Showing papers by "Jennifer A. Smith published in 2016"

Genome-wide association study identifies 74 loci associated with educational attainment

Abstract: Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Abstract: Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.

Event generator tunes obtained from underlying event and multiparton scattering measurements

Abstract: New sets of parameters ("tunes") for the underlying-event (UE) modeling of the PYTHIA8, PYTHIA6 and HERWIG++ Monte Carlo event generators are constructed using different parton distribution functions. Combined fits to CMS UE data at sqrt(s) = 7 TeV and to UE data from the CDF experiment at lower sqrt(s), are used to study the UE models and constrain their parameters, providing thereby improved predictions for proton-proton collisions at 13 TeV. In addition, it is investigated whether the values of the parameters obtained from fits to UE observables are consistent with the values determined from fitting observables sensitive to double-parton scattering processes. Finally, comparisons of the UE tunes to "minimum bias" (MB) events, multijet, and Drell-Yan (q q-bar to Z / gamma* to lepton-antilepton + jets) observables at 7 and 8 TeV are presented, as well as predictions of MB and UE observables at 13 TeV.

Epigenetic Signatures of Cigarette Smoking

Abstract: Background —DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders. Methods and Results —To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15,907 blood derived DNA samples from participants in 16 cohorts (including 2,433 current, 6,518 former, and 6,956 never smokers). Comparing current versus never smokers, 2,623 CpG sites (CpGs), annotated to 1,405 genes, were statistically significantly differentially methylated at Bonferroni threshold of p<1×10-7 (18,760 CpGs at False Discovery Rate (FDR)<0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant p<1×10-7 (2,623 CpGs at FDR<0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs. Conclusions —Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biologic effects of smoking, and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Abstract: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

Genome-wide analysis identifies 12 loci influencing human reproductive behavior

Abstract: The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits

DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

Abstract: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation. We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10–7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10–4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10–5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10–3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10–5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants. We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.

Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci

Abstract: Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

Loci associated with ischaemic stroke and its subtypes (SiGN) : A genome-wide association study

Abstract: Summary Background The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes. Methods To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16 851 cases with state-of-the-art phenotyping data and 32 473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20 941 cases and 364 736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10 172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis. Findings We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13–1·30, p=4·50 × 10 −8 ; joint OR 1·19, 1·12–1·26, p=1·30 × 10 −9 ). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29–1·49, p=3·26 × 10 −19 ; joint OR 1·37, 1·30–1·45, p=2·79 × 10 −32 ) and ZFHX3 (first stage OR 1·19, 1·11–1·27, p=2·93 × 10 −7 ; joint OR 1·17, 1·11–1·23, p=2·29 × 10 −10 ) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18–1·42, p=3·50 × 10 −8 ; joint OR 1·24, 1·15–1·33, p=4·52 × 10 −9 ) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2 , which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12–1·28, p=6·82 × 10 −8 ; joint OR 1·17, 1·11–1·23, p=2·92 × 10 −9 ). Other loci associated with stroke in previous studies, including NINJ2 , were not confirmed. Interpretation Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke. Funding US National Institute of Neurological Disorders and Stroke, National Institutes of Health.

Search for Narrow Resonances Decaying to Dijets in Proton-Proton Collisions at √[s]=13 TeV.

Abstract: A search for narrow resonances in proton-proton collisions at sqrt(s) = 13 TeV is presented. The invariant mass distribution of the two leading jets is measured with the CMS detector using a data set corresponding to an integrated luminosity of 2.4 inverse femtobarns. The highest observed dijet mass is 6.1 TeV. The distribution is smooth and no evidence for resonant particles is observed. Upper limits at 95% confidence level are set on the production cross section for narrow resonances with masses above 1.5 TeV. When interpreted in the context of specific models, the limits exclude string resonances with masses below 7.0 TeV, scalar diquarks below 6.0 TeV, axigluons and colorons below 5.1 TeV, excited quarks below 5.0 TeV, color-octet scalars below 3.1 TeV, and W' bosons below 2.6 TeV. These results significantly extend previously published limits.

Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Abstract: Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (\textbarρ^\textbar ? 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.

Search for s channel single top quark production in pp collisions at √s = 7 and 8 TeV

Abstract: A search is presented for single top quark production in the s channel in proton-proton collisions with the CMS detector at the CERN LHC in decay modes of the top quark containing a muon or an electron in the final state. The signal is extracted through a maximum-likelihood fit to the distribution of a multivariate discriminant defined using boosted decision trees to separate the expected signal contribution from background processes. Data collected at centre-of-mass energies of 7 and 8 TeV yield cross sections of 7.1 +/- 8.1 pb and 13.4 +/- 7.3 pb, respectively, and a best fit value of 2.0 +/- 0.9 for the combined ratio of the measured and expected values. The signal significance is 2.5 standard deviations, and the upper limit on the rate relative to the standard model expectation is 4.7 at 95% confidence level.

Search for Resonant Production of High-Mass Photon Pairs in Proton-Proton Collisions at s =8 and 13 TeV

Abstract: A search for the resonant production of high-mass photon pairs is presented. The analysis is based on samples of proton-proton collision data collected by the CMS experiment at center-of-mass energies of 8 and 13 TeV, corresponding to integrated luminosities of 19.7 and 3.3 fb(-1), respectively. The interpretation of the search results focuses on spin-0 and spin-2 resonances with masses between 0.5 and 4 TeV and with widths, relative to the mass, between 1.4 x 10(-4) and 5.6 x 10(-2). Limits are set on scalar resonances produced through gluon-gluon fusion, and on Randall-Sundrum gravitons. A modest excess of events compatible with a narrow resonance with a mass of about 750 GeV is observed. The local significance of the excess is approximately 3.4 standard deviations. The significance is reduced to 1.6 standard deviations once the effect of searching under multiple signal hypotheses is considered. More data are required to determine the origin of this excess.

GWAS for executive function and processing speed suggests involvement of the CADM2 gene

Abstract: To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

Search for vectorlike charge 2/3 T quarks in proton-proton collisions at √(s) = 8 TeV

Abstract: A search for fermionic top quark partners T of charge 2/3 is presented. The search is carried out in proton-proton collisions corresponding to an integrated luminosity of 19.7 inverse femtobarns collected at a center-of-mass energy of sqrt(s) = 8 TeV with the CMS detector at the LHC. The T quarks are assumed to be produced strongly in pairs and can decay into tH, tZ, and bW. The search is performed in five exclusive channels: a single-lepton channel, a multilepton channel, two all-hadronic channels optimized either for the bW or the tH decay, and one channel in which the Higgs boson decays into two photons. The results are found to be compatible with the standard model expectations in all the investigated final states. A statistical combination of these results is performed and lower limits on the T quark mass are set. Depending on the branching fractions, lower mass limits between 720 and 920 GeV at 95% confidence level are found. These are among the strongest limits on vector-like T quarks obtained to date.

GWAS for executive function and processing speed suggests involvement of the CADM2 gene

Abstract: To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429–32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10−8) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10−9 after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10−4). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10−15), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10−11) and neuron cell-cell adhesion (P-value=1.48 × 10−13). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

Search for Narrow Resonances in Dijet Final States at sqrt[s]=8 TeV with the Novel CMS Technique of Data Scouting.

Abstract: A search for narrow resonances decaying into dijet final states is performed on data from proton-proton collisions at a center-of-mass energy of 8 TeV, corresponding to an integrated luminosity of 18.8 fb(-1). The data were collected with the CMS detector using a novel technique called data scouting, in which the information associated with these selected events is much reduced, permitting collection of larger data samples. This technique enables CMS to record events containing jets at a rate of 1 kHz, by collecting the data from the high-level-trigger system. In this way, the sensitivity to low-mass resonances is increased significantly, allowing previously inaccessible couplings of new resonances to quarks and gluons to be probed. The resulting dijet mass distribution yields no evidence of narrow resonances. Upper limits are presented on the resonance cross sections as a function of mass, and compared with a variety of models predicting narrow resonances. The limits are translated into upper limits on the coupling of a leptophobic resonance Z'(B) to quarks, improving on the results obtained by previous experiments for the mass range from 500 to 800 GeV.

Genetic variants linked to education predict longevity

Abstract: Educational attainment is associated with many health outcomes, including longevity It is also known to be substantially heritable Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ∼17,000; UK Biobank, n = ∼115,000; and the Estonian Biobank, n = ∼6,000) to test whether education-linked genetic variants can predict lifespan length We did so by using cohort members' polygenic profile score for education to predict their parents' longevity Across the three cohorts, meta-analysis showed that a 1 SD higher polygenic education score was associated with ∼27% lower mortality risk for both mothers (total ndeaths = 79,702) and ∼24% lower risk for fathers (total ndeaths = 97,630) On average, the parents of offspring in the upper third of the polygenic score distribution lived 055 y longer compared with those of offspring in the lower third Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity

Genome-wide association study (gwas) and genome-wide by environment interaction study (gweis) of depressive symptoms in african american and hispanic/latina women.

Abstract: Background Genome-wide association studies (GWAS) have made little progress in identifying variants linked to depression. We hypothesized that examining depressive symptoms and considering gene–environment interaction (GxE) might improve efficiency for gene discovery. We therefore conducted a GWAS and genome-wide by environment interaction study (GWEIS) of depressive symptoms. Methods Using data from the SHARe cohort of the Women's Health Initiative, comprising African Americans (n = 7,179) and Hispanics/Latinas (n = 3,138), we examined genetic main effects and GxE with stressful life events and social support. We also conducted a heritability analysis using genome-wide complex trait analysis (GCTA). Replication was attempted in four independent cohorts. Results No SNPs achieved genome-wide significance for main effects in either discovery sample. The top signals in African Americans were rs73531535 (located 20 kb from GPR139, P = 5.75 × 10−8) and rs75407252 (intronic to CACNA2D3, P = 6.99 × 10−7). In Hispanics/Latinas, the top signals were rs2532087 (located 27 kb from CD38, P = 2.44 × 10−7) and rs4542757 (intronic to DCC, P = 7.31 × 10−7). In the GEWIS with stressful life events, one interaction signal was genome-wide significant in African Americans (rs4652467; P = 4.10 × 10−10; located 14 kb from CEP350). This interaction was not observed in a smaller replication cohort. Although heritability estimates for depressive symptoms and stressful life events were each less than 10%, they were strongly genetically correlated (rG = 0.95), suggesting that common variation underlying self-reported depressive symptoms and stressful life event exposure, though modest on their own, were highly overlapping in this sample. Conclusions Our results underscore the need for larger samples, more GEWIS, and greater investigation into genetic and environmental determinants of depressive symptoms in minorities.

A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

Abstract: Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.

Search for a massive resonance decaying into a Higgs boson and a W or Z boson in hadronic final states in proton-proton collisions at √s = 8 TeV

Abstract: A search for a massive resonance decaying into a standard- model-like Higgs boson (H) and a W or Z boson is reported. The analysis is performed on a data sample corresponding to an integrated luminosity of 19.7 inverse femtobarns, collected in proton-proton collisions at a centre-of-mass energy of 8 TeV with the CMS detector at the LHC. Signal events, in which the decay products of Higgs, W, or Z bosons at high Lorentz boost are contained within single reconstructed jets, are identified using jet substructure techniques, including the tagging of b hadrons. This is the first search for heavy resonances decaying into HW or HZ resulting in an all-jet final state, as well as the first application of jet substructure techniques to identify H to WW* to 4q decays at high Lorentz boost. No significant signal is observed and limits are set at 95% confidence level on the production cross section of W' and Z' in a model with mass-degenerate charged and neutral spin-1 resonances. Resonance masses are excluded for W' in the interval [1.0, 1.6] TeV, for Z' in the intervals [1.0, 1.1] and [1.3, 1.5] TeV, and for mass-degenerate W' and Z' in the interval [1.0, 1.7] TeV.

Measurement of the differential cross section and charge asymmetry for inclusive pp→W±+X production at s√=8 TeV

Abstract: The differential cross section and charge asymmetry for inclusive pp to W + X to mu-nu + X production at sqrt(s) = 8 TeV are measured as a function of muon pseudorapidity. The data sample corresponds to an integrated luminosity of 18.8 inverse-femtobarns recorded with the CMS detector at the LHC. These results provide important constraints on the parton distribution functions of the proton in the range of the Bjorken scaling variable x from 10 to the minus 3 to 10 to the minus 1.

Measurement of the W+W- cross section in pp collisions at s=8 TeVand limits on anomalous gauge couplings

Abstract: A measurement of the W boson pair production cross section in proton-proton collisions at √s = 8 TeV is presented. The data collected with the CMS detector at the LHC correspond to an integrated luminosity of 19.4 fb^(-1). The W^+W^− candidates are selected from events with two charged leptons, electrons or muons, and large missing transverse energy. The measured W^+W^− cross section is 60.1 ± 0.9(stat) ± 3.2 (exp) ± 3.1(theo)±1.6 (lumi)\,pb = 60.1 ± 4.8\,pb60.1 ± 0.9 (stat) ±3.2 (exp)±3.1 (theo) ± 1.6 (lumi)\,pb = 60.1 ± 4.8\, pb, consistent with the standard model prediction. The W^+W^− cross sections are also measured in two different fiducial phase space regions. The normalized differential cross section is measured as a function of kinematic variables of the final-state charged leptons and compared with several perturbative QCD predictions. Limits on anomalous gauge couplings associated with dimension-six operators are also given in the framework of an effective field theory. The corresponding 95 % confidence level intervals are −5.7