Identifying drug targets for schizophrenia through gene prioritization.

Background: Schizophrenia genome-wide association studies (GWASes) have identified >250 significant loci and prioritized >100 disease-related genes. However, gene prioritization efforts have mostly been restricted to locus-based methods that ignore information from the rest of the genome. Methods: To more accurately characterize genes involved in schizophrenia etiology, we applied a combination of highly-predictive tools to a published GWAS of 67,390 schizophrenia cases and 94,015 controls. We combined both locus-based methods (fine-mapped coding variants, distance to GWAS signals) and genome-wide methods (PoPS, MAGMA, ultra-rare coding variant burden tests). To validate our findings, we compared them with previous prioritization efforts, known neurodevelopmental genes, and results from the PsyOPS tool. Results: We prioritized 62 schizophrenia genes, 41 of which were also highlighted by our validation methods. In addition to DRD2 , the principal target of antipsychotics, we prioritized 9 genes that are targeted by approved or investigational drugs. These included drugs targeting glutamatergic receptors ( GRIN2A and GRM3 ), calcium channels ( CACNA1C and CACNB2 ), and GABA B receptor ( GABBR2 ). These also included genes in loci that are shared with an addiction GWAS ( e.g. PDE4B and VRK2 ). Conclusions: We curated a high-quality list of 62 genes that likely play a role in the development of schizophrenia. Developing or repurposing drugs that target these genes may lead to a new generation of schizophrenia therapies. Rodent models of addiction more closely resemble the human disorder than rodent models of schizophrenia. As such, genes prioritized for both disorders could be explored in rodent addiction models, potentially facilitating drug development.

Fine-mapping genomic loci refines bipolar disorder risk genes.

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).

The combination of oxytocin and mindfulness-based group therapy for empathy and negative symptoms in schizophrenia spectrum disorders - A double-blinded, randomized, placebo-controlled pilot study.

Treatment options for social cognition and negative symptoms in schizophrenia spectrum disorders (SSD) remain limited. Oxytocin could be a promising augmentation approach, but the social context influences the effect in humans. This pilot study hypothesized that oxytocin in a positive social setting through mindfulness-based group therapy (MBGT) would positively affect empathy and negative symptoms as well as affect and stress in an exploratory approach in SSD. An experimental, randomized, double-blinded (participants, psychotherapists), placebo-controlled pilot study with 41 individuals with SSD was conducted at the Charité - Universitätsmedizin Berlin. Oxytocin or placebo (24 I.U.) was administered intranasally 45 min before two sessions of MBGT each. A 2 × 2 mixed model ANCOVA design was calculated to assess empathy by the Interpersonal Reactivity Index and the Multifaceted Empathy Test and negative symptoms by the Self-Evaluation of Negative Symptoms. No benefit of oxytocin compared to placebo on empathy was observed, but significant between-group differences favoring oxytocin were found regarding the negative symptoms Diminished emotional range and Avolition. Negative affect and stress were significantly reduced compared to baseline. Mindfulness increased in both groups. Results indicated protocol adherence and retention rate of 91.1%, a drop-out rate of 8.9 % and a completion of 96 % of all sessions by the participants. No severe adverse events or side effects were reported. Our findings indicate proof-of-concept and suggest a potential role of oxytocin on negative symptoms and related variables in SSD in combination with MBGT. Future research should examine the stability of these effects with larger sample sizes.

Study protocol of the Berlin Research Initiative for Diagnostics, Genetics and Environmental Factors in Schizophrenia (BRIDGE-S).

BACKGROUND: Large-scale collaborative efforts in the field of psychiatric genetics have made substantial progress in unraveling the biological architecture of schizophrenia (SCZ). Although both genetic and environmental factors are known to play a role in schizophrenia etiology our mechanistic understanding of how they shape risk, resilience and disease trajectories remains limited. METHODS: Here, we present the study protocol of the Berlin Research Initiative for Diagnostics, Genetic and Environmental Factors of Schizophrenia (BRIDGE-S), which aims to collect a densely phenotyped genetic cohort of 1,000 schizophrenia cases and 1,000 controls. The study's main objectives are to build a resource for i) promoting genetic discoveries and ii) genotype-phenotype associations to infer specific disease subtypes, and iii) exploring gene-environment interactions using polyrisk models. All subjects provide a biological sample for genotyping and complete a core questionnaire capturing a variety of environmental exposures, demographic, psychological and health data. Approximately 50% of individuals in the sample will further undergo a comprehensive clinical and neurocognitive assessment. DISCUSSION: With BRIDGE-S we created a valuable database to study genomic and environmental contributions to schizophrenia risk, onset, and outcomes. Results of the BRIDGE-S study could yield insights into the etiological mechanisms of schizophrenia that could ultimately inform risk prediction, and early intervention and treatment strategies.

Detailed stratified GWAS analysis for severe COVID-19 in four European populations.

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.

The Relationship Between the Recognition of Basic Emotions and Negative Symptoms in Individuals With Schizophrenia Spectrum Disorders - An Exploratory Study.

Current research suggests that emotion recognition is impaired in individuals affected by schizophrenia spectrum disorders (SSD). However, the specific impact of negative symptoms on the ability to recognize single basic emotions has not yet been explored sufficiently and is the aim of the present study. A sample of N = 66 individuals diagnosed with SSD was recruited at the Charité - Universitätsmedizin Berlin. In a first step, correlation analyses were conducted between seven different negative symptom subdomains of the Positive and Negative Syndrome Scale (PANSS) and the accuracy and latency in recognizing the six basic emotions (anger, disgust, fear, happiness, sadness, surprise) using the Emotion Recognition Task (ERT) of the Cambridge Neuropsychological Test Automated Battery (CANTAB). The significant correlations were subjected to linear regression models that controlled for the significant covariates diagnoses, age, sex, and education. Results revealed that in individuals with SSD the negative symptom domain of blunted affect significantly predicted the accuracy of emotion recognition performance (p < 0.05), particularly, when recognizing happiness (p < 0.05). Additionally, we found that stereotyped thinking also predicted the performance of emotion recognition, especially the response latency (p < 0.05) and difficulty in abstract thinking predicted the recognition of fear (p < 0.05). However, the nominal significances did not withstand correction for multiple tests and therefore need to be followed up in further studies with a larger sample.