A meta-analysis of gene expression quantitative trait loci in brain

Current catalogs of brain expression quantitative trait loci (eQTL) are incomplete and the findings do not replicate well across studies. All existing cortical eQTL studies are small and emphasize the need for a meta-analysis. We performed a meta-analysis of 424 brain samples across five studies to identify regulatory variants influencing gene expression in human cortex. We identified 3584 genes in autosomes and chromosome X with false discovery rate q<0.05 whose expression was significantly associated with DNA sequence variation. Consistent with previous eQTL studies, local regulatory variants tended to occur symmetrically around transcription start sites and the effect was more evident in studies with large sample sizes. In contrast to random SNPs, we observed that significant eQTLs were more likely to be near 5'-untranslated regions and intersect with regulatory features. Permutation-based enrichment analysis revealed that SNPs associated with schizophrenia and bipolar disorder were enriched among brain eQTLs. Genes with significant eQTL evidence were also strongly associated with diseases from OMIM (Online Mendelian Inheritance in Man) and the NHGRI (National Human Genome Research Institute) genome-wide association study catalog. Surprisingly, we found that a large proportion (28%) of ~1000 autosomal genes encoding proteins needed for mitochondrial structure or function were eQTLs (enrichment P-value=1.3 × 10−9), suggesting a potential role for common genetic variation influencing the robustness of energy supply in brain and a possible role in the etiology of some psychiatric disorders. These systematically generated eQTL information should be a valuable resource in determining the functional mechanisms of brain gene expression and the underlying biology of associations with psychiatric disorders

Gene expression changes following chronic antipsychotic exposure in single cells from mouse striatum

Schizophrenia is an idiopathic psychiatric disorder with a high degree of polygenicity. Evidence from genetics, single-cell transcriptomics, and pharmacological studies suggest an important, but untested, overlap between genes involved in the etiology of schizophrenia and the cellular mechanisms of action of antipsychotics. To directly compare genes with antipsychotic-induced differential expression to genes involved in schizophrenia, we applied single-cell RNA-sequencing to striatal samples from male C57BL/6 J mice chronically exposed to a typical antipsychotic (haloperidol), an atypical antipsychotic (olanzapine), or placebo. We identified differentially expressed genes in three cell populations identified from the single-cell RNA-sequencing (medium spiny neurons [MSNs], microglia, and astrocytes) and applied multiple analysis pipelines to contextualize these findings, including comparison to GWAS results for schizophrenia. In MSNs in particular, differential expression analysis showed that there was a larger share of differentially expressed genes (DEGs) from mice treated with olanzapine compared with haloperidol. DEGs were enriched in loci implicated by genetic studies of schizophrenia, and we highlighted nine genes with convergent evidence. Pathway analyses of gene expression in MSNs highlighted neuron/synapse development, alternative splicing, and mitochondrial function as particularly engaged by antipsychotics. In microglia, we identified pathways involved in microglial activation and inflammation as part of the antipsychotic response. In conclusion, single-cell RNA sequencing may provide important insights into antipsychotic mechanisms of action and links to findings from psychiatric genomic studies

The Infrared Behaviour of the Pure Yang-Mills Green Functions

We review the infrared properties of the pure Yang-Mills correlators and discuss recent results concerning the two classes of low-momentum solutions for them reported in literature; i.e. decoupling and scaling solutions. We will mainly focuss on the Landau gauge and pay special attention to the results inferred from the analysis of the Dyson-Schwinger equations of the theory and from "{\it quenched}" lattice QCD. The results obtained from properly interplaying both approaches are strongly emphasized.Comment: Final version to be published in FBS (54 pgs., 11 figs., 4 tabs

Common-variant associations with fragile X syndrome

Fragile X syndrome is rare but a prominent cause of intellectual disability. It is usually caused by a de novo mutation that occurs on multiple haplotypes and thus would not be expected to be detectible using genome-wide association (GWA). We conducted GWA in 89 male FXS cases and 266 male controls, and detected multiple genome-wide significant signals near FMR1 (odds ratio = 8.10, P = 2.5 × 10 −10 ). These findings withstood robust attempts at falsification. Fine-mapping yielded a minimum P = 1.13 × 10 −14 , but did not narrow the interval. Comprehensive functional genomic integration did not provide a mechanistic hypothesis. Controls carrying a risk haplotype had significantly longer FMR1 CGG repeats than controls with the protective haplotype (P = 4.75 × 10 −5 ), which may predispose toward increases in CGG number to the premutation range over many generations. This is a salutary reminder of the complexity of even “simple” monogenetic disorders

Comparative genomic evidence for the involvement of schizophrenia risk genes in antipsychotic effects

Genome-wide association studies (GWAS) for schizophrenia have identified over 100 loci encoding >500 genes. It is unclear whether any of these genes, other than dopamine receptor D 2, are immediately relevant to antipsychotic effects or represent novel antipsychotic targets. We applied an in vivo molecular approach to this question by performing RNA sequencing of brain tissue from mice chronically treated with the antipsychotic haloperidol or vehicle. We observed significant enrichments of haloperidol-regulated genes in schizophrenia GWAS loci and in schizophrenia-associated biological pathways. Our findings provide empirical support for overlap between genetic variation underlying the pathophysiology of schizophrenia and the molecular effects of a prototypical antipsychotic

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011

Expected Performance of the ATLAS Experiment - Detector, Trigger and Physics

A detailed study is presented of the expected performance of the ATLAS detector. The reconstruction of tracks, leptons, photons, missing energy and jets is investigated, together with the performance of b-tagging and the trigger. The physics potential for a variety of interesting physics processes, within the Standard Model and beyond, is examined. The study comprises a series of notes based on simulations of the detector and physics processes, with particular emphasis given to the data expected from the first years of operation of the LHC at CERN

Measurement of the top quark-pair production cross section with ATLAS in pp collisions at \sqrt{s}=7\TeV

A measurement of the production cross-section for top quark pairs(\ttbar) in $pp$ collisions at \sqrt{s}=7 \TeV is presented using data recorded with the ATLAS detector at the Large Hadron Collider. Events are selected in two different topologies: single lepton (electron $e$ or muon $\mu$) with large missing transverse energy and at least four jets, and dilepton ($ee$, $\mu\mu$ or $e\mu$) with large missing transverse energy and at least two jets. In a data sample of 2.9 pb-1, 37 candidate events are observed in the single-lepton topology and 9 events in the dilepton topology. The corresponding expected backgrounds from non-\ttbar Standard Model processes are estimated using data-driven methods and determined to be $12.2 \pm 3.9$ events and $2.5 \pm 0.6$ events, respectively. The kinematic properties of the selected events are consistent with SM \ttbar production. The inclusive top quark pair production cross-section is measured to be \sigmattbar=145 \pm 31 ^{+42}_{-27} pb where the first uncertainty is statistical and the second systematic. The measurement agrees with perturbative QCD calculations.Comment: 30 pages plus author list (50 pages total), 9 figures, 11 tables, CERN-PH number and final journal adde