MyMedR

Fulltext Rapid Targeted Next-Generation Sequencing Platform for Molecular Screening and Clinical Genotyping in Subjects with Hemoglobinopathies

Shang X, Peng Z, Ye Y, Asan, Zhang X, Chen Y, et al.

EBioMedicine, 2017 Sep;23:150-159.

PMID: 28865746 DOI: 10.1016/j.ebiom.2017.08.015

Hemoglobinopathies are among the most common autosomal-recessive disorders worldwide. A comprehensive next-generation sequencing (NGS) test would greatly facilitate screening and diagnosis of these disorders. An NGS panel targeting the coding regions of hemoglobin genes and four modifier genes was designed. We validated the assay by using 2522 subjects affected with hemoglobinopathies and applied it to carrier testing in a cohort of 10,111 couples who were also screened through traditional methods. In the clinical genotyping analysis of 1182 β-thalassemia subjects, we identified a group of additional variants that can be used for accurate diagnosis. In the molecular screening analysis of the 10,111 couples, we detected 4180 individuals in total who carried 4840 mutant alleles, and identified 186 couples at risk of having affected offspring. 12.1% of the pathogenic or likely pathogenic variants identified by our NGS assay, which were undetectable by traditional methods. Compared with the traditional methods, our assay identified an additional at-risk 35 couples. We describe a comprehensive NGS-based test that offers advantages over the traditional screening/molecular testing methods. To our knowledge, this is among the first large-scale population study to systematically evaluate the application of an NGS technique in carrier screening and molecular diagnosis of hemoglobinopathies.

Fulltext Re-evaluating genetic variants identified in candidate gene studies of breast cancer risk using data from nearly 280,000 women of Asian and European ancestry

Yang Y, Shu X, Shu XO, Bolla MK, Kweon SS, Cai Q, et al.

EBioMedicine, 2019 Oct;48:203-211.

PMID: 31629678 DOI: 10.1016/j.ebiom.2019.09.006

BACKGROUND: We previously conducted a systematic field synopsis of 1059 breast cancer candidate gene studies and investigated 279 genetic variants, 51 of which showed associations. The major limitation of this work was the small sample size, even pooling data from all 1059 studies. Thereafter, genome-wide association studies (GWAS) have accumulated data for hundreds of thousands of subjects. It's necessary to re-evaluate these variants in large GWAS datasets.

METHODS: Of these 279 variants, data were obtained for 228 from GWAS conducted within the Asian Breast Cancer Consortium (24,206 cases and 24,775 controls) and the Breast Cancer Association Consortium (122,977 cases and 105,974 controls of European ancestry). Meta-analyses were conducted to combine the results from these two datasets.

FINDINGS: Of those 228 variants, an association was observed for 12 variants in 10 genes at a Bonferroni-corrected threshold of P 

Fulltext Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics

Jia G, Ping J, Shu X, Yang Y, Cai Q, Kweon SS, et al.

Am J Hum Genet, 2022 Dec 01;109(12):2185-2195.

PMID: 36356581 DOI: 10.1016/j.ajhg.2022.10.011

By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p

Fulltext Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants

Shu X, Long J, Cai Q, Kweon SS, Choi JY, Kubo M, et al.

Nat Commun, 2020 Mar 05;11(1):1217.

PMID: 32139696 DOI: 10.1038/s41467-020-15046-w

Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P

Fulltext Mendelian Randomization Analysis of n-6 Polyunsaturated Fatty Acid Levels and Pancreatic Cancer Risk

Ghoneim DH, Zhu J, Zheng W, Long J, Murff HJ, Ye F, et al.

Cancer Epidemiol Biomarkers Prev, 2020 Dec;29(12):2735-2739.

PMID: 32967863 DOI: 10.1158/1055-9965.EPI-20-0651

BACKGROUND: Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome.

METHODS: We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data.

RESULTS: Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98-1.02; arachidonic acid OR = 1.00, 95% CI = 0.99-1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87-1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex.

CONCLUSIONS: Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk.

IMPACT: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.

Fulltext Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk

Yang Y, Wu L, Shu X, Lu Y, Shu XO, Cai Q, et al.

Cancer Res, 2019 Feb 01;79(3):505-517.

PMID: 30559148 DOI: 10.1158/0008-5472.CAN-18-2726

DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.

Erratum to: Methods for evaluating medical tests and biomarkers

Gopalakrishna G, Langendam M, Scholten R, Bossuyt P, Leeflang M, Noel-Storr A, et al.

Diagn Progn Res, 2017;1:11.

PMID: 31095132 DOI: 10.1186/s41512-017-0011-4

[This corrects the article DOI: 10.1186/s41512-016-0001-y.].

Phylogenomics and the rise of the angiosperms

Zuntini AR, Carruthers T, Maurin O, Bailey PC, Leempoel K, Brewer GE, et al.

Nature, 2024 Apr 24.

PMID: 38658746 DOI: 10.1038/s41586-024-07324-0

Angiosperms are the cornerstone of most terrestrial ecosystems and human livelihoods1,2. A robust understanding of angiosperm evolution is required to explain their rise to ecological dominance. So far, the angiosperm tree of life has been determined primarily by means of analyses of the plastid genome3,4. Many studies have drawn on this foundational work, such as classification and first insights into angiosperm diversification since their Mesozoic origins5-7. However, the limited and biased sampling of both taxa and genomes undermines confidence in the tree and its implications. Here, we build the tree of life for almost 8,000 (about 60%) angiosperm genera using a standardized set of 353 nuclear genes8. This 15-fold increase in genus-level sampling relative to comparable nuclear studies9 provides a critical test of earlier results and brings notable change to key groups, especially in rosids, while substantiating many previously predicted relationships. Scaling this tree to time using 200 fossils, we discovered that early angiosperm evolution was characterized by high gene tree conflict and explosive diversification, giving rise to more than 80% of extant angiosperm orders. Steady diversification ensued through the remaining Mesozoic Era until rates resurged in the Cenozoic Era, concurrent with decreasing global temperatures and tightly linked with gene tree conflict. Taken together, our extensive sampling combined with advanced phylogenomic methods shows the deep history and full complexity in the evolution of a megadiverse clade.

Fulltext Suppression of Excited ϒ States Relative to the Ground State in Pb-Pb Collisions at sqrt[s]_{NN}=5.02 TeV

Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, Brandstetter J, et al.

Phys Rev Lett, 2018 Apr 06;120(14):142301.

PMID: 29694144 DOI: 10.1103/PhysRevLett.120.142301

The relative yields of ϒ mesons produced in pp and Pb-Pb collisions at sqrt[s_{NN}]=5.02 TeV and reconstructed via the dimuon decay channel are measured using data collected by the CMS experiment. Double ratios are formed by comparing the yields of the excited states, ϒ(2S) and ϒ(3S), to the ground state, ϒ(1S), in both Pb-Pb and pp collisions at the same center-of-mass energy. The double ratios, [ϒ(nS)/ϒ(1S)]_{Pb-Pb}/[ϒ(nS)/ϒ(1S)]_{pp}, are measured to be 0.308±0.055(stat)±0.019(syst) for the ϒ(2S) and less than 0.26 at 95% confidence level for the ϒ(3S). No significant ϒ(3S) signal is found in the Pb-Pb data. The double ratios are studied as a function of collision centrality, as well as ϒ transverse momentum and rapidity. No significant dependencies are observed.

Fulltext Relative Modification of Prompt ψ(2S) and J/ψ Yields from pp to PbPb Collisions at sqrt[s_{NN}]=5.02 TeV

Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, Brandstetter J, et al.

Phys Rev Lett, 2017 Apr 21;118(16):162301.

PMID: 28474955 DOI: 10.1103/PhysRevLett.118.162301

The relative modification of the prompt ψ(2S) and J/ψ yields from pp to PbPb collisions, at the center-of-mass energy of 5.02 TeV per nucleon pair, is presented. The analysis is based on pp and PbPb data samples collected by the CMS experiment at the LHC in 2015, corresponding to integrated luminosities of 28.0 pb^{-1} and 464 μb^{-1}, respectively. The double ratio of measured yields of prompt charmonia reconstructed through their decays into muon pairs, (N_{ψ(2S)}/N_{J/ψ})_{PbPb}/(N_{ψ(2S)}/N_{J/ψ})_{pp}, is determined as a function of PbPb collision centrality and charmonium transverse momentum p_{T}, in two kinematic intervals: |y|<1.6 covering 6.5y|<2.4 covering 3

Fulltext Observation of Charge-Dependent Azimuthal Correlations in p-Pb Collisions and Its Implication for the Search for the Chiral Magnetic Effect

Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, et al.

Phys Rev Lett, 2017 Mar 24;118(12):122301.

PMID: 28388204 DOI: 10.1103/PhysRevLett.118.122301

Charge-dependent azimuthal particle correlations with respect to the second-order event plane in p-Pb and PbPb collisions at a nucleon-nucleon center-of-mass energy of 5.02 TeV have been studied with the CMS experiment at the LHC. The measurement is performed with a three-particle correlation technique, using two particles with the same or opposite charge within the pseudorapidity range |η|<2.4, and a third particle measured in the hadron forward calorimeters (4.4

Fulltext Search for dark matter produced in association with heavy-flavor quark pairs in proton-proton collisions at s = 13 TeV

Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, Brandstetter J, et al.

Eur Phys J C Part Fields, 2017;77(12):845.

PMID: 31985736 DOI: 10.1140/epjc/s10052-017-5317-4

A search is presented for an excess of events with heavy-flavor quark pairs (

t

t
¯

and

b

b
¯

) and a large imbalance in transverse momentum in data from proton-proton collisions at a center-of-mass energy of 13

TeV

. The data correspond to an integrated luminosity of 2.2

fb

-
1

collected with the CMS detector at the CERN LHC. No deviations are observed with respect to standard model predictions. The results are used in the first interpretation of dark matter production in

t

t
¯

and

b

b
¯

final states in a simplified model. This analysis is also the first to perform a statistical combination of searches for dark matter produced with different heavy-flavor final states. The combination provides exclusions that are stronger than those achieved with individual heavy-flavor final states.

Fulltext Study of dijet events with a large rapidity gap between the two leading jets in pp collisions at s = 7 TeV

Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, Brandstetter J, et al.

Eur Phys J C Part Fields, 2018;78(3):242.

PMID: 31264999 DOI: 10.1140/epjc/s10052-018-5691-6

Events with no charged particles produced between the two leading jets are studied in proton-proton collisions at s = 7 TeV . The jets were required to have transverse momentum p T jet > 40 GeV and pseudorapidity 1.5 < | η jet | < 4.7 , and to have values of η jet with opposite signs. The data used for this study were collected with the CMS detector during low-luminosity running at the LHC, and correspond to an integrated luminosity of 8 pb - 1 . Events with no charged particles with p T > 0.2 GeV in the interval - 1 < η < 1 between the jets are observed in excess of calculations that assume no color-singlet exchange. The fraction of events with such a rapidity gap, amounting to 0.5-1% of the selected dijet sample, is measured as a function of the p T of the second-leading jet and of the rapidity separation between the jets. The data are compared to previous measurements at the Tevatron, and to perturbative quantum chromodynamics calculations based on the Balitsky-Fadin-Kuraev-Lipatov evolution equations, including different models of the non-perturbative gap survival probability.

Fulltext Measurement of the triple-differential dijet cross section in proton-proton collisions at s = 8 TeV and constraints on parton distribution functions

Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, Brandstetter J, et al.

Eur Phys J C Part Fields, 2017;77(11):746.

PMID: 31999281 DOI: 10.1140/epjc/s10052-017-5286-7

A measurement is presented of the triple-differential dijet cross section at a centre-of-mass energy of 8 TeV using 19.7 fb -1 of data collected with the CMS detector in proton-proton collisions at the LHC. The cross section is measured as a function of the average transverse momentum, half the rapidity separation, and the boost of the two leading jets in the event. The cross section is corrected for detector effects and compared to calculations in perturbative quantum chromodynamics at next-to-leading order accuracy, complemented with electroweak and nonperturbative corrections. New constraints on parton distribution functions are obtained and the inferred value of the strong coupling constant is α S ( M Z ) = 0.1199 ± 0.0015 ( exp ) - 0.0020 + 0.0031 ( theo ) , where M Z is the mass of the Z boson.

Fulltext Measurement of associated Z + charm production in proton-proton collisions at s = 8 TeV

Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, et al.

Eur Phys J C Part Fields, 2018;78(4):287.

PMID: 31007580 DOI: 10.1140/epjc/s10052-018-5752-x

A study of the associated production of a Z boson and a charm quark jet ( Z + c ), and a comparison to production with a b quark jet ( Z + b ), in p p collisions at a centre-of-mass energy of 8 TeV are presented. The analysis uses a data sample corresponding to an integrated luminosity of 19.7 fb - 1 , collected with the CMS detector at the CERN LHC. The Z boson candidates are identified through their decays into pairs of electrons or muons. Jets originating from heavy flavour quarks are identified using semileptonic decays of c or b flavoured hadrons and hadronic decays of charm hadrons. The measurements are performed in the kinematic region with two leptons with p T ℓ > 20 GeV , | η ℓ | < 2.1 , 71 < m ℓ ℓ < 111 GeV , and heavy flavour jets with p T jet > 25 GeV and | η jet | < 2.5 . The Z + c production cross section is measured to be σ ( p p → Z + c + X ) B ( Z → ℓ + ℓ - ) = 8.8 ± 0.5 (stat) ± 0.6 (syst) pb . The ratio of the Z + c and Z + b production cross sections is measured to be σ ( p p → Z + c + X ) / σ ( p p → Z + b + X ) = 2.0 ± 0.2 (stat) ± 0.2 (syst) . The Z + c production cross section and the cross section ratio are also measured as a function of the transverse momentum of the Z boson and of the heavy flavour jet. The measurements are compared with theoretical predictions.

Fulltext Measurement of double-differential cross sections for top quark pair production in pp collisions at [Formula: see text][Formula: see text] and impact on parton distribution functions

Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, Brandstetter J, et al.

Eur Phys J C Part Fields, 2017;77(7):459.

PMID: 28943791 DOI: 10.1140/epjc/s10052-017-4984-5

Normalized double-differential cross sections for top quark pair ([Formula: see text]) production are measured in pp collisions at a centre-of-mass energy of 8[Formula: see text] with the CMS experiment at the LHC. The analyzed data correspond to an integrated luminosity of 19.7[Formula: see text]. The measurement is performed in the dilepton [Formula: see text] final state. The [Formula: see text] cross section is determined as a function of various pairs of observables characterizing the kinematics of the top quark and [Formula: see text] system. The data are compared to calculations using perturbative quantum chromodynamics at next-to-leading and approximate next-to-next-to-leading orders. They are also compared to predictions of Monte Carlo event generators that complement fixed-order computations with parton showers, hadronization, and multiple-parton interactions. Overall agreement is observed with the predictions, which is improved when the latest global sets of proton parton distribution functions are used. The inclusion of the measured [Formula: see text] cross sections in a fit of parametrized parton distribution functions is shown to have significant impact on the gluon distribution.

Fulltext Measurement of the jet mass in highly boosted [Formula: see text] events from pp collisions at [Formula: see text][Formula: see text]

Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, Brandstetter J, et al.

Eur Phys J C Part Fields, 2017;77(7):467.

PMID: 28943793 DOI: 10.1140/epjc/s10052-017-5030-3

The first measurement of the jet mass [Formula: see text] of top quark jets produced in [Formula: see text] events from pp collisions at [Formula: see text] [Formula: see text] is reported for the jet with the largest transverse momentum [Formula: see text] in highly boosted hadronic top quark decays. The data sample, collected with the CMS detector, corresponds to an integrated luminosity of 19.7[Formula: see text]. The measurement is performed in the lepton+jets channel in which the products of the semileptonic decay [Formula: see text] with [Formula: see text] where [Formula: see text] is an electron or muon, are used to select [Formula: see text] events with large Lorentz boosts. The products of the fully hadronic decay [Formula: see text] with [Formula: see text] are reconstructed using a single Cambridge-Aachen jet with distance parameter [Formula: see text], and [Formula: see text] [Formula: see text]. The [Formula: see text] cross section as a function of [Formula: see text] is unfolded at the particle level and is used to test the modelling of highly boosted top quark production. The peak position of the [Formula: see text] distribution is sensitive to the top quark mass [Formula: see text], and the data are used to extract a value of [Formula: see text] to assess this sensitivity.

Fulltext A search for new phenomena in pp collisions at [Formula: see text] in final states with missing transverse momentum and at least one jet using the [Formula: see text] variable

Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, et al.

Eur Phys J C Part Fields, 2017;77(5):294.

PMID: 28579921 DOI: 10.1140/epjc/s10052-017-4787-8

A search for new phenomena is performed in final states containing one or more jets and an imbalance in transverse momentum in pp collisions at a centre-of-mass energy of 13[Formula: see text]. The analysed data sample, recorded with the CMS detector at the CERN LHC, corresponds to an integrated luminosity of 2.3[Formula: see text]. Several kinematic variables are employed to suppress the dominant background, multijet production, as well as to discriminate between other standard model and new physics processes. The search provides sensitivity to a broad range of new-physics models that yield a stable weakly interacting massive particle. The number of observed candidate events is found to agree with the expected contributions from standard model processes, and the result is interpreted in the mass parameter space of fourteen simplified supersymmetric models that assume the pair production of gluinos or squarks and a range of decay modes. For models that assume gluino pair production, masses up to 1575 and 975[Formula: see text] are excluded for gluinos and neutralinos, respectively. For models involving the pair production of top squarks and compressed mass spectra, top squark masses up to 400[Formula: see text] are excluded.

Fulltext Measurement of the [Formula: see text] production cross section using events in the [Formula: see text] final state in pp collisions at [Formula: see text]

Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, et al.

Eur Phys J C Part Fields, 2017;77(3):172.

PMID: 28408859 DOI: 10.1140/epjc/s10052-017-4718-8

The cross section of top quark-antiquark pair production in proton-proton collisions at [Formula: see text] is measured by the CMS experiment at the LHC, using data corresponding to an integrated luminosity of 2.2[Formula: see text]. The measurement is performed by analyzing events in which the final state includes one electron, one muon, and two or more jets, at least one of which is identified as originating from hadronization of a b quark. The measured cross section is [Formula: see text], in agreement with the expectation from the standard model.

Fulltext Suppression and azimuthal anisotropy of prompt and nonprompt [Formula: see text] production in PbPb collisions at [Formula: see text][Formula: see text]

Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Asilar E, Bergauer T, et al.

Eur Phys J C Part Fields, 2017;77(4):252.

PMID: 28515669 DOI: 10.1140/epjc/s10052-017-4781-1

The nuclear modification factor [Formula: see text] and the azimuthal anisotropy coefficient [Formula: see text] of prompt and nonprompt (i.e. those from decays of b hadrons) [Formula: see text] mesons, measured from PbPb and pp collisions at [Formula: see text] [Formula: see text] at the LHC, are reported. The results are presented in several event centrality intervals and several kinematic regions, for transverse momenta [Formula: see text] [Formula: see text] and rapidity [Formula: see text], extending down to [Formula: see text] [Formula: see text] in the [Formula: see text] range. The [Formula: see text] of prompt [Formula: see text] is found to be nonzero, but with no strong dependence on centrality, rapidity, or [Formula: see text] over the full kinematic range studied. The measured [Formula: see text] of nonprompt [Formula: see text] is consistent with zero. The [Formula: see text] of prompt [Formula: see text] exhibits a suppression that increases from peripheral to central collisions but does not vary strongly as a function of either y or [Formula: see text] in the fiducial range. The nonprompt [Formula: see text] [Formula: see text] shows a suppression which becomes stronger as rapidity or [Formula: see text] increases. The [Formula: see text] and [Formula: see text] of open and hidden charm, and of open charm and beauty, are compared.

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