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.

What kind of science for dual diagnosis? A pragmatic examination of the enactive approach to psychiatry.

The recommended treatment for - the co-occurrence of substance use and another mental disorder - requires seamless integration of the involved disciplines and services. However, no integrative framework exists for communicating about dual diagnosis cases across disciplinary or sectoral boundaries. We examine if may bridge this theoretical gap.

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.

Evaluation of polygenic prediction methodology within a reference-standardized framework.

The predictive utility of polygenic scores is increasing, and many polygenic scoring methods are available, but it is unclear which method performs best. This study evaluates the predictive utility of polygenic scoring methods within a reference-standardized framework, which uses a common set of variants and reference-based estimates of linkage disequilibrium and allele frequencies to construct scores. Eight polygenic score methods were tested: p-value thresholding and clumping (pT+clump), SBLUP, lassosum, LDpred1, LDpred2, PRScs, DBSLMM and SBayesR, evaluating their performance to predict outcomes in UK Biobank and the Twins Early Development Study (TEDS).

Imputed gene expression risk scores: a functionally informed component of polygenic risk.

Integration of functional genomic annotations when estimating polygenic risk scores (PRS) can provide insight into aetiology and improve risk prediction. This study explores the predictive utility of gene expression risk scores (GeRS), calculated using imputed gene expression and transcriptome-wide association study (TWAS) results. The predictive utility of GeRS was evaluated using 12 neuropsychiatric and anthropometric outcomes measured in two target samples: UK Biobank and the Twins Early Development Study.

Expression of CARD8 in human atherosclerosis and its regulation of inflammatory proteins in human endothelial cells.

The Caspase activation and recruitment domain 8 (CARD8) protein is a component of innate immunity and overexpression of CARD8 mRNA was previously identified in atherosclerosis. However, very little is known about the regulation of CARD8 in endothelial cells and atherosclerosis. The aim of this study was to investigate CARD8 in the regulation of cytokine and chemokine expression in endothelial cells.

Mechanisms of Action of the KCa2-Negative Modulator AP30663, a Novel Compound in Development for Treatment of Atrial Fibrillation in Man.

Aims: Small conductance Ca-activated K channels (SK channels, K2) are a new target for treatment of atrial fibrillation (AF). AP30663 is a small molecule inhibitor of K2 channels that is currently in clinical development for treatment of AF. The aim of this study is to present the electrophysiological profile and mechanism of action of AP30663 and its efficacy in prolonging atrial refractoriness in rodents, and by bioinformatic analysis investigate if genetic variants in or influence the expression level of these in human heart tissue.

New candidate genes for ST-elevation myocardial infarction.

Background: Despite extensive research in atherosclerosis, the mechanisms of coronary atherothrombosis in ST-elevation myocardial infarction (STEMI) patients are undetermined.

Objectives: Our aim was to find candidate genes involved in STEMI by analysing leucocyte gene expression in STEMI patients, without the influence of secondary inflammation from innate immunity, which was assumed to be a consequence rather than the cause of coronary atherothrombosis.

Methods: Fifty-one patients were included at coronary angiography because of STEMI.

KLF12 Regulates Mouse NK Cell Proliferation.

NK cells are innate lymphocytes that play an integral role in tumor rejection and viral clearance. Unlike their other lymphocyte counterparts, NK cells have the unique ability to recognize and lyse target cells without prior exposure. However, there are no known NK cell-specific genes that are exclusively expressed by all NK cells.

Prevalence, predictors, and patterns of mechanical restraint use for inpatients with dual diagnosis.

Purpose: This study examined the prevalence, predictors, and patterns of mechanical restraint in an inpatient dual diagnosis population.

Design And Methods: Data were longitudinally collected from patients affected by severe mental illness and comorbid substance abuse that were hospitalized in three large wards from 2006 to 2012.

Findings: In a sample of 1698 hospitalizations, the use of mechanical restraint ranged between 1% and 4% per year.

Can Animal Models of Copy Number Variants That Predispose to Schizophrenia Elucidate Underlying Biology?

The diagnosis of schizophrenia rests on clinical criteria that cannot be assessed in animal models. Together with absence of a clear underlying pathology and understanding of what causes schizophrenia, this has hindered development of informative animal models. However, recent large-scale genomic studies have identified copy number variants (CNVs) that confer high risk of schizophrenia and have opened a new avenue for generation of relevant animal models.

Novel Mutations in a Chinese Pedigree of Limb Girdle Muscular Dystrophy.

Limb girdle muscular dystrophies (LGMDs) are a heterogeneous group of genetic myopathies leading primarily to proximal muscle weakness. It is caused by mutations at over 50 known genetic loci typically from mutations in genes encoding constituents of the sarcolemmal dystrophin complex or related functions. Herein we describe the case of two siblings with LGMD that were investigated using whole-exome sequencing followed by Sanger sequencing validation of a specific double-mutation in the gene.

Systematic approach demonstrates enrichment of multiple interactions between non- risk variants and risk alleles in rheumatoid arthritis.

Objective: In anti-citrullinated protein antibody positive rheumatoid arthritis (ACPA-positive RA), a particular subset of alleles, called shared epitope (SE) alleles, is a highly influential genetic risk factor. Here, we investigated whether non- single nucleotide polymorphisms (SNP), conferring low disease risk on their own, interact with SE alleles more frequently than expected by chance and if such genetic interactions influence the SE effect concerning risk to ACPA-positive RA.

Methods: We computed the attributable proportion (AP) due to additive interaction at genome-wide level for two independent ACPA-positive RA cohorts: the Swedish epidemiological investigation of rheumatoid arthritis (EIRA) and the North American rheumatoid arthritis consortium (NARAC).

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.

Association of the leucine-7 to proline-7 variation in the signal sequence of neuropeptide Y with major depression.

Objective: There is clear evidence of a genetic component in major depression, and several studies indicate that neuropeptide Y (NPY) could play an important role in the pathophysiology of the disease. A well-known polymorphism encoding the substitution of leucine to proline in the signal peptide sequence of NPY (Leu7Pro variation) was previously found to protect against depression. Our study aimed at replicating this association in a large Danish population with major depression.

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.