JaCVAM)-initiative international validation study of the in vivo rat alkaline comet assay, 4,4'-diaminodiphenyl ether (DPE), a known rodent genotoxic carcinogen, was tested in this laboratory. Sprague Dawley rats (7-9 weeks of age) were given three oral doses of DPE, 24 and 21 h apart and liver or stomach sampled 3h after the final dose. Under the conditions of the test, no increases in DNA damage in liver and stomach were observed with DPE (up to 200 mg/kg/day). A dose-dependent decrease in DNA migration, compared to vehicle controls, was noted for DPE in rat stomach. Further analysis is required to elucidate fully whether this decrease is a consequence of the mode of action or due to the toxicity of DPE. What is perhaps surprising is the inability of the comet assay to detect a known rat genotoxic carcinogen in liver. Further investigation is needed to clarify whether this apparent lack of response results from limited tissue exposure or metabolic differences between species. This finding highlights a need for careful consideration of study design when evaluating assay performance as a measure of in vivo genotoxicity., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: Twin studies and genome-wide complex trait analysis (GCTA) are not in agreement regarding heritability estimates for behavioral traits in children from the general population. This has sparked a debate on the possible difference in genetic architecture between behavioral traits and psychiatric disorders. In this study, we test whether polygenic risk scores associated with variation in attention-deficit/hyperactivity disorder (ADHD) trait levels in children from the general population predict ADHD diagnostic status and severity in an independent clinical sample., Method: Single nucleotide polymorphisms (SNPs) with p < .5 from a genome-wide association study of ADHD traits in 4,546 children (mean age, 7 years 7 months) from the Avon Longitudinal Study of Parents and Children (ALSPAC; general population sample) were selected to calculate polygenic risk scores in 508 children with an ADHD diagnosis (independent clinical sample) and 5,081 control participants. Polygenic scores were tested for association with case-control status and severity of disorder in the clinical sample., Results: Increased polygenic score for ADHD traits predicted ADHD case-control status (odds ratio = 1.17 [95% CI = 1.08-1.28], p = .0003), higher ADHD symptom severity (β = 0.29 [95% CI = 0.04-0.54], p = 0.02), and symptom domain severity in the clinical sample., Conclusion: This study highlights the relevance of additive genetic variance in ADHD, and provides evidence that shared genetic factors contribute to both behavioral traits in the general population and psychiatric disorders at least in the case of ADHD., (Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Polygenic risk scores, based on risk variants identified in genome-wide-association-studies (GWAS), explain a considerable portion of the heritability for schizophrenia (SZ) and bipolar disorder (BD). However, little is known about the combined effects of these variants, although polygenic neuroimaging has developed into a powerful tool of translational neuroscience. In this study, we used genome wide significant SZ risk variants to test the predictive capacity of the polygenic model and explored potential associations with white matter volume, a key candidate in imaging phenotype for psychotic disorders. By calculating the combined additive schizophrenia risk of seven SNPs (significant hits from a recent schizophrenia GWAS study), we show that increased additive genetic risk for SZ was associated with reduced white matter volume in a group of participants (n = 94) consisting of healthy individuals, SZ first-degree relatives, SZ patients and BD patients. This effect was also seen in a second independent sample of healthy individuals (n = 89). We suggest that a moderate portion of variance (~4%) of white matter volume can be explained by the seven hits from the recent schizophrenia GWAS. These results provide evidence for associations between cumulative genetic risk for schizophrenia and intermediate neuroimaging phenotypes in models of psychosis. Our work contributes to a growing body of literature suggesting that polygenic risk may help to explain white matter alterations associated with familial risk for psychosis.

Recent large-scale genomic studies have revealed two broad classes of risk alleles for schizophrenia: a polygenic component of risk mediated through multiple common risk variants and rarer more highly penetrant submicroscopic chromosomal deletions and duplications, known as copy number variants. The focus of this review is on the emerging findings from the latter and subsequent exome sequencing data of smaller, deleterious single nucleotide variants and indels. In these studies, schizophrenia patients were found to have enriched de novo mutations in genes belonging to the postsynaptic density at glutamatergic synapses, particularly components of the N-methyl-D-aspartate receptor signaling complex, including the PSD-95 complex, activity-regulated cytoskeleton-associated protein interactors, the fragile X mental retardation protein complex, voltage-gated calcium channels, and genes implicated in actin cytoskeletal dynamics. The convergence of these implicated genes onto a coherent biological pathway at the synapse, with a specific role in plasticity, provides a significant advance in understanding pathogenesis and points to new targets for biological investigation. We consider the implications of these studies in the context of existing genetic data and the potential need to reassess diagnostic boundaries of neuropsychiatric disorders before discussing ways forward for more directed mechanistic studies to develop stratified, novel therapeutic approaches in the future., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Attention-deficit/hyperactivity disorder (ADHD) can be viewed as the extreme end of traits in the general population. Epidemiological and twin studies suggest that ADHD frequently co-occurs with and shares genetic susceptibility with autism spectrum disorder (ASD) and ASD-related traits. The aims of this study were to determine whether a composite of common molecular genetic variants, previously found to be associated with clinically diagnosed ADHD, predicts ADHD and ASD-related traits in the general population., Methods: Polygenic risk scores were calculated in the Avon Longitudinal Study of Parents and Children (ALSPAC) population sample (N = 8229) based on a discovery case-control genome-wide association study of childhood ADHD. Regression analyses were used to assess whether polygenic scores predicted ADHD traits and ASD-related measures (pragmatic language abilities and social cognition) in the ALSPAC sample. Polygenic scores were also compared in boys and girls endorsing any (rating ≥ 1) ADHD item (n = 3623)., Results: Polygenic risk for ADHD showed a positive association with ADHD traits (hyperactive-impulsive, p = .0039; inattentive, p = .037). Polygenic risk for ADHD was also negatively associated with pragmatic language abilities (p = .037) but not with social cognition (p = .43). In children with a rating ≥ 1 for ADHD traits, girls had a higher polygenic score than boys (p = .003)., Conclusions: These findings provide molecular genetic evidence that risk alleles for the categorical disorder of ADHD influence hyperactive-impulsive and attentional traits in the general population. The results further suggest that common genetic variation that contributes to ADHD diagnosis may also influence ASD-related traits, which at their extreme are a characteristic feature of ASD., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often co-occur and share genetic risks. The aim of this analysis was to determine more broadly whether ADHD and ASD share biological underpinnings., Method: We compared copy number variant (CNV) data from 727 children with ADHD and 5,081 population controls to data from 996 individuals with ASD and an independent set of 1,287 controls. Using pathway analyses, we investigated whether CNVs observed in individuals with ADHD have an impact on genes in the same biological pathways as on those observed in individuals with ASD., Results: The results suggest that the biological pathways affected by CNVs in ADHD overlap with those affected by CNVs in ASD more than would be expected by chance. Moreover, this was true even when specific CNV regions common to both disorders were excluded from the analysis. After correction for multiple testing, genes involved in 3 biological processes (nicotinic acetylcholine receptor signalling pathway, cell division, and response to drug) showed significant enrichment for case CNV hits in the combined ADHD and ASD sample., Conclusion: The results of this study indicate the presence of significant overlap of shared biological processes disrupted by large rare CNVs in children with these 2 neurodevelopmental conditions., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Several copy number variants (CNVs) have been implicated as susceptibility factors for schizophrenia (SZ). Some of these same CNVs also increase risk for autism spectrum disorders, suggesting an etiologic overlap between these conditions. Recently, de novo duplications of a region on chromosome 7q11.23 were associated with autism spectrum disorders. The reciprocal deletion of this region causes Williams-Beuren syndrome., Methods: We assayed an Ashkenazi Jewish cohort of 554 SZ cases and 1014 controls for genome-wide CNV. An excess of large rare and de novo CNVs were observed, including a 1.4 Mb duplication on chromosome 7q11.23 identified in two unrelated patients. To test whether this 7q11.23 duplication is also associated with SZ, we obtained data for 14,387 SZ cases and 28,139 controls from seven additional studies with high-resolution genome-wide CNV detection. We performed a meta-analysis, correcting for study population of origin, to assess whether the duplication is associated with SZ., Results: We found duplications at 7q11.23 in 11 of 14,387 SZ cases with only 1 in 28,139 control subjects (unadjusted odds ratio 21.52, 95% confidence interval: 3.13-922.6, p value 5.5 × 10(-5); adjusted odds ratio 10.8, 95% confidence interval: 1.46-79.62, p value .007). Of three SZ duplication carriers with detailed retrospective data, all showed social anxiety and language delay premorbid to SZ onset, consistent with both human studies and animal models of the 7q11.23 duplication., Conclusions: We have identified a new CNV associated with SZ. Reciprocal duplication of the Williams-Beuren syndrome deletion at chromosome 7q11.23 confers an approximately tenfold increase in risk for SZ., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Several recurrent copy number variants (CNVs) have been shown to increase the risk of developing schizophrenia (SCZ), developmental delay (DD), autism spectrum disorders (ASD), and various congenital malformations (CM). Their penetrance for SCZ has been estimated to be modest. However, comparisons between their penetrance for SCZ or DD/ASD/CM, or estimates of the total penetrance for any of these disorders have not yet been made., Methods: We use data from the largest available studies on SCZ and DD/ASD/CM, including a new sample of 6882 cases and 6316 controls, to estimate the frequencies of 70 implicated CNVs in carriers with these disorders, healthy control subjects, and the general population. On the basis of these frequencies, we estimate their penetrance. We also estimate the strength of the selection pressure against CNVs and correlate this against their overall penetrance., Results: The rates of nearly all CNVs are higher in DD/ASD/CM compared with SCZ. The penetrance of CNVs is at least several times higher for the development of a disorder from the group of DD/ASD/CM. The overall penetrance of SCZ-associated CNVs for developing any disorder is high, ranging between 10.6% and 100%., Conclusions: CNVs associated with SCZ have high pathogenicity. The majority of the increased risk conferred by CNVs is toward the development of an earlier-onset disorder, such as DD/ASD/CM, rather than SCZ. The penetrance of CNVs correlates strongly with their selection coefficients. The improved estimates of penetrance will provide crucial information for genetic counselling., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian disorder. Abnormal tau inclusions, in selected regions of the brain, are a hallmark of the disease and the H1 haplotype of MAPT, the gene encoding tau, is the major risk factor in PSP. A 3-repeat and 4-repeat (4R) tau isoform ratio imbalance has been strongly implicated as a cause of disease. Thus, understanding tau isoform regional expression in disease and pathology-free states is crucial to elucidating the mechanisms involved in PSP and other tauopathies. We used a tau isoform-specific fluorescent assay to investigate relative 4R-tau expression in 6 different brain regions in PSP cases and healthy control samples. We identified a marked difference in 4R-tau relative expression, across brain regions and between MAPT haplotypes. Highest 4R-tau expression levels were identified in the globus pallidus compared with pons, cerebellum, and frontal cortex. 4R-tau expression levels were related to the MAPT H1 and H1c haplotypes. Similar regional variation was seen in PSP case and in control samples., (Copyright © 2013 Elsevier Inc. All rights reserved.)

During development of a novel kinase inhibitor for an anti-inflammatory therapy at AstraZeneca UK, the lead compound was found to be potently active in the mouse lymphoma assay (MLA). This was not believed to be due to primary pharmacology because structural alert relationships and a negative Ames test indicated that the compound was unlikely to form DNA adducts. A number of investigations were performed to assess whether mammalian cell genotoxicity was inherent to the chemical series. The in vitro micronucleus assay (MN(vit)) combined with a semi-automated analysis system, was used as a high-throughput screen. A number of additional compounds were selected for testing, all with different substituents around a core isoquinolinone. These modifications did not affect the kinase and non-kinase selectivity of the compounds. Several of these compounds were positive in the MN(vit), however, two compounds were found to be negative and these were also confirmed to be negative in the MLA. It was considered possible that topoisomerase II or off-target kinase inhibition may have been responsible for the observed mammalian cell genotoxicity. The present investigations show how an iterative chemical design, along with genotoxicity screening by use of a semi-automated MN(vit), can identify and remove the genotoxic hazard from pharmaceutical projects at an early stage of development, and produce high-quality molecules suitable for further progression., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: At least 10 large and rare recurrent DNA copy number variants (CNVs) have been identified as risk factors for schizophrenia and other neurodevelopmental disorders. Because such conditions are associated with reduced fecundity, these pathogenic CNVs should be filtered out from the population by selection and must be replenished by de novo events., Methods: To estimate the mutation rate (μ) for these CNVs and the selection pressure (s) against them, we first conducted a literature review on the rate of each of these CNVs in the population and the rate of their de novo occurrence. In each generation, the number of CNVs lost because of reduced fertility must be replenished by the same number of de novo CNVs. Therefore, the observed ratio of de novo versus all (inherited + de novo) CNVs approximates the selection coefficient (s) of that CNV. The mutation rate approximates to μ = s × q, where q is the frequency of the CNV in the population., Results: High selection pressure operates at all these loci (s = .12 - .88), suggesting that following de novo occurrence, each of these CNVs persists in the population in only a few generations. The mutation rate for each CNV is high, affecting between 1:3500 and 1:30,000 individuals. The rarest CNVs have the highest selection coefficients., Conclusions: The CNVs that increase risk to develop schizophrenia are caused by recent de novo mutations and are under strong selection pressure. They persist in the population because of high mutation rates., (2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Boronic acids and their esters are important building blocks in organic syntheses including those for drug substances and for which, as far as it can be determined, there are no published reports of testing for genotoxicity. A number of boronic acids have now been tested in this laboratory using Salmonella typhimurium strains TA1535, TA1537, TA98 and TA100 and Escherichia coli strain WP2uvrA(pKM101). Twelve of the 13 structures presented here were found to be mutagenic. All the compounds except one were active only in TA100 and/or WP2uvrA(pKM101), did not require S9 activation and produced relatively weak responses, i.e. no more than seven times the concurrent solvent-control values at >1000μg/plate. The single exception was also weakly mutagenic for TA1537 in the presence of S9. Results with two compounds mutagenic for both TA100 and WP2uvrA(pKM101) showed no evidence of DNA-adduct formation detectable by (32)P-postlabelling. It appears that boronic acids represent a novel class of bacterial mutagen that may not act by direct covalent binding to DNA. However, their mechanism of action remains to be elucidated and it cannot yet be determined whether or not they present a real genotoxic hazard., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Given that genome-wide association studies (GWAS) of psychiatric disorders have identified only a small number of convincingly associated variants (single nucleotide polymorphism [SNP]), there is interest in seeking additional evidence for associated variants with tests of gene-gene interaction. Comprehensive pair-wise single SNP-SNP interaction analysis is computationally intensive, and the penalty for multiple testing is severe, given the number of interactions possible. Aiming to minimize these statistical and computational burdens, we have explored approaches to prioritize SNPs for interaction analyses., Methods: Primary interaction analyses were performed with the Wellcome Trust Case-Control Consortium bipolar disorder GWAS (1868 cases, 2938 control subjects). Replication analyses were performed with the Genetic Association Information Network bipolar disorder dataset (1001 cases, 1033 control subjects). The SNPs were prioritized for interaction analysis that showed evidence for association that surpassed a number of nominally significant thresholds, are within genome-wide significant genes, or are within genes that are functionally related., Results: For no set of prioritized SNPs did we obtain evidence to support the hypothesis that the selection strategy identified pairs of variants that were enriched for true (statistical) interactions., Conclusions: The SNPs prioritized according to a number of criteria do not have a raised prior probability for significant interaction that is detectable in samples of this size. We argue that the use of significance levels reflecting only the number of tests performed, as is now widely accepted for single SNP analysis, does not offer an appropriate degree of protection against the potential for GWAS studies to generate an enormous number of false positive interactions., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)