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

A functional variant in the serotonin receptor 7 gene (HTR7), rs7905446, is associated with good response to SSRIs in bipolar and unipolar depression.

Predicting antidepressant response has been a clinical challenge for mood disorder. Although several genome-wide association studies have suggested a number of genetic variants to be associated with antidepressant response, the sample sizes are small and the results are difficult to replicate. Previous animal studies have shown that knockout of the serotonin receptor 7 gene (HTR7) resulted in an antidepressant-like phenotype, suggesting it was important to antidepressant action. In this report, in the first stage, we used a cost-effective pooled-sequencing strategy to sequence the entire HTR7 gene and its regulatory regions to investigate the association of common variants in HTR7 and clinical response to four selective serotonin reuptake inhibitors (SSRIs: citalopram, paroxetine, fluoxetine and sertraline) in a retrospective cohort mainly consisting of subjects with bipolar disorder (n = 359). We found 80 single-nucleotide polymorphisms (SNPs) with false discovery rate < 0.05 associated with response to paroxetine. Among the significant SNPs, rs7905446 (T/G), which is located at the promoter region, also showed nominal significance (P < 0.05) in fluoxetine group. GG/TG genotypes for rs7905446 and female gender were associated with better response to two SSRIs (paroxetine and fluoxetine). In the second stage, we replicated this association in two independent prospective samples of SSRI-treated patients with major depressive disorder: the MARS (n = 253, P = 0.0169) and GENDEP studies (n = 432, P = 0.008). The GG/TG genotypes were consistently associated with response in all three samples. Functional study of rs7905446 showed greater activity of the G allele in regulating expression of HTR7. The G allele displayed higher luciferase activity in two neuronal-related cell lines, and estrogen treatment decreased the activity of only the G allele. Electrophoretic mobility shift assay suggested that the G allele interacted with CCAAT/enhancer-binding protein beta transcription factor (TF), while the T allele did not show any interaction with any TFs. Our results provided novel pharmacogenomic evidence to support the role of HTR7 in association with antidepressant response

Solution of the Multi-Channel Anderson Impurity Model: Ground state and thermodynamics

We present the solution of the SU(N) x SU(M) Anderson impurity model using the Bethe-Ansatz. We first explain what extensions to the formalism were required for the solution. Subsequently we determine the ground state and derive the thermodynamics over the full range of temperature and fields. We identify the different regimes of valence fluctuation at high temperatures, followed by moment formation or intrinsic mixed valence at intermediate temperatures and a low temperature non-Fermi liquid phase. Among other things we obtain the impurity entropy, charge valence and specific heat over the full range of temperature. We show that the low-energy physics is governed by a line of fixed points. This describes non-Fermi-liquid behavior in the integral valence regime, associated with moment formation, as well as in the mixed valence regime where no moment forms.Comment: 28 pages, 8 figures, 1 tabl

The Influence of Social Evaluation on Heart Rate Variability and Motor Performance: A Study of “Real-Life” Competition

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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

Parity nonconserving cold neutron-parahydrogen interactions

Three pion dominated observables of the parity nonconserving interactions between the cold neutrons and parahydrogen are calculated. The transversely polarized neutron spin rotation, unpolarized neutron longitudinal polarization, and photon-asymmetry of the radiative polarized neutron capture are considered. For the numerical evaluation of the observables, the strong interactions are taken into account by the Reid93 potential and the parity nonconserving interactions by the DDH model along with the two-pion exchange.Comment: 17 pages, 2 figure

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-