Predictive power of the ADHD GWAS 2019 polygenic risk scores in independent samples of bipolar patients with childhood ADHD

BACKGROUND Although there is evidence of genetic correlation between bipolar disorder (BP) and ADHD, the extent of the shared genetic risk and whether childhood ADHD (cADHD) influences the characteristics of the adult BP remain unclear. Our objectives were: (i) to test the ability of polygenic risk scores (PRS) derived from the latest PGC ADHD-GWAS (Demontis et al., 2019) to predict the presence of cADHD in BP patients; (ii) to examine the hypothesis that BP preceded by cADHD is a BP subtype with particular clinical traits and (iii) partially shares its molecular basis with ADHD. METHOD PRS derived from the ADHD-GWAS-2019 were tested in BP patients (N = 942) assessed for cADHD with the Wender Utah Rating Scale and in controls from Romania and UK (N = 1616). RESULTS The ADHD-PRS differentiated BP cases with cADHD from controls. Proband sex and BP age-of-onset significantly influenced the discriminative power of the ADHD-PRS. The ADHD-PRS predicted the cADHD score only in males and in BP cases with early age-of-onset (≤21 years). Bipolar patients with cADHD had a younger age-of-onset of mania/depression than patients without cADHD. The ADHD-PRS predicted the BP-affection status in the comparison of early-onset BP cases with controls suggesting a partial molecular overlap between early-onset BP and ADHD. LIMITATIONS Retrospective diagnosis of cADHD, small sample size. CONCLUSIONS The PRS-analysis indicated an acceptable predictive ability of the ADHD-SNP-set 2019 in independent BP samples. The best prediction of both cADHD and BP-affection status was found in the early-onset BP cases. The results may have impact on the individual disease monitoring

A Hybrid Spam Detection Method Based on Unstructured Datasets

This document is the accepted manuscript version of the following article: Shao, Y., Trovati, M., Shi, Q. et al. Soft Comput (2017) 21: 233. The final publication is available at Springer via http://dx.doi.org/10.1007/s00500-015-1959-z. © Springer-Verlag Berlin Heidelberg 2015.The identification of non-genuine or malicious messages poses a variety of challenges due to the continuous changes in the techniques utilised by cyber-criminals. In this article, we propose a hybrid detection method based on a combination of image and text spam recognition techniques. In particular, the former is based on sparse representation-based classification, which focuses on the global and local image features, and a dictionary learning technique to achieve a spam and a ham sub-dictionary. On the other hand, the textual analysis is based on semantic properties of documents to assess the level of maliciousness. More specifically, we are able to distinguish between meta-spam and real spam. Experimental results show the accuracy and potential of our approach.Peer reviewedFinal Accepted Versio

INDCOR white paper on the Design of Complexity IDNs

This white paper was written by the members of the Work Group focusing on design practices of the COST Action 18230 - Interactive Narrative Design for Complexity Representation (INDCOR, WG1). It presents an overview of Interactive Digital Narratives (IDNs) design for complexity representations through IDN workflows and methodologies, IDN authoring tools and applications. It provides definitions of the central elements of the IDN alongside its best practices, designs and methods. Finally, it describes complexity as a feature of IDN, with related examples. In summary, this white paper serves as an orienting map for the field of IDN design, understanding where we are in the contemporary panorama while charting the grounds of their promising futures

Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors.

Recent investigations have revealed that the genetic deletion of P2X7 receptors (P2rx7) results in an antidepressant phenotype in mice. However, the link between the deficiency of P2rx7 and changes in behavior has not yet been explored. In the present study, we studied the effect of genetic deletion of P2rx7 on neurochemical changes in the hippocampus that might underlie the antidepressant phenotype. P2X7 receptor deficient mice (P2rx7-/-) displayed decreased immobility in the tail suspension test (TST) and an attenuated anhedonia response in the sucrose preference test (SPT) following bacterial endotoxin (LPS) challenge. The attenuated anhedonia was reproduced through systemic treatments with P2rx7 antagonists. The activation of P2rx7 resulted in the concentration-dependent release of [3H]glutamate in P2rx7+/+ but not P2rx7-/- mice, and the NR2B subunit mRNA and protein was upregulated in the hippocampus of P2rx7-/- mice. The brain-derived neurotrophic factor (BDNF) expression was higher in saline but not LPS-treated P2rx7-/- mice; the P2rx7 antagonist Brilliant blue G elevated and the P2rx7 agonist benzoylbenzoyl ATP (BzATP) reduced BDNF level. This effect was dependent on the activation of NMDA and non-NMDA receptors but not on Group I metabotropic glutamate receptors (mGluR1,5). An increased 5-bromo-2-deoxyuridine (BrdU) incorporation was also observed in the dentate gyrus derived from P2rx7-/- mice. Basal level of 5-HT was increased, whereas the 5HIAA/5-HT ratio was lower in the hippocampus of P2rx7-/- mice, which accompanied the increased uptake of [3H]5-HT and an elevated number of [3H]citalopram binding sites. The LPS-induced elevation of 5-HT level was absent in P2rx7-/- mice. In conclusion there are several potential mechanisms for the antidepressant phenotype of P2rx7-/- mice, such as the absence of P2rx7-mediated glutamate release, elevated basal BDNF production, enhanced neurogenesis and increased 5-HT bioavailability in the hippocampus

Lack of guidelines and translational knowledge is hindering the implementation of psychiatric genetic counseling and testing within Europe - A multi-professional survey study

Genetic research has identified a large number of genetic variants, both rare and common, underlying neurodevelopmental disorders (NDD) and major psychiatric disorders. Currently, these findings are being translated into clinical practice. However, there is a lack of knowledge and guidelines for psychiatric genetic testing (PsychGT) and genetic counseling (PsychGC). The European Union-funded COST action EnGagE (CA17130) network was started to investigate the current implementation status of PsychGT and PsychGC across 35 participating European countries. Here, we present the results of a pan-European online survey in which we gathered the opinions, knowledge, and practices of a self-selected sample of professionals involved/interested in the field. We received answers from 181 respondents. The three main occupational categories were genetic counselor (21.0%), clinical geneticist (24.9%), and researcher (25.4%). Of all 181 respondents, 106 provide GC for any psychiatric disorder or NDD, corresponding to 58.6% of the whole group ranging from 43.2% in Central Eastern Europe to 66.1% in Western Europe. Overall, 65.2% of the respondents reported that genetic testing is offered to individuals with NDD, and 26.5% indicated the same for individuals with major psychiatric disorders. Only 22.1% of the respondents indicated that they have guidelines for PsychGT. Pharmacogenetic testing actionable for psychiatric disorders was offered by 15%. Interestingly, when genetic tests are fully covered by national health insurance, more genetic testing is provided for individuals with NDD but not those with major psychiatric disorders. Our qualitative analyses of responses highlight the lack of guidelines and knowledge on utilizing and using genetic tests and education and training as the major obstacles to implementation. Indeed, the existence of psychiatric genetic training courses was confirmed by only 11.6% of respondents. The question on the relevance of up-to-date education and training in psychiatric genetics on everyday related practice was highly relevant. We provide evidence that PsychGC and PsychGT are already in use across European countries, but there is a lack of guidelines and education. Harmonization of practice and development of guidelines for genetic counseling, testing, and training professionals would improve equality and access to quality care for individuals with psychiatric disorders within Europe

Characterisation of age and polarity at onset in bipolar disorder

Background Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.publishedVersio

Paroxetine suppresses recombinant human P2X7 responses

P2X7 receptor (P2X7) activity may link inflammation to depressive disorders. Genetic variants of human P2X7 have been linked with major depression and bipolar disorders, and the P2X7 knockout mouse has been shown to exhibit anti-depressive-like behaviour. P2X7 is an ATP-gated ion channel and is a major regulator of the pro-inflammatory cytokine interleukin 1β (IL-1β) secretion from monocytes and microglia. We hypothesised that antidepressants may elicit their mood enhancing effects in part via modulating P2X7 activity and reducing inflammatory responses. In this study, we determined whether common psychoactive drugs could affect recombinant and native human P2X7 responses in vitro. Common antidepressants demonstrated opposing effects on human P2X7-mediated responses; paroxetine inhibited while fluoxetine and clomipramine mildly potentiated ATP-induced dye uptake in HEK-293 cells stably expressing recombinant human P2X7. Paroxetine inhibited dye uptake mediated by human P2X7 in a concentration-dependent manner with an IC50 of 24 μM and significantly reduces ATP-induced inward currents. We confirmed that trifluoperazine hydrochloride suppressed human P2X7 responses (IC50 of 6.4 μM). Both paroxetine and trifluoperazine did not inhibit rodent P2X7 responses, and mutation of a known residue (F 95L) did not alter the effect of either drug, suggesting neither drug binds at this site. Finally, we demonstrate that P2X7-induced IL-1β secretion from lipopolysaccharide (LPS)-primed human CD14+ monocytes was suppressed with trifluoperazine and paroxetine