Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia.

Schizophrenia is a severe psychiatric disorder with strong heritability and marked heterogeneity in symptoms, course, and treatment response. There is strong interest in identifying genetic risk factors that can help to elucidate the pathophysiology and that might result in the development of improved treatments. Linkage and genome-wide association studies (GWASs) suggest that the genetic basis of schizophrenia is heterogeneous. However, it remains unclear whether the underlying genetic variants are mostly moderately rare and can be identified by the genotyping of variants observed in sequenced cases in large follow-up cohorts or whether they will typically be much rarer and therefore more effectively identified by gene-based methods that seek to combine candidate variants. Here, we consider 166 persons who have schizophrenia or schizoaffective disorder and who have had either their genomes or their exomes sequenced to high coverage. From these data, we selected 5,155 variants that were further evaluated in an independent cohort of 2,617 cases and 1,800 controls. No single variant showed a study-wide significant association in the initial or follow-up cohorts. However, we identified a number of case-specific variants, some of which might be real risk factors for schizophrenia, and these can be readily interrogated in other data sets. Our results indicate that schizophrenia risk is unlikely to be predominantly influenced by variants just outside the range detectable by GWASs. Rather, multiple rarer genetic variants must contribute substantially to the predisposition to schizophrenia, suggesting that both very large sample sizes and gene-based association tests will be required for securely identifying genetic risk factors. © 2012 The American Society of Human Genetics

Filicide in Austria and Finland - A register-based study on all filicide cases in Austria and Finland 1995-2005

<p>Abstract</p> <p>Background</p> <p>Filicide is the tragic crime of murdering one's own child. Previous research has found that the offending parents are commonly depressed and that suicide is often associated as an actual act or an intention. Yet, filicide is an underreported crime and previous studies have been strained with methodological problems. No comprehensive international studies on filicide have been presented in the literature until now.</p> <p>Methods</p> <p>This was a descriptive, comprehensive, register-based study of all filicides in Austria and Finland during 1995-2005. Filicide-suicide cases were also included.</p> <p>Results</p> <p>Most of the perpetrators were the biological mothers; in Austria 72%, in Finland 52%. Suicide followed filicide either as an attempt or a fulfilled act in 32% and 54% of the cases in Austria and Finland, respectively. Psychotic mood disorders were diagnosed for 10% of the living perpetrators in Austria, and 12% in Finland. Non-psychotic depression was diagnosed in 9% of surviving perpetrators in Austria, 35% in Finland.</p> <p>Conclusion</p> <p>The data from the two countries demonstrated that filicide is such a multifaceted and rare phenomenon that national data from individual countries seldom offer sufficient scope for its thorough study. Further analyses are needed to produce a complete picture of filicide.</p

Genomic prediction of relapse in recipients of allogeneic haematopoietic stem cell transplantation

Allogeneic haematopoietic stem cell transplantation currently represents the primary potentially curative treatment for cancers of the blood and bone marrow. While relapse occurs in approximately 30% of patients, few risk-modifying genetic variants have been identified. The present study evaluates the predictive potential of patient genetics on relapse risk in a genome-wide manner. We studied 151 graft recipients with HLA-matched sibling donors by sequencing the whole-exome, active immunoregulatory regions, and the full MHC region. To assess the predictive capability and contributions of SNPs and INDELs, we employed machine learning and a feature selection approach in a cross-validation framework to discover the most informative variants while controlling against overfitting. Our results show that germline genetic polymorphisms in patients entail a significant contribution to relapse risk, as judged by the predictive performance of the model (AUC = 0.72 [95% CI: 0.63–0.81]). Furthermore, the top contributing variants were predictive in two independent replication cohorts (n = 258 and n = 125) from the same population. The results can help elucidate relapse mechanisms and suggest novel therapeutic targets. A computational genomic model could provide a step toward individualized prognostic risk assessment, particularly when accompanied by other data modalities.</p

Computational Analysis of HLA-presentation of Non-synonymous Recipient Mismatches Indicates Effect on the Risk of Chronic Graft-vs.-Host Disease After Allogeneic HSCT

Genetic mismatches in protein coding genes between allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipient and donor can elicit an alloimmunity response via peptides presented by the recipient HLA receptors as minor histocompatibility antigens (mHAs). While the impact of individual mHAs on allo-HSCT outcome such as graft-vs.-host and graft-vs.-leukemia effects has been demonstrated, it is likely that established mHAs constitute only a small fraction of all immunogenic non-synonymous variants. In the present study, we have analyzed the genetic mismatching in 157 exome-sequenced sibling allo-HSCT pairs to evaluate the significance of polymorphic HLA class I associated peptides on clinical outcome. We applied computational mismatch estimation approaches based on experimentally verified HLA ligands available in public repositories, published mHAs, and predicted HLA-peptide affinites, and analyzed their associations with chronic graft-vs.-host disease (cGvHD) grades. We found that higher estimated recipient mismatching consistently increased the risk of severe cGvHD, suggesting that HLA-presented mismatching influences the likelihood of long-term complications in the patient. Furthermore, computational approaches focusing on estimation of HLA-presentation instead of all non-synonymous mismatches indiscriminately may be beneficial for analysis sensitivity and could help identify novel mHAs

Increased deep sleep in a medication-free, detoxified female offender with schizophrenia, alcoholism and a history of attempted homicide: Case report

BACKGROUND: Psychiatric sleep research has attempted to identify diagnostically sensitive and specific sleep patterns associated with particular disorders. Both schizophrenia and alcoholism are typically characterized by a severe sleep disturbance associated with decreased amounts of slow wave sleep, the physiologically significant, refreshing part of the sleep. Antisocial behaviour with severe aggression, on the contrary, has been reported to associate with increased deep sleep reflecting either specific brain pathology or a delay in the normal development of sleep patterns. The authors are not aware of previous sleep studies in patients with both schizophrenia and antisocial personality disorder. CASE PRESENTATION: The aim of the present case-study was to characterize the sleep architecture of a violent, medication-free and detoxified female offender with schizophrenia, alcoholism and features of antisocial personality disorder using polysomnography. The controls consisted of three healthy, age-matched women with no history of physical violence. The offender's sleep architecture was otherwise very typical for patients with schizophrenia and/or alcoholism, but an extremely high amount of deep sleep was observed in her sleep recording. CONCLUSIONS: The finding strengthens the view that severe aggression is related to an abnormal sleep pattern with increased deep sleep. The authors were able to observe this phenomenon in an antisocially behaving, violent female offender with schizophrenia and alcohol dependence, the latter disorders previously reported to be associated with low levels of slow wave sleep. New studies are, however, needed to confirm and explain this preliminary finding

Band alignment and enhanced breakdown field of simultaneously oxidized and nitrided Zr film on Si

The band alignment of ZrO2/interfacial layer/Si structure fabricated by simultaneous oxidation and nitridation of sputtered Zr on Si in N2O at 700°C for different durations has been established by using X-ray photoelectron spectroscopy. Valence band offset of ZrO2/Si was found to be 4.75 eV, while the highest corresponding conduction offset of ZrO2/interfacial layer was found to be 3.40 eV; owing to the combination of relatively larger bandgaps, it enhanced electrical breakdown field to 13.6 MV/cm at 10-6 A/cm2

Impact of transient groundwater storage on the discharge of Himalayan rivers

International audienceIn the course of the transfer of precipitation into rivers, water is temporarily stored in reservoirs with different residence times such as soils, groundwater, snow and glaciers. In the central Himalaya, the water budget is thought to be primarily controlled by monsoon rainfall, snow and glacier melt, and secondarily by evapotranspiration. An additional contribution from deep groundwater has been deduced from the chemistry of Himalayan rivers, but its importance in the annual water budget remains to be evaluated. Here we analyse records of daily precipitation and discharge within twelve catchments in Nepal over about 30 years. We observe annual hysteresis loops--that is, a time lag between precipitation and discharge--in both glaciated and unglaciated catchments and independent of the geological setting. We infer that water is stored temporarily in a reservoir with characteristic response time of about 45 days, suggesting a diffusivity typical of fractured basement aquifers. We estimate this transient storage capacity at about 28km3 for the three main Nepal catchments; snow and glacier melt contribute around 14km3yr-1, about 10% of the annual river discharge. We conclude that groundwater storage in a fractured basement influences significantly the Himalayan river discharge cycle

Women convicted for violent offenses: Adverse childhood experiences, low level of education and poor mental health

<p>Abstract</p> <p>Background</p> <p>In past years, the female offender population has grown, leading to an increased interest in the characteristics of female offenders. The aim of this study was to assess the prevalence of female violent offending in a Swiss offender population and to compare possible socio-demographic and offense-related gender differences.</p> <p>Methods</p> <p>Descriptive and bivariate logistic regression analyses were performed for a representative sample of N = 203 violent offenders convicted in Zurich, Switzerland.</p> <p>Results</p> <p>7.9% (N = 16) of the sample were female. Significant gender differences were found: Female offenders were more likely to be married, less educated, to have suffered from adverse childhood experiences and to be in poor mental health. Female violent offending was less heterogeneous than male violent offending, in fact there were only three types of violent offenses females were convicted for in our sample: One third were convicted of murder, one third for arson and only one woman was convicted of a sex offense.</p> <p>Conclusions</p> <p>The results of our study point toward a gender-specific theory of female offending, as well as toward the importance of developing models for explaining female criminal behavior, which need to be implemented in treatment plans and intervention strategies regarding female offenders.</p