Genetic risk for schizophrenia is associated with increased proportion of indirect connections in brain networks revealed by a semi-metric analysis: evidence from population sample stratified for polygenic risk.

Research studies based on tractography have revealed a prominent reduction of asymmetry in some key white-matter tracts in schizophrenia (SCZ). However, we know little about the influence of common genetic risk factors for SCZ on the efficiency of routing on structural brain networks (SBNs). Here, we use a novel recall-by-genotype approach, where we sample young adults from a population-based cohort (ALSPAC:N genotyped = 8,365) based on their burden of common SCZ risk alleles as defined by polygenic risk score (PRS). We compared 181 individuals at extremes of low (N = 91) or high (N = 90) SCZ-PRS under a robust diffusion MRI-based graph theoretical SBN framework. We applied a semi-metric analysis revealing higher SMR values for the high SCZ-PRS group compared with the low SCZ-PRS group in the left hemisphere. Furthermore, a hemispheric asymmetry index showed a higher leftward preponderance of indirect connections for the high SCZ-PRS group compared with the low SCZ-PRS group (PFDR < 0.05). These findings might indicate less efficient structural connectivity in the higher genetic risk group. This is the first study in a population-based sample that reveals differences in the efficiency of SBNs associated with common genetic risk variants for SCZ.

Genetic covariance components for measures of nitrogen utilization in grazing dairy cows.

Improved nitrogen utilization of dairy production systems should improve not only the economic output of the systems but also the environmental metrics. One strategy to improve efficiency is through breeding programs. Improving a trait through breeding is conditional on the presence of exploitable genetic variability. Using a database of 1,291 deeply phenotyped grazing dairy cows, the genetic variability for 2 definitions of nitrogen utilization was studied: nitrogen use efficiency (i.e., nitrogen output in milk and meat divided by nitrogen available) and nitrogen balance (i.e., nitrogen available less nitrogen output in milk and meat). Variance components for both variables were estimated using animal repeatability linear mixed models. Genetic variability was detected for both nitrogen utilization metrics, even though their heritability estimates were low (<0.10). Validation of genetic evaluations revealed that animals divergent for nitrogen use efficiency or nitrogen balance indeed differed phenotypically, further demonstrating that breeding for improved nitrogen efficiency should result in a shift in the population mean toward better efficiency. Nitrogen use efficiency and nitrogen balance were not genetically correlated with each other (<|0.28|), and neither metric was correlated with milk urea nitrogen (<|0.12|). Nitrogen balance was unfavorably correlated with milk yield, showing the importance of including the nitrogen utilization metrics in a breeding index to improve nitrogen utilization without negatively impacting milk yield. In conclusion, improvement of nitrogen utilization through breeding is possible, even if more nitrogen utilization phenotypic data need to be collected to improve the selection accuracy considering the low heritability estimates.

The dynamic interplay between sleep and mood: an intensive longitudinal study of individuals with bipolar disorder.

BACKGROUND: Sleep disturbances are important symptoms to monitor in people with bipolar disorder (BD) but the precise longitudinal relationships between sleep and mood remain unclear. We aimed to examine associations between stable and dynamic aspects of sleep and mood in people with BD, and assess individual differences in the strength of these associations. METHODS: Participants (N = 649) with BD-I (N = 400) and BD-II (N = 249) provided weekly self-reports of insomnia, depression and (hypo)mania symptoms using the True Colours online monitoring tool for 21 months. Dynamic structural equation models were used to examine the interplay between weekly reports of insomnia and mood. The effects of clinical and demographic characteristics on associations were also assessed. RESULTS: Increased variability in insomnia symptoms was associated with increased mood variability. In the sample as a whole, we found strong evidence of bidirectional relationships between insomnia and depressive symptoms but only weak support for bidirectional relationships between insomnia and (hypo)manic symptoms. We found substantial variability between participants in the strength of prospective associations between insomnia and mood, which depended on age, gender, bipolar subtype, and a history of rapid cycling. CONCLUSIONS: Our results highlight the importance of monitoring sleep in people with BD. However, researchers and clinicians investigating the association between sleep and mood should consider subgroup differences in this relationship. Advances in digital technology mean that intensive longitudinal data on sleep and mood are becoming increasingly available. Novel methods to analyse these data present an exciting opportunity for furthering our understanding of BD.

Cow-level factors associated with nitrogen utilization in grazing dairy cows using a cross-sectional analysis of a large database.

Reducing nitrogen pollution while maintaining milk production is a major challenge of dairy production. One of the keys to delivering on this challenge is to improve the efficiency of how dairy cows use nitrogen. Thus, estimating the nitrogen utilization of lactating grazing dairy cows and exploring the association between animal factors and productivity with nitrogen utilization are the first steps to understanding the nitrogen utilization complex in dairy cows. Nitrogen utilization metrics were derived from milk and body weight records from 1,291 grazing dairy cows of multiple breeds and crossbreeds; all cows had sporadic information on nitrogen intake concurrent with information on nitrogen sinks (and other nitrogen sources, such as body tissue mobilization). Several nitrogen utilization metrics were investigated, including nitrogen use efficiency (nitrogen output as products such as milk and meat divided by nitrogen intake) and nitrogen excreted (nitrogen intake less the nitrogen output as products such as milk and meat). In the present study, a primiparous Holstein-Friesian used, on average, 20.6% of the nitrogen it ate, excreting the surplus as feces and urine, representing 402 g of nitrogen per day. Intercow variability existed, with a between-cow standard deviation of 0.0094 for nitrogen use efficiency and 24 g of nitrogen per day for nitrogen excretion. As lactation progressed, nitrogen use efficiency declined and nitrogen excretion increased. Nevertheless, nitrogen use efficiency improved (i.e., decreased) from first to second parity, even though it did not improve from second to third parity or greater. Furthermore, nitrogen excretion continued to increase from first to third parity or greater. Nitrogen use efficiency and nitrogen excretion were negatively correlated (-0.56 to -0.40), signifying that dairy cows who partition more of the ingested nitrogen into products such as milk and meat, on average, also excrete less nitrogen. Milk urea nitrogen was, at best, weakly correlated with nitrogen use efficiency and nitrogen excretion; the correlations were between -0.01 and 0.06. In conclusion, several cow-level factors such as parity, stage of lactation, and breed were associated with the range of different nitrogen efficiency metrics investigated; moreover, even after accounting for such effects, 4.8% to 6.3% of the remaining variation in the nitrogen use efficiency and nitrogen balance metrics were attributable to intercow differences.

An ethical analysis of divergent clinical approaches to the application of genetic testing for autism and schizophrenia.

Genetic testing to identify genetic syndromes and copy number variants (CNVs) via whole genome platforms such as chromosome microarray (CMA) or exome sequencing (ES) is routinely performed clinically, and is considered by a variety of organizations and societies to be a "first-tier" test for individuals with developmental delay (DD), intellectual disability (ID), or autism spectrum disorder (ASD). However, in the context of schizophrenia, though CNVs can have a large effect on risk, genetic testing is not typically a part of routine clinical care, and no clinical practice guidelines recommend testing. This raises the question of whether CNV testing should be similarly performed for individuals with schizophrenia. Here we consider this proposition in light of the history of genetic testing for ID/DD and ASD, and through the application of an ethical analysis designed to enable robust, accountable and justifiable decision-making. Using a systematic framework and application of relevant bioethical principles (beneficence, non-maleficence, autonomy, and justice), our examination highlights that while CNV testing for the indication of ID has considerable benefits, there is currently insufficient evidence to suggest that overall, the potential harms are outweighed by the potential benefits of CNV testing for the sole indications of schizophrenia or ASD. However, although the application of CNV tests for children with ASD or schizophrenia without ID/DD is, strictly speaking, off-label use, there may be clinical utility and benefits substantive enough to outweigh the harms. Research is needed to clarify the harms and benefits of testing in pediatric and adult contexts. Given that genetic counseling has demonstrated benefits for schizophrenia, and has the potential to mitigate many of the potential harms from genetic testing, any decisions to implement genetic testing for schizophrenia should involve high-quality evidence-based genetic counseling.

Disruption of Long-Term Depression Potentiates Latent Inhibition: Key Role for Central Nucleus of the Amygdala.

BACKGROUND: Latent inhibition (LI) reflects an adaptive form of learning impaired in certain forms of mental illness. Glutamate receptor activity is linked to LI, but the potential role of synaptic plasticity remains unspecified. METHODS: Accordingly, the present study examined the possible role of long-term depression (LTD) in LI induced by prior exposure of rats to an auditory stimulus used subsequently as a conditional stimulus to signal a pending footshock. We employed 2 mechanistically distinct LTD inhibitors, the Tat-GluA23Y peptide that blocks endocytosis of the GluA2-containing glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, or the selective glutamate n-methyl-d-aspartate receptor 2B antagonist, Ro25-6981, administered prior to the acquisition of 2-way conditioned avoidance with or without tone pre-exposure. RESULTS: Systemic LTD blockade with the Tat-GluA23Y peptide strengthened the LI effect by further impairing acquisition of conditioned avoidance in conditional stimulus-preexposed rats compared with normal conditioning in non-preexposed controls. Systemic Ro25-6981 had no significant effects. Brain region-specific microinjections of the Tat-GluA23Y peptide into the nucleus accumbens, medial prefrontal cortex, or central or basolateral amygdala demonstrated that disruption of glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor endocytosis in the central amygdala also potentiated the LI effect. CONCLUSIONS: These data revealed a previously unknown role for central amygdala LTD in LI as a key mediator of cognitive flexibility required to respond to previously irrelevant stimuli that acquire significance through reinforcement. The findings may have relevance both for our mechanistic understanding of LI and its alteration in disease states such as schizophrenia, while further elucidating the role of LTD in learning and memory.

Perceptions of Race and Ancestry in Teaching, Research, and Public Engagement in Biological Anthropology.

The concept of race has a complex history in the field of biological anthropology. Despite increased recognition of the racist origins of the discipline, there remains little agreement about what the concept means, how it is used, or how it is discussed. This study presents the results of a survey of biological anthropologists to investigate the relationship of biological anthropologists with race and ancestry. The survey focuses on the areas of research, public engagement, and teaching as related to these concepts. Results indicate that a large majority of biological anthropologists agree that race (as a social not biological concept) is separate from ancestry. The majority of respondents agreed that ancestry categories should be based on geography (e.g., Asian, European, and African), and more anthropologists thought the terms "Hispanic" and "Latino" were inappropriate ancestry categories. While most respondents felt that discussions of these terms were not matters of "political correctness," nearly a quarter of respondents suggested that concerns over the moral and ethical implications of research (e.g., photos, terminology, and ancestry) result in the silencing of anthropological research. Overwhelmingly, respondents felt that anthropologists have a responsibility to ensure the avoidance of misappropriation of their work by race science and by white nationalists/supremacists. Some differences in survey responses were found relating to respondents' subdiscipline, educational level, location, age, self-identified racial/ethnic categories, and gender. In regard to teaching, survey results indicate that these concepts are minimally covered in university classrooms. When taught, topics focus on the colonialist/racist history of anthropology, the presence of white privilege/supremacy, and racism. Based on the results of this survey, the authors argue for greater public engagement on these concepts, a standardized system of teaching race and ancestry, and a disciplinary conversation about practice and terminology. In this way, biological anthropologists can best place themselves to combat racism in a socially responsible way.

Incorporation of the grazing utilization subindex and new updates to the Pasture Profit Index.

Grazing efficiency has been shown to differ between perennial ryegrass varieties. Such differences affect the utilization of grass within grazing systems, influencing the profitability of grass-based ruminant production systems. The Pasture Profit Index (PPI) is an economic merit grass variety selection tool developed to identify varieties with the greatest economic potential for grass-based dairy production systems. A new grass utilization subindex was developed and incorporated into the PPI to identify varieties with superior grazing efficiency. The subindex rewards varieties with superior grazing efficiency, measured as Residual grazed height, as these varieties allow increased amounts of herbage dry matter to be used by grazing animals. The economic values of all other traits within the PPI were reviewed and updated to ensure that the index was reflective of the current economic scenarios with appropriate assumptions included in the models, thus ensuring that varieties excelling in the agronomic traits with the greatest effect on profitability were recognized. The difference between the highest and lowest performing varieties for the grass utilization trait ranged from €23 to -€24. A range of €211 to €43 was recorded between the highest and lowest ranked varieties within the updated PPI. Spearman's rank correlation between the updated and original PPI lists was 0.96. The introduction of the utilization subindex will allow farmers to make informed variety selection decisions when reseeding pasture, particularly on their grazing platforms and it will allow a demand-based communication process between the farmer and the grass merchant or breeder, ultimately affecting trait selection for future breeding strategies.

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia.

This corrects the article DOI: 10.1038/mp.2016.97.

Observer error and its impact on ancestry estimation using dental morphology.

Dental morphology is becoming increasingly visible in forensic anthropology as part of the estimation of ancestry. As methods are developed based on these data, it is important to understand the role of observer error in data collection and method application. In this study, 10 observers collected dental morphological data on 19 traits on the same set of nine plaques. Various measures of interrater reliability were calculated to assess observer error. Data were then input into one of three ancestry estimation methods based on dental morphology to understand the role of observer error in these methods. Results show low rater reliability for all dental morphological traits when all 10 observers are compared. Rater reliability increases when only experienced observers are compared and traits are dichotomized. Further, differences in trait scores by observers resulted in disparate estimations of ancestry in each of the methods. While observer error appears to be an issue in dental morphological methods of ancestry estimation, these problems can be addressed. An argument is made for advanced training in dental anthropology in laboratories and in graduate programs. Further, methods need to test for and employ traits with high rater agreement.

The Hybrid Electronic Medical Registry Allows Benchmarking of Quality of Trauma Care: A Five-Year Temporal Overview of the Trauma Burden at a Major Trauma Centre in South Africa.

INTRODUCTION: This study is a five-year follow-up of previously published review of the trauma workload at our institution. It aims to provide evidence about the quality of trauma care delivered by a major academic trauma service in South Africa to provide a temporal analysis of trauma trends in the city of Pietermaritzburg. MATERIALS AND METHODS: All trauma patients admitted by the Pietermaritzburg Metropolitan Trauma Service (PMTS) for the period December 2012-April 2018 were retrieved from the Hybrid Electronic Medical Registry (HEMR) for analysis. RESULTS: Over the five-year period, a total of 8722 trauma patients were admitted to Grey's Hospital. There were 7242 (83.0%) males. The average age was 29.66 years. A total of 1719 (19.7%) patients less than 19 years of age, 377 (4.3%) older than 60 years of age and 1480 (17.0%) female patients were admitted following trauma. Table 3 breaks down the mechanism of trauma. A total of 5027 patients sustained blunt trauma (57.6%), and 3334 (38.5%) sustained penetrating trauma. A total of 4808 patients sustained intentional trauma implying that 55.1% of all trauma was secondary to grievous bodily harm or assault either in the form of a stab wound or GSW or of an assault. There was a total of 2232 road traffic-related incidents, of which 37.9% (845) were pedestrian victims. The mortality rate for all trauma admissions was 4.5% (396). Of these 396 deaths, 64 (16.2%) were classified at the morbidity and mortality conference as being avoidable. CONCLUSIONS: The HEMR has allowed us to track the burden of trauma presenting to our institution over a five-year period. This confirms previous studies over shorter time periods from our institution. The pattern of trauma has remained consistent, and the previously described high levels show no sign of decreasing. Interventions to try and reduce this burden are urgently required.

Impact of population-specific dental development on age estimation using dental atlases.

OBJECTIVES: The steady development and subsequent eruption of the dentition is particularly useful for the estimation of age in juveniles. There are few studies that examine and test methods on a population-diverse sample. Our goal is to test the Ubelaker () and London Atlas (2010) dental charts on a sample representing several different population backgrounds to infer if refinement for population-specific standards should be developed. MATERIALS AND METHODS: The first and second authors examined panoramic radiographs of 335 individuals from the James K. Economides Orthodontic Collection blind to chronological age, sex, and ancestry and scored using both dental atlases. RESULTS: The age of Native Americans and African Americans was generally overestimated, suggesting faster rates of development. European Americans and New Mexico Hispanics, while not always showing the highest success rates, generally were closer to the correct age than other ancestry groups. The overall success rate for Ubelaker () was 80.00% for both observers, while the London Atlas was significantly lower at approximately 21.79-23.28%. Accuracy rates did not differ significantly between ancestry groups, though patterns were evident regarding under- or over-estimation of age. DISCUSSION: The present study demonstrates that incorrect age estimations were typically still within 1.5 years of the actual age. Ubelaker () had higher rates of success due to broader age ranges. The results suggest that though accuracy rates did not significantly differ, different developmental rates may affect age estimates and population-specific standards should be considered for known-ancestry individuals, while aging standards constructed from a diverse sample should be utilized for unknown-ancestry cases.

A biomarker panel predicts progression of Barrett's esophagus to esophageal adenocarcinoma.

Progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) is uncommon but the consequences are serious. Predictors of progression are essential to optimize resource utilization. This study assessed the utility of a promising panel of biomarkers applicable to routine paraffin embedded biopsies (FFPE) to predict progression of BE to EAC in a large population-based, nested case-control study.We utilized the Amsterdam-based ReBus nested case-control cohort. BE patients who progressed to high-grade dysplasia (HGD)/EAC (n = 130) and BE patients who never progressed (n = 130) were matched on age, sex, length of the BE segment, and duration of endoscopic surveillance. All progressors had minimum 2 years of endoscopic surveillance without HGD/EAC to exclude prevalent neoplasia. We assessed abnormal DNA content, p53, Cyclin A, and Aspergillus oryzae lectin (AOL) in FFPE sections. We performed conditional logistic regression analysis to estimate odds ratio (OR) of progression based on biomarker status.Expert LGD (OR, 8.3; 95% CI, 1.7-41.0), AOL (3 vs. 0 epithelial compartments abnormal; OR, 3.6; 95% CI, 1.2-10.6) and p53 (OR, 2.3; 95% CI, 1.2-4.6) were independently associated with neoplastic progression. Cyclin A did not predict progression and DNA ploidy analysis by image cytometry was unsuccessful in the majority of cases, both were excluded from the multivariate analysis. The multivariable biomarker model had an area under the receiver operating characteristic curve of 0.73.Expert LGD, AOL, and p53 independently predict neoplastic progression in BE patients and are applicable to routine practice. These biomarkers can aid in selecting patients for endoscopic ablation or more intensive surveillance.

Susceptibility to Spear-Phishing Emails: Effects of Internet User Demographics and Email Content.

Phishing is fundamental to cyber attacks. This research determined the effect of Internet user age and email content such as weapons of influence (persuasive techniques that attackers can use to lure individuals to fall for an attack) and life domains (a specific topic or aspect of an individual's life that attackers can focus an emails on) on spear-phishing (targeted phishing) susceptibility. One-hundred young and 58 older users received, without their knowledge, daily simulated phishing emails over 21 days. A browser plugin recorded their clicking on links in the emails as an indicator of their susceptibility. Forty-three percent of users fell for the simulated phishing emails, with older women showing the highest susceptibility. While susceptibility in young users declined across the study, susceptibility in older users remained stable. The relative effectiveness of the attacks differed by weapons of influence and life domains with age-group variability. In addition, older compared to young users reported lower susceptibility awareness. These findings support effects of Internet user demographics and email content on susceptibility to phishing and emphasize the need for personalization of the next generation of security solutions.

Exome arrays capture polygenic rare variant contributions to schizophrenia.

Schizophrenia is a highly heritable disorder. Genome-wide association studies based largely on common alleles have identified over 100 schizophrenia risk loci, but it is also evident from studies of copy number variants (CNVs) and from exome-sequencing studies that rare alleles are also involved. Full characterization of the contribution of rare alleles to the disorder awaits the deployment of sequencing technology in very large sample sizes, meanwhile, as an interim measure, exome arrays allow rare non-synonymous variants to be sampled at a fraction of the cost. In an analysis of exome array data from 13 688 individuals (5585 cases and 8103 controls) from the UK, we found that rare (minor allele frequency < 0.1%) variant association signal was enriched among genes that map to autosomal loci that are genome-wide significant (GWS) in common variant studies of schizophrenia genome-wide association study (PGWAS = 0.01) as well as gene sets known to be enriched for rare variants in sequencing studies (PRARE = 0.026). We also identified the gene-wise equivalent of GWS support for WDR88 (WD repeat-containing protein 88), a gene of unknown function (P = 6.5 × 10(-7)). Rare alleles represented on exome chip arrays contribute to the genetic architecture of schizophrenia, but as is the case for GWAS, very large studies are required to reveal additional susceptibility alleles for the disorder.

New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation.

Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation. A meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies was performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. Coverage of genetic variants was increased compared with previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation. Standard quality control was applied. Phenotypes were symptom improvement and remission after 12 weeks of antidepressant treatment. Significant findings were investigated in NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication. A total of 7062 950 SNPs were analyzed in GENDEP (n=738) and STAR*D (n=1409). rs116692768 (P=1.80e-08, ITGA9 (integrin α9)) and rs76191705 (P=2.59e-08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At the gene level, no consistent effect was found. At the pathway level, the Gene Ontology (GO) terms GO: 0005694 (chromosome) and GO: 0044427 (chromosomal part) were associated with improvement (corrected P=0.007 and 0.045, respectively). The association between rs116692768 and symptom improvement was replicated in PGRN-AMPS (P=0.047), whereas rs76191705 was not. The two SNPs did not replicate in NEWMEDS. ITGA9 codes for a membrane receptor for neurotrophins and NRXN3 is a transmembrane neuronal adhesion receptor involved in synaptic differentiation. Despite their meaningful biological rationale for being involved in antidepressant effect, replication was partial. Further studies may help in clarifying their role.

Genetically predicted complement component 4A expression: effects on memory function and middle temporal lobe activation.

BACKGROUND: The longstanding association between the major histocompatibility complex (MHC) locus and schizophrenia (SZ) risk has recently been accounted for, partially, by structural variation at the complement component 4 (C4) gene. This structural variation generates varying levels of C4 RNA expression, and genetic information from the MHC region can now be used to predict C4 RNA expression in the brain. Increased predicted C4A RNA expression is associated with the risk of SZ, and C4 is reported to influence synaptic pruning in animal models. METHODS: Based on our previous studies associating MHC SZ risk variants with poorer memory performance, we tested whether increased predicted C4A RNA expression was associated with reduced memory function in a large (n = 1238) dataset of psychosis cases and healthy participants, and with altered task-dependent cortical activation in a subset of these samples. RESULTS: We observed that increased predicted C4A RNA expression predicted poorer performance on measures of memory recall (p = 0.016, corrected). Furthermore, in healthy participants, we found that increased predicted C4A RNA expression was associated with a pattern of reduced cortical activity in middle temporal cortex during a measure of visual processing (p < 0.05, corrected). CONCLUSIONS: These data suggest that the effects of C4 on cognition were observable at both a cortical and behavioural level, and may represent one mechanism by which illness risk is mediated. As such, deficits in learning and memory may represent a therapeutic target for new molecular developments aimed at altering C4's developmental role.

Schizophrenia copy number variants and associative learning.

Large-scale genomic studies have made major progress in identifying genetic risk variants for schizophrenia. A key finding from these studies is that there is an increased burden of genomic copy number variants (CNVs) in schizophrenia cases compared with controls. The mechanism through which these CNVs confer risk for the symptoms of schizophrenia, however, remains unclear. One possibility is that schizophrenia risk CNVs impact basic associative learning processes, abnormalities of which have long been associated with the disorder. To investigate whether genes in schizophrenia CNVs impact on specific phases of associative learning we combined human genetics with experimental gene expression studies in animals. In a sample of 11 917 schizophrenia cases and 16 416 controls, we investigated whether CNVs from patients with schizophrenia are enriched for genes expressed during the consolidation, retrieval or extinction of associative memories. We show that CNVs from cases are enriched for genes expressed during fear extinction in the hippocampus, but not genes expressed following consolidation or retrieval. These results suggest that CNVs act to impair inhibitory learning in schizophrenia, potentially contributing to the development of core symptoms of the disorder.

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia.

The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10-8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia.

This corrects the article DOI: 10.1038/mp.2016.97.