Meta-analysis of exome array data identifies six novel genetic loci for lung function

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<2·8x10-7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs (SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease

Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of l

The effectiveness of Theraplay for children under 12 – a systematic literature review

Background Theraplay is a relationship‐focused model of treatment based on attachment theory involving both adult and child. The study aims to review the quality of Theraplay research and Theraplay’s effectiveness for children aged 12 years and under with a range of presenting difficulties, to inform future practice and identify areas for further research. Methods A systematic literature search was conducted using PsycINFO, CINAHL, MEDLINE and Web of Science. Quantitative studies using Theraplay only as a treatment for children aged 12 years and under with any presenting difficulty were identified. Additional manual searching was conducted, including eligible studies’ reference lists. Critical appraisal tools were used to provide a narrative synthesis of Theraplay’s effectiveness and research quality. Results Only six eligible articles were identified, meaning there was a lack of rigorous evidence eligible to offer conclusions into Theraplay’s effectiveness. The review highlighted the small evidence base, mixed quality research methodology and high levels of heterogeneity in how Theraplay is practiced and evaluated. Of the eligible studies, Theraplay was found promising in its effectiveness when used with internalising and externalising difficulties, dual diagnoses and developmental disabilities. Conclusions Theraplay is regularly practiced across the world; however, the evidence base of rigorous research to inform Theraplay’s effectiveness and mechanisms of change is lacking. Firm conclusions could not be offered, although Theraplay was shown to be promising intervention for some presentations. Further research into Theraplay’s effectiveness and key mechanisms of change are recommended to enhance the quality and depth of Theraplay literature

Omega-3 fatty acids and genome-wide interaction analyses reveal DPP10–pulmonary function association

Rationale: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health. Objective: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility. Methods: Associations of n-3 PUFA biomarkers (a-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (FEV 1 , FVC, and FEV 1 /FVC) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N = 16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N = 11,962) and replicated in one cohort (N = 1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of SNP associations and their interactions with n-3 PUFAs Results: DPA and DHA were positively associated with FEV 1 and FVC (P, 0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320—an intronic DPP10 SNP—with FVC when incorporating an interaction with DHA, and the finding was replicated (P 2df = 9.4 3 10 29 across discovery and replication cohorts). The rs11693320-A allele (frequency, z80%) was associated with lower FVC (P SNP = 2.1 3 10 29 ; b SNP = 2161.0 ml), and the association was attenuated by higher DHA levels (P SNP 3DHA interaction = 2.1 3 10 27 ; b SNP 3DHA interaction = 36.2 ml). Conclusions: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction

Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry

Search for single vector-like B quark production and decay via B → bH(b¯b) in pp collisions at √s = 13 TeV with the ATLAS detector

A search is presented for single production of a vector-like B quark decaying into a Standard Model b-quark and a Standard Model Higgs boson, which decays into a b¯b pair. The search is carried out in 139 fb−1 of √s = 13 TeV proton-proton collision data collected by the ATLAS detector at the LHC between 2015 and 2018. No significant deviation from the Standard Model background prediction is observed, and mass-dependent exclusion limits at the 95% confidence level are set on the resonance production cross-section in several theoretical scenarios determined by the couplings cW, cZ and cH between the B quark and the Standard Model W, Z and Higgs bosons, respectively. For a vector-like B occurring as an isospin singlet, the search excludes values of cW greater than 0.45 for a B resonance mass (mB) between 1.0 and 1.2 TeV. For 1.2 TeV < mB < 2.0 TeV, cW values larger than 0.50–0.65 are excluded. If the B occurs as part of a (B, Y) doublet, the smallest excluded cZ coupling values range between 0.3 and 0.5 across the investigated resonance mass range 1.0 TeV < mB < 2.0 TeV

Search for long-lived neutral particles in pp collisions at s√=13 TeV that decay into displaced hadronic jets in the ATLAS calorimeter

This paper describes a search for pairs of neutral, long-lived particles decaying in the ATLAS calorimeter. Long-lived particles occur in many extensions to the Standard Model and may elude searches for new promptly decaying particles. The analysis considers neutral, long-lived scalars with masses between 5 and 400 GeV, produced from decays of heavy bosons with masses between 125 and 1000 GeV, where the long-lived scalars decay into Standard Model fermions. The analysis uses either 10.8 fb−1 or 33.0 fb−1 of data (depending on the trigger) recorded in 2016 at the LHC with the ATLAS detector in proton–proton collisions at a centre-of-mass energy of 13 TeV. No significant excess is observed, and limits are reported on the production cross section times branching ratio as a function of the proper decay length of the long-lived particles

Search for exclusive Higgs and Z boson decays to ϕγ and ργ with the ATLAS detector

A search for the exclusive decays of the Higgs and Z bosons to a φ or ρ meson and a photon is performed with a pp collision data sample corresponding to an integrated luminosity of up to 35.6 fb−1 collected at √s = 13 TeV with the ATLAS detector at the CERN Large Hadron Collider. These decays have been suggested as a probe of the Higgs boson couplings to light quarks. No significant excess of events is observed above the background, as expected from the Standard Model. Upper limits at 95% confidence level were obtained on the branching fractions of the Higgs boson decays to φγ and ργ of 4.8 × 10−4 and 8.8 × 10−4, respectively. The corresponding 95% confidence level upper limits for the Z boson decays are 0.9 × 10−6 and 25 × 10−6 for φγ and ργ, respectively