Multiallelic Copy Number Variation in ORM1 is Associated with Plasma Cell-Free DNA Levels as an Intermediate Phenotype for Venous Thromboembolism.

Venous thromboembolism (VTE) is a common disease with high heritability. However, only a small portion of the genetic variance of VTE can be explained by known genetic risk factors. Neutrophil extracellular traps (NETs) have been associated with prothrombotic activity.

Integrated GWAS and Gene Expression Suggest ORM1 as a Potential Regulator of Plasma Levels of Cell-Free DNA and Thrombosis Risk.

Plasma cell-free DNA (cfDNA) is a surrogate marker of neutrophil extracellular traps (NETs) that contribute to immunothrombosis. There is growing interest about the mechanisms underlying NET formation and elevated cfDNA, but little is known about the factors involved. We aimed to identify genes involved in the regulation of cfDNA levels using data from the Genetic Analysis of Idiopathic Thrombophilia (GAIT-2) Project.

Brief Report: Clusters and Trajectories Across the Autism and/or ADHD Spectrum.

Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD) frequently co-occur and show high genetic correlation. With the introduction of DSM-5, there is a new concept of an ASD and/or ADHD spectrum (ASD/ADHD). This study aimed to identify predictors of severity and need of healthcare within this spectrum.

Novel Loci Associated With Attention-Deficit/Hyperactivity Disorder Are Revealed by Leveraging Polygenic Overlap With Educational Attainment.

Objective: Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable psychiatric condition. By exploiting the reported relationship between ADHD and educational attainment (EA), we aimed to improve discovery of ADHD-associated genetic variants and to investigate genetic overlap between these phenotypes.

Method: A conditional/conjunctional false discovery rate (condFDR/conjFDR) method was applied to genome-wide association study (GWAS) data on ADHD (2,064 trios, 896 cases, and 2,455 controls) and EA (n=328,917) to identify ADHD-associated loci and loci overlapping between ADHD and EA.

Genetic evidence for role of integration of fast and slow neurotransmission in schizophrenia.

The most recent genome-wide association studies (GWAS) of schizophrenia (SCZ) identified hundreds of risk variants potentially implicated in the disease. Further, novel statistical methodology designed for polygenic architecture revealed more potential risk variants. This can provide a link between individual genetic factors and the mechanistic underpinnings of SCZ.

Estimating Effect Sizes and Expected Replication Probabilities from GWAS Summary Statistics.

Genome-wide Association Studies (GWAS) result in millions of summary statistics ("z-scores") for single nucleotide polymorphism (SNP) associations with phenotypes. These rich datasets afford deep insights into the nature and extent of genetic contributions to complex phenotypes such as psychiatric disorders, which are understood to have substantial genetic components that arise from very large numbers of SNPs. The complexity of the datasets, however, poses a significant challenge to maximizing their utility.

Leveraging Genomic Annotations and Pleiotropic Enrichment for Improved Replication Rates in Schizophrenia GWAS.

Most of the genetic architecture of schizophrenia (SCZ) has not yet been identified. Here, we apply a novel statistical algorithm called Covariate-Modulated Mixture Modeling (CM3), which incorporates auxiliary information (heterozygosity, total linkage disequilibrium, genomic annotations, pleiotropy) for each single nucleotide polymorphism (SNP) to enable more accurate estimation of replication probabilities, conditional on the observed test statistic ("z-score") of the SNP. We use a multiple logistic regression on z-scores to combine information from auxiliary information to derive a "relative enrichment score" for each SNP.

Effects of cannabinoid CB1 receptor agonism and antagonism on SKF81297-induced dyskinesia and haloperidol-induced dystonia in Cebus apella monkeys.

Antipsychotic drugs may cause extrapyramidal symptoms (EPS), such as dyskinesia and dystonia. These effects are believed to involve dysfunctional striatal dopamine transmission. Patients with schizophrenia show increased prevalence of cannabis abuse and this has been linked to severity of EPS.

CYP2D6 genotype predicts antipsychotic side effects in schizophrenia inpatients: a retrospective matched case-control study.

Objective: The aim of the present retrospective pilot study was to examine the clinical impact of the cytochrome P450 (CYP) enzyme CYP2D6 poor metabolizer (PM) genotype in patients taking antipsychotic medication. The impaired metabolic capacity of the PM genotype results in higher steady-state plasma concentrations at a given dose, thus increasing the risk of toxic effects from medication.

Methods: We identified 18 PM patients with a schizophrenia spectrum diagnosis from a clinical database covering all patients who have been analyzed in an ongoing standardized CYP2D6 screening program.

Lack of association of the serotonin transporter gene promoter region polymorphism, 5-HTTLPR, including rs25531 with cigarette smoking and alcohol consumption.

We addressed the question whether 5-HTTLPR, a variable number of tandem repeats located in the 5' end of the serotonin transporter gene, is associated with smoking or alcohol consumption. Samples of DNA from 1,365 elderly women with a mean age of 69.2 years were genotyped for this polymorphism using a procedure, which allowed the simultaneous determination of variation in the number of repeat units and single nucleotide changes, including the A > G variation at rs25531 for discrimination between the L(A) and L(G) alleles.

Coercion in patients who at their first contact with the psychiatric services system were diagnosed within the schizophrenia-spectrum in Denmark. A register study.

The level of use of coercive measures in patients diagnosed with a schizophrenia-spectrum disorder at their first contact with the psychiatric services system in Denmark is not known. The aim of the study was to investigate the level of use of coercive measures during first year of contact in this group of patients. Using the longitudinal national registers, the use of coercive measures for each individual was calculated in a 1-year period from 1 January 1999 to 31 December 2001, for patients in Denmark who at their first contact with the psychiatric services system were diagnosed within the schizophrenia-spectrum (F2 in ICD 10); 2222 patients were identified.

[Cognitive milieu therapy and restraint within dual diagnosis populations].

Introduction: The use of restraint is common practice within psychiatry and is most frequently used with patients with a co-occurring serious mental illness and substance abuse or dual diagnosis. Furthermore restraint has being shown to have a negative impact on treatment outcomes and on the psychological wellbeing of patients. Cognitive behavioural therapy has been shown to contribute to positive treatment outcomes for a range of mental health problems, including schizophrenia and substance abuse.

Effect of integrated treatment on the use of coercive measures in first-episode schizophrenia-spectrum disorder. A randomized clinical trial.

The effect of integrated treatment on the use of coercive measures in first-episode schizophrenia-spectrum disorder in Denmark is not known. A total of 328 patients were randomly assigned to integrated treatment (167 patients) or standard treatment (161 patients). Integrated treatment consisted of assertive community treatment, psycho-educational multi-family groups, and social skills training.

Intensive treatment models and coercion.

Little evidence exists concerning the optimal treatment for patients with first-episode schizophrenia-spectrum disorders and the effect on traditional outcomes. The aim was to investigate whether optimal treatment models have an effect on the level of use of coercion and on traditional outcomes. Hospital-based Rehabilitation, an intensified inpatient treatment model, Integrated Treatment, an intensified model of Assertive Community Treatment, and standard treatment were compared for patients with first-episode schizophrenia-spectrum disorders.

Brain expressed microRNAs implicated in schizophrenia etiology.

Background: Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors. Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation.

Novel procedure for genotyping of the human serotonin transporter gene-linked polymorphic region (5-HTTLPR)--a region with a high level of allele diversity.

Background: The serotonin transporter, the target of a group of antidepressant drugs, is involved in the regulation of the availability and reuptake of serotonin. A variable number of tandem repeats in the promoter region of the serotonin transporter gene, designated 5-HTTLPR, affects the transcription of this gene and appears to modulate the susceptibility to a variety of diseases including depression. Of importance, 5-HTTLPR alleles composed of the same number of basic units may differ at single nucleotide positions providing an additional source of variation.

Diagnostic stability among chronic patients with functional psychoses: an epidemiological and clinical study.

Background: Diagnostic stability and illness course of chronic non-organic psychoses are complex phenomena and only few risk factors or predictors are known that can be used reliably. This study investigates the diagnostic stability during the entire course of illness in patients with non-organic psychoses and attempts to identify non-psychopathological risk factors or predictors.

Method: 100 patients with functional psychosis were initially characterised using the Operational Criteria Checklist for Psychotic Illness and Affective Illness (OPCRIT), medical records and health registers.

Association of a dopamine beta-hydroxylase gene variant with depression in elderly women possibly reflecting noradrenergic dysfunction.

Background: Depression has a multifactorial etiology which involves genetic factors and comorbid diseases.

Methods: A cross-sectional sample of 1371 elderly women (mean age=69.2 years) was examined.

The tachykinin tale: molecular recognition in a historical perspective.

Crystallography, mutational mapping and crosslinking are but a few of the experimental techniques that have helped to elucidate the underlying principles of molecular recognition between macromolecules and to improve our understanding of the evolution of the structure-activity relationship (SAR). While this development has been particularly successful for small and rigid ligands and substrates that bind to larger hydrophilic biomolecules, our understanding of membrane-embedded proteins is still rather limited. This review uses the example of the neuropeptide family of tachykinins and their G-protein coupled receptors (GPCR) to present how complementary experimental strategies over the past decades have nourished and modified conceptual models of the structural requisites of molecular recognition and function.

The acetylcholinesterase inhibitor galantamine inhibits d-amphetamine-induced psychotic-like behavior in Cebus monkeys.

Cholinergic receptors (AChR) are reported altered in brains from schizophrenic patients, and a growing body of evidence suggests that muscarinic receptor agonists exhibit antipsychotic potential. Centrally acting selective muscarinic receptor agonists are currently not available for clinical use, but acetylcholinesterase (AChE) inhibitors, which indirectly stimulate AChR by blocking the breakdown of acetylcholine by AChE, are widely used in the clinic against Alzheimer's disease. AChE inhibitors have been reported to exhibit antipsychotic efficacy in Alzheimer's disease patients, and these compounds have also been investigated as adjunctive treatment to antipsychotic medication in schizophrenic patients with varying results.

Substance abuse and first-episode schizophrenia-spectrum disorders. The Danish OPUS trial.

Aim: To evaluate whether integrated treatment (given by OPUS), in comparison with standard treatment, significantly reduced the number of patients with substance abuse and improved clinical and social outcome in the group of substance abusers after 2 years.

Methods: A total of 547 patients with first-episode schizophrenia-spectrum disorders were included in the study, 275 randomly assigned to OPUS treatment and 272 to standard treatment. OPUS treatment consisted of assertive community treatment with family involvement and social skills training.

Sexual desire in a nationally representative Danish population.

Introduction: There are only a few studies on the frequency of sexual desire in the general population, whereas studies investigating the frequency of disordered sexual desire are more common.

Aim: The aim of this study was to describe the frequency of sexual desire in a representative sample of the adult Danish population and to analyze the relationships between a number of relevant variables and sexual desire.

Methods: The study population (N = 10,458, response rate 84.