Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through the cAMP/PKA pathway

Heterozygous loss-of-function (LoF) mutations in SETD1A, which encodes a subunit of histone H3 lysine 4 methyltransferase, cause a neurodevelopmental syndrome and increase the risk for schizophrenia. Using CRISPR-Cas9, we generate excitatory/inhibitory neuronal networks from human induced pluripotent stem cells with a SETD1A heterozygous LoF mutation (SETD1A+/−). Our data show that SETD1A haploinsufficiency results in morphologically increased dendritic complexity and functionally increased bursting activity. This network phenotype is primarily driven by SETD1A haploinsufficiency in glutamatergic neurons. In accordance with the functional changes, transcriptomic profiling reveals perturbations in gene sets associated with glutamatergic synaptic function. At the molecular level, we identify specific changes in the cyclic AMP (cAMP)/Protein Kinase A pathway pointing toward a hyperactive cAMP pathway in SETD1A+/− neurons. Finally, by pharmacologically targeting the cAMP pathway, we are able to rescue the network deficits in SETD1A+/− cultures. Our results demonstrate a link between SETD1A and the cAMP-dependent pathway in human neurons.publishedVersio

Rapid Health and Needs assessments after disasters: a systematic review

<p>Abstract</p> <p>Background</p> <p>Publichealth care providers, stakeholders and policy makers request a rapid insight into health status and needs of the affected population after disasters. To our knowledge, there is no standardized rapid assessment tool for European countries. The aim of this article is to describe existing tools used internationally and analyze them for the development of a workable rapid assessment.</p> <p>Methods</p> <p>A review was conducted, including original studies concerning a rapid health and/or needs assessment. The studies used were published between 1980 and 2009. The electronic databasesof Medline, Embase, SciSearch and Psychinfo were used.</p> <p>Results</p> <p>Thirty-three studies were included for this review. The majority of the studies was of US origin and in most cases related to natural disasters, especially concerning the weather. In eighteen studies an assessment was conducted using a structured questionnaire, eleven studies used registries and four used both methods. Questionnaires were primarily used to asses the health needs, while data records were used to assess the health status of disaster victims.</p> <p>Conclusions</p> <p>Methods most commonly used were face to face interviews and data extracted from existing registries. Ideally, a rapid assessment tool is needed which does not add to the burden of disaster victims. In this perspective, the use of existing medical registries in combination with a brief questionnaire in the aftermath of disasters is the most promising. Since there is an increasing need for such a tool this approach needs further examination.</p

Heterozygous Mutations of FREM1 Are Associated with an Increased Risk of Isolated Metopic Craniosynostosis in Humans and Mice

The premature fusion of the paired frontal bones results in metopic craniosynostosis (MC) and gives rise to the clinical phenotype of trigonocephaly. Deletions of chromosome 9p22.3 are well described as a cause of MC with variably penetrant midface hypoplasia. In order to identify the gene responsible for the trigonocephaly component of the 9p22.3 syndrome, a cohort of 109 patients were assessed by high-resolution arrays and MLPA for copy number variations (CNVs) involving 9p22. Five CNVs involving FREM1, all of which were de novo variants, were identified by array-based analyses. The remaining 104 patients with MC were then subjected to targeted FREM1 gene re-sequencing, which identified 3 further mutant alleles, one of which was de novo. Consistent with a pathogenic role, mouse Frem1 mRNA and protein expression was demonstrated in the metopic suture as well as in the pericranium and dura mater. Micro-computed tomography based analyses of the mouse posterior frontal (PF) suture, the human metopic suture equivalent, revealed advanced fusion in all mice homozygous for either of two different Frem1 mutant alleles, while heterozygotes exhibited variably penetrant PF suture anomalies. Gene dosage-related penetrance of midfacial hypoplasia was also evident in the Frem1 mutants. These data suggest that CNVs and mutations involving FREM1 can be identified in a significant percentage of people with MC with or without midface hypoplasia. Furthermore, we present Frem1 mutant mice as the first bona fide mouse model of human metopic craniosynostosis and a new model for midfacial hypoplasia

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth

Prediction of adolescent outcome in children with disruptive behaviour disorders

In this preliminary study we explored the predictive influence of various family, psychological, demographic, and neurobiological characteristics on the persistence of antisocial behaviour in adolescence. Existing data were combined with case-records in a sample of 47 disruptive behaviour disordered (DBD) children who had been treated in in-patient and/or day-treatment units when they were between seven to 12 years old. Parent-rated and self-rated externalizing problem scores and the presence of a DBD diagnosis served as the outcome measures in adolescence. We used linear regression analyses to examine the predictors of adolescent outcome. A lower basal skin conductance level (SCL) was repeatedly found to predict poor adolescent outcome, either when rated by parents or by participants themselves. In addition, comorbid attention-deficit hyperactivity disorder, one aspect of performance on the door-opening task, and a mother of low socioeconomic status also predicted that a child would have more antisocial problems in adolescence, depending on the type of outcome measure. Results of this study support the fearlessness theory, according to which low activity of the autonomous nervous system, as manifested by low SCL, is related to the effectiveness of socializing punishment and accordingly to poor socialization and adolescent outcome

Developing a new assessment procedure of social information processing in adolescents within secure residential care

The purpose of the present study was to develop a new assessment procedure of social information processing (SIP) for adolescents, to explore its validity and to examine whether it differentiated between IQ groups. Ninety-four adolescents within secure residential care were administered the SIP instrument, the Youth Self Report and two subtests of the WISC/WAIS. Results showed that the constructs underlying the items of the instrument were associated with profiles from the SIP theory, the subsequent SIP steps were correlated, and several SIP steps were correlated to self-reported behavior. No differences were found between IQ groups. These first results have implications for adjustment of the instrument. Further research should confirm construct validity and psychometric qualities of the scales. (C) 2014 Elsevier Ltd. All rights reserved

Salivary testosterone and aggression, delinquency, and social dominance in a population-based longitudinal study of adolescent males

Testosterone (T) has been found to have a stimulating effect on aggressive behavior in a wide range of vertebrate species. There is also some evidence of a positive relationship in humans, albeit less consistently. In the present study we investigated the relationship between T and aggression, dominance and delinquency over time, covering a period from early adolescence to adulthood. From a large population-based sample (n = 1.161) a subgroup of 96 boys was selected whose behavior had been assessed repeatedly by different informants from age 12 to 21 years, and who had provided multiple T samples over these years of assessment. On the whole, a decrease in aggressive and delinquent behavior was observed in a period in which T rises dramatically. Boys who developed a criminal record, had higher T levels at age 16. In addition, positive associations were observed between T and proactive and reactive aggression and self-reported delinquent behavior. Over the pubertal years different forms of aggressive and delinquent behavior were positively related to T, which may indicate that specific positive links are dependent on the social setting in which this relationship is assessed

Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through the cAMP/PKA pathway

Heterozygous loss-of-function (LoF) mutations in SETD1A, which encodes a subunit of histone H3 lysine 4 methyltransferase, cause a neurodevelopmental syndrome and increase the risk for schizophrenia. Using CRISPR-Cas9, we generate excitatory/inhibitory neuronal networks from human induced pluripotent stem cells with a SETD1A heterozygous LoF mutation (SETD1A+/−). Our data show that SETD1A haploinsufficiency results in morphologically increased dendritic complexity and functionally increased bursting activity. This network phenotype is primarily driven by SETD1A haploinsufficiency in glutamatergic neurons. In accordance with the functional changes, transcriptomic profiling reveals perturbations in gene sets associated with glutamatergic synaptic function. At the molecular level, we identify specific changes in the cyclic AMP (cAMP)/Protein Kinase A pathway pointing toward a hyperactive cAMP pathway in SETD1A+/− neurons. Finally, by pharmacologically targeting the cAMP pathway, we are able to rescue the network deficits in SETD1A+/− cultures. Our results demonstrate a link between SETD1A and the cAMP-dependent pathway in human neurons