Associations between SNPs and immune-related circulating proteins in schizophrenia

Genome-wide association studies (GWAS) and proteomic studies have provided convincing evidence implicating alterations in immune/inflammatory processes in schizophrenia. However, despite the convergence of evidence, direct links between the genetic and proteomic findings are still lacking for schizophrenia. We investigated associations between single nucleotide polymorphisms (SNPs) from the custom-made PsychArray and the expression levels of 190 multiplex immunoassay profiled serum proteins in 149 schizophrenia patients and 198 matched controls. We identified associations between 81 SNPs and 29 proteins, primarily involved in immune/inflammation responses. Significant SNPxDiagnosis interactions were identified for eight serum proteins including Factor-VII[rs555212], Alpha-1-Antitrypsin[rs11846959], Interferon-Gamma Induced Protein 10[rs4256246] and von-Willebrand-Factor[rs12829220] in the control group; Chromogranin-A[rs9658644], Cystatin-C[rs2424577] and Vitamin K-Dependent Protein S[rs6123] in the schizophrenia group; Interleukin-6 receptor[rs7553796] in both the control and schizophrenia groups. These results suggested that the effect of these SNPs on expression of the respective proteins varies with diagnosis. The combination of patient-specific genetic information with blood biomarker data opens a novel approach to investigate disease mechanisms in schizophrenia and other psychiatric disorders. Our findings not only suggest that blood protein expression is influenced by polymorphisms in the corresponding gene, but also that the effect of certain SNPs on expression of proteins can vary with diagnosis

DeepWAS: Multivariate genotype-phenotype associations by directly integrating regulatory information using deep learning

Genome-wide association studies (GWAS) identify genetic variants associated with traits or diseases. GWAS never directly link variants to regulatory mechanisms. Instead, the functional annotation of variants is typically inferred by post hoc analyses. A specific class of deep learning-based methods allows for the prediction of regulatory effects per variant on several cell type-specific chromatin features. We here describe \textquotedblDeepWAS\textquotedbl, a new approach that integrates these regulatory effect predictions of single variants into a multivariate GWAS setting. Thereby, single variants associated with a trait or disease are directly coupled to their impact on a chromatin feature in a cell type. Up to 61 regulatory SNPs, called dSNPs, were associated with multiple sclerosis (MS, 4,888 cases and 10,395 controls), major depressive disorder (MDD, 1,475 cases and 2,144 controls), and height (5,974 individuals). These variants were mainly non-coding and reached at least nominal significance in classical GWAS. The prediction accuracy was higher for DeepWAS than for classical GWAS models for 91% of the genome-wide significant, MS-specific dSNPs. DSNPs were enriched in public or cohort-matched expression and methylation quantitative trait loci and we demonstrated the potential of DeepWAS to generate testable functional hypotheses based on genotype data alone. DeepWAS is available at https://github.com/cellmapslab/DeepWAS

Reduced Anxiety and Depression-Like Behaviours in the Circadian Period Mutant Mouse Afterhours

Disruption of the circadian rhythm is a key feature of bipolar disorder. Variation in genes encoding components of the molecular circadian clock has been associated with increased risk of the disorder in clinical populations. Similarly in animal models, disruption of the circadian clock can result in altered mood and anxiety which resemble features of human mania; including hyperactivity, reduced anxiety and reduced depression-like behaviour. One such mutant, after hours (Afh), an ENU-derived mutant with a mutation in a recently identified circadian clock gene Fbxl3, results in a disturbed (long) circadian rhythm of approximately 27 hours.Anxiety, exploratory and depression-like behaviours were evaluated in Afh mice using the open-field, elevated plus maze, light-dark box, holeboard and forced swim test. To further validate findings for human mania, polymorphisms in the human homologue of FBXL3, genotyped by three genome wide case control studies, were tested for association with bipolar disorder.Afh mice showed reduced anxiety- and depression-like behaviour in all of the behavioural tests employed, and some evidence of increased locomotor activity in some tests. An analysis of three separate human data sets revealed a gene wide association between variation in FBXL3 and bipolar disorder (P = 0.009).Our results are consistent with previous studies of mutants with extended circadian periods and suggest that disruption of FBXL3 is associated with mania-like behaviours in both mice and humans

Quasiparticle Effective Mass for the Two- and Three-Dimensional Electron Gas

We calculate the quasiparticle effective mass for the electron gas in two and three dimensions in the metallic region. We employ the single particle scattering potential coming from the Sj\"{o}lander-Stott theory and enforce the Friedel sum rule by adjusting the effective electron mass in a scattering calculation. In 3D our effective mass is a monotonically decreasing function of $r_s$ throughout the whole metallic domain, as implied by the most recent numerical results. In 2D we obtain reasonable agreement with the experimental data, as well as with other calculations based on the Fermi liquid theory. We also present results of a variety of different treatments for the effective mass in 2D and 3D.Comment: 12 pages, 2 figure

Electronic Collective Modes and Superconductivity in Layered Conductors

A distinctive feature of layered conductors is the presence of low-energy electronic collective modes of the conduction electrons. This affects the dynamic screening properties of the Coulomb interaction in a layered material. We study the consequences of the existence of these collective modes for superconductivity. General equations for the superconducting order parameter are derived within the strong-coupling phonon-plasmon scheme that account for the screened Coulomb interaction. Specifically, we calculate the superconducting critical temperature Tc taking into account the full temperature, frequency and wave-vector dependence of the dielectric function. We show that low-energy plasmons may contribute constructively to superconductivity. Three classes of layered superconductors are discussed within our model: metal-intercalated halide nitrides, layered organic materials and high-Tc oxides. In particular, we demonstrate that the plasmon contribution (electronic mechanism) is dominant in the first class of layered materials. The theory shows that the description of so-called ``quasi-two-dimensional superconductors'' cannot be reduced to a purely 2D model, as commonly assumed. While the transport properties are strongly anisotropic, it remains essential to take into account the screened interlayer Coulomb interaction to describe the superconducting state of layered materials.Comment: Final version (minor changes) 14 pages, 6 figure

UV-curable gels as topical nail medicines: in vivo residence, anti-fungal efficacy and influence of gel components on their properties

UV-curable gels, used as nail cosmetics for their in vivo durability, were reported to be promising as topical nail medicines. Our first aim was thus to investigate whether such durability applies to drug-loaded formulations. This was found to be true. However, ethanol inclusion in the pharmaceutical formulation (to enable drug loading) reduced the in vivo residence. The second aim was therefore to determine any other effects of ethanol, and if ethanol could be avoided by the choice of monomers. Thus, three methacrylate monomers, ethyl methacrylate, isobornyl methacrylate and 2-hydroxyethyl methacrylate (HEMA) were selected, and their influence on the formulation properties were determined. Ethanol and the methacrylate monomer influenced some (but not all) of the formulation properties. The most significant was that HEMA could dissolve drug and enable the preparation of ethanol-free, drug-loaded formulations, which would benefit in vivo residence. The absence of ethanol reduced drug loading, release and ungual flux, but had no negative impact on the in vitro anti-fungal efficacy. Thus, judicious selection of gel components enabled the exclusion of ethanol. The long in vivo residence, little residual monomers, sufficient ungual permeation and in vitro anti-fungal activity of the gels indicates their potential as anti-onychomycotic topical medicines

Polarons and bipolarons in strongly interacting electron-phonon systems

The Holstein Hubbard and Holstein t--J models are studied for a wide range of phonon frequencies, electron--electron and electron--phonon interaction strengths on finite lattices with up to ten sites by means of direct Lanczos diagonalization. Previously the necessary truncation of the phononic Hilbert space caused serious limitations to either very small systems (four or even two sites) or to weak electron--phonon coupling, in particular in the adiabatic regime. Using parallel computers we were able to investigate the transition from `large' to `small' polarons in detail. By resolving the low--lying eigenstates of the Hamiltonian and by calculating the spectral function we can identify a polaron band in the strong--coupling case, whose dispersion deviates from the free--particle dispersion at low and intermediate phonon frequencies. For two electrons (holes) we establish the existence of bipolaronic states and discuss the formation of a bipolaron band. For the 2D Holstein t--J model we demonstrate that the formation of hole--polarons is favoured by strong Coulomb correlations. Analyzing the hole--hole correlation functions we find that hole binding is enhanced as a dynamical effect of the electron--phonon interaction.Comment: 23 pages (Revtex) with 13 figures (ps, uuencoded

Role of Van Hove Singularities and Momentum Space Structure in High-Temperature Superconductivity

There is a great deal of interest in attributing the high critical temperatures of the cuprates to either the proximity of the Fermi level to a van Hove singularity or to structure of the superconducting pairing potential in momentum space far from the Fermi surface. We examine these ideas by calculating the critical temperature Tc for model Einstein-phonon- and spin-fluctuation-mediated superconductors within both the standard, Fermi-surface-restricted Eliashberg theory and the exact mean field theory, which accounts for the full momentum structure of the pairing potential and the energy dependence of the density of states. By using two models of spin-fluctuation-mediated pairing in the cuprates, we demonstrate that our results are independent of the details of the dynamical susceptibility, which is taken to be the pairing potential. We also compare these two models against available neutron scattering data, since these data provide the most direct constraints on the susceptibility. We conclude that the van Hove singularity does not drastically alter Tc from its value when the density of states is constant and that the effect of momentum structure is significant but secondary in importance to that of the energy dependence in the density of states.Comment: 23 pages, 6 figures upon request, revtex version 2, vHs-