Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies

Background: Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. Methods and findings: Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders\u2014namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)\u2014and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD\u2013immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal. Conclusions: We show immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD

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Measurement of the ratio B(t -> Wb)/B(t -> Wq) in pp collisions at root s=8 TeV

The ratio of the top-quark branching fractions R = B(t --> Wb)/B(t --> Wq), where the denominator includes the sum over all down-type quarks (q = b, s, d), is measured in the t (t) over bar dilepton final state with proton-proton collision data at root s = 8 TeV from an integrated luminosity of 19.7 fb(-1), collected with the CMS detector. In order to quantify the purity of the signal sample, the cross section is measured by fitting the observed jet multiplicity, thereby constraining the signal and background contributions. By counting the number of b jets per event, an unconstrained value of R = 1.014 +/- 0.003 (stat.) +/- 0.032 (syst.) is measured, in a good agreement with current precision measurements in electroweak and flavour sectors. A lower limit R > 0.955 at the 95% confidence level is obtained after requiring R 0.975 is set at 95% confidence level. The result is combined with a previous CMS measurement of the t-channel single-top-quark cross section to determine the top-quark total decay width, Gamma(t) = 1.36 +/- 0.02 (stat.)(-0.11)(+0.14) (syst.) GeV

Measurement of the cross section ratio sigma(t(t)over-barb(b)over-bar)/sigma(t(t)over-barjj) in pp collisions at root s=8 TeV

The first measurement of the cross section ratio sigma(t (t) over barb (b) over bar)/sigma(t (t) over bar jj) is presented using a data sample corresponding to an integrated luminosity of 19.6 fb(-1) collected in pp collisions at root s = 8 TeV with the CMS detector at the LHC. Events with two leptons (e or mu) and four reconstructed jets, including two identified as b quark jets, in the final state are selected. The ratio is determined for a minimum jet transverse momentum p(T) of both 20 and 40 GeV/c. The measured ratio is 0.022 +/- 0.003 (stat) +/- 0.005 (syst) for p(T) > 20GeV/c. The absolute cross sections sigma(t (t) over barb (b) over bar) and sigma(t (t) over bar jj) are also measured. The measured ratio for p(T) > 40 GeV/c is compatible with a theoretical quantum chromodynamics calculation at next-to-leading order. (C) 2015 CERN for the benefit of the CMS Collaboration

Measurement of the t(t)over-bar production cross section in pp collisions at root s=8 TeV in dilepton final states containing one tau lepton

The top-quark pair production cross section is measured in final states with one electron or muon and one hadronically decaying tau lepton from the process t (t) over bar -> (l nu(l))(tau nu(tau))b (b) over bar, where l = e, mu. The data sample corresponds to an integrated luminosity of 19.6 fb(-1) collected with the CMS detector in proton-proton collisions at root s = 8 TeV. The measured cross section sigma(t (t) over bar) = 257 +/- 3 (stat) +/- 24 (syst) +/- 7 (lumi) pb, assuming a top-quark mass of 172.5 GeV, is consistent with the standard model prediction

Search for a standard model-like Higgs boson in the mu(+)mu(-) and e(+)e(-) decay channels at the LHC

A search is presented for a standard model-like Higgs boson decaying to the mu(+)mu(-) or e(+)e(-) final states based on proton-proton collisions recorded by the CMS experiment at the CERN LHC. The data correspond to integrated luminosities of 5.0 fb(-1) at a centre-of-mass energy of 7 TeV and 19.7 fb(-1) at 8 TeV for the mu(+)mu(-) search, and of 19.7 fb(-1) at 8 TeV for the e(+)e(-) search. Upper limits on the production cross section times branching fraction at the 95% confidence level are reported for Higgs boson masses in the range from 120 to 150 GeV. For a Higgs boson with a mass of 125 GeV decaying to mu(+)mu(-), the observed (expected) upper limit on the production rate is found to be 7.4 (6.5(-1.9)(+2.8)) times the standard model value. This corresponds to an upper limit on the branching fraction of 0.0016. Similarly, for e(+)e(-), an upper limit of 0.0019 is placed on the branching fraction, which is approximate to 3.7 x 10(5) times the standard model value. These results, together with recent evidence of the 125 GeV boson coupling to tau-leptons with a larger branching fraction consistent with the standard model, confirm that the leptonic couplings of the new boson are not flavour-universal

Measurement of the production cross section for a W boson and two b jets in pp collisions at root s=7 TeV

The production cross section for a Wboson and two b jets is measured using proton-proton collisions at v root s = 7 TeV in a data sample collected with the CMS experiment at the LHC corresponding to an integrated luminosity of 5.0 fb(-1). The W + bbevents are selected in the W..decay mode by requiring a muon with transverse momentum pT> 25GeVand pseudorapidity |eta| 25GeVand |eta| < 2.4. The measured W + bbproduction cross section in the fiducial region, calculated at the level of final-state particles, is s(pp. W + bb) xB(W..) = 0.53 +/- 0.05 (stat.) +/- 0.09 (syst.) +/- 0.06 (theo.) 0.01 (lum.) pb, in agreement with the standard model prediction. In addition, kinematic distributions of the W + bbsystem are in agreement with the predictions of a simulation usingMadGraphandpythia