Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity: a Meta-Analysis and Comparison with Lung Cancer and COPD

Recently, genetic association findings for nicotine dependence, smoking behavior, and smoking-related diseases converged to implicate the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes. In particular, association with the nonsynonymous CHRNA5 SNP rs16969968 and correlates has been replicated in several independent studies. Extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence, tagged by rs578776 and rs588765. One goal of the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking), lung cancer, and chronic obstructive pulmonary disease (COPD). We performed a meta-analysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-per-day, 7,700 lung cancer cases and 5,914 lung-cancer-free controls (all smokers), and 2,614 COPD cases and 3,568 COPD-free controls (all smokers). We demonstrate statistically independent associations of rs16969968 and rs588765 with smoking (mutually adjusted p-values<10$^{−35}$ and <10$^{−8}$ respectively). Because the risk alleles at these loci are negatively correlated, their association with smoking is stronger in the joint model than when each SNP is analyzed alone. Rs578776 also demonstrates association with smoking after adjustment for rs16969968 (p<10$^{−6}$). In models adjusting for cigarettes-per-day, we confirm the association between rs16969968 and lung cancer (p<10$^{−20}$) and observe a nominally significant association with COPD (p = 0.01); the other loci are not significantly associated with either lung cancer or COPD after adjusting for rs16969968. This study provides strong evidence that multiple statistically distinct loci in this region affect smoking behavior. This study is also the first report of association between rs588765 (and correlates) and smoking that achieves genome-wide significance; these SNPs have previously been associated with mRNA levels of CHRNA5 in brain and lung tissue

Time to maximum amplitude of thromboelastography can predict mortality in patients with severe COVID-19: a retrospective observational study

ObjectiveTo predict mortality in severe patients with COVID-19 at admission to the intensive care unit (ICU) using thromboelastography (TEG).MethodsThis retrospective, two-center, observational study involved 87 patients with PCR-and chest CT-confirmed severe COVID-19 who were admitted to at Wuhan Huoshenshan Hospital and the 908th Hospital of Chinese PLA Logistic Support Force between February 2020 and February 2023. Clinic demographics, laboratory results, and outcomes were compared between those who survived and those who died during hospitalization.ResultsThromboelastography showed that of the 87 patients, 14 were in a hypercoagulable state, 25 were in a hypocoagulable state, and 48 were normal, based on the time to maximum amplitude (TMA). Patients who died showed significantly lower α angle, but significantly longer R-time, K-time and TMA than patients who survived. Random forest selection showed that K-time, TMA, prothrombin time (PT), international normalized ratio (INR), D-dimer, C-reactive protein (CRP), aspartate aminotransferase (AST), and total bilirubin (Tbil) were significant predictors. Multivariate logistic regression identified that TMA and CRP were independently associated with mortality. TMA had a greater predictive power than CRP levels based on time-dependent AUCs. Patients with TMA ≥ 26.4 min were at significantly higher risk of mortality (hazard ratio 3.99, 95% Confidence Interval, 1.92–8.27, p &lt; 0.01).ConclusionTMA ≥26.4 min at admission to ICU may be an independent predictor of in-hospital mortality for patients with severe COVID-19

Increased genetic vulnerability to smoking at CHRNA5 in early-onset smokers

Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968.Objective: To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking.Data Sources: Primary data.Study Selection: Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy.DataExtraction: Uniform statistical analysis scripts were runlocally. Starting with 94 050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD &gt;20) and light smokers (CPD 16 years), and a logistic regression of heavy vs light smoking with ther s16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum.Data Synthesis: Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR]=1.45; 95% CI, 1.36-1.55; n=13 843) than were carriers of the risk allele who were late-onset smokers (OR=1.27; 95% CI, 1.21-1.33, n=19 505) (P=.01).Conclusion: These results highlight an increased genetic vulnerability to smoking in early-onset smokers

Diagenetic–Porosity Evolution and Reservoir Evaluation in Multiprovenance Tight Sandstones: Insight from the Lower Shihezi Formation in Hangjinqi Area, Northern Ordos Basin

AbstractThe reservoir property of tight sandstones is closely related to the provenance and diagenesis, and multiprovenance system and complex diagenesis are developed in Hangjinqi area. However, the relationship between provenance, diagenesis, and physical characteristics of tight reservoirs in Hangjinqi area has not yet been reported. The Middle Permian Lower Shihezi Formation is one of the most important tight gas sandstone reservoirs in the Hangjinqi area of Ordos Basin. This research compared the diagenesis-porosity quantitative evolution mechanisms of Lower Shihezi Formation sandstones from various provenances in the Hangjinqi area using thin-section descriptions, cathodoluminescence imaging, X-ray diffraction (XRD), scanning electron microscopy (SEM), and homogenization temperature of fluid inclusions, along with general physical data and high-pressure mercury intrusion (HPMI) data. The sandstones mainly comprise quartzarenite, sublitharenite, and litharenite with low porosity and low permeability and display obvious zonation in the content of detrital components as a result of multiprovenance. Pore space of those sandstone mainly consists of primary pores, secondary pores, and microfractures, but their proportion varies in different provenances. According to HPMI, the order of the pore-throat radius from largest to smallest is central provenance, eastern provenance, and western provenance, which is consistent with the change tend of porosity (middle part&gt;northern part&gt;western part) in Hangjinqi region. The diagenetic evolution path of those sandstones is comparable, with compaction, cementation, dissolution, and fracture development. The central provenance has the best reservoir quality, followed by the eastern provenance and the western provenance, and this variation due to the diverse diagenesis (diagenetic stage and intensity) of different provenances. These findings reveal that the variations in detrital composition and structure caused by different provenances are the material basis of reservoir differentiation, and the main rationale for reservoir differentiation is varying degrees of diagenesis during burial process

Pure spin current polarizer enabled by antiferromagnetic insulator

Pure spin current enables the transport of spin information without charge flow, providing opportunities for next-generation information technologies. A pure spin current polarizer, capable of controlling both its transmittance and spin polarization, is critical for the development of spintronics; however, it has not yet been demonstrated. Here, we demonstrate a highly efficient pure spin current polarizer at room temperature using a single-domain antiferromagnetic insulator film, through structural engineering and spin-lattice coupling. Our device exhibits a large differential magnon current transmittance at room temperature. Remarkably, we find that the spin polarization of the transmitted magnon current aligns with the Néel vector of the polarizer. This enables a large modulation of damping-like torque and generation of out-of-plane-polarized magnon current, offering alternative routes for developing energy-efficient spintronic devices. We anticipate that this pure spin current polarizer will serve as a building block for spintronics based on pure spin current

The chromatin accessibility landscape of primary human cancers

We present the genome-wide chromatin accessibility profiles of 410 tumor samples spanning 23 cancer types from The Cancer Genome Atlas (TCGA). We identify 562,709 transposase-accessible DNA elements that substantially extend the compendium of known cis-regulatory elements. Integration of ATAC-seq (the assay for transposase-accessible chromatin using sequencing) with TCGA multi-omic data identifies a large number of putative distal enhancers that distinguish molecular subtypes of cancers, uncovers specific driving transcription factors via protein-DNA footprints, and nominates long-range gene-regulatory interactions in cancer. These data reveal genetic risk loci of cancer predisposition as active DNA regulatory elements in cancer, identify gene-regulatory interactions underlying cancer immune evasion, and pinpoint noncoding mutations that drive enhancer activation and may affect patient survival. These results suggest a systematic approach to understanding the noncoding genome in cancer to advance diagnosis and therapy

A user guide for the online exploration and visualization of PCAWG data.

Funder: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)Funder: Ontario Institute for Cancer Research (Institut Ontarien de Recherche sur le Cancer); doi: https://doi.org/10.13039/100012118Funder: EMBL Member States EU FP7 Programme projects EurocanPlatform (260791) CAGEKID (241669)Funder: European Union’s Framework Programme For Research and Innovation Horizon 2020 under the Marie Sklodowska-Curie grant agreement no. 703543Funder: Michael & Susan Dell Foundation; Mary K. Chapman Foundation; CCSG Grant P30 CA016672 (Bioinformatics Shared Resource); ITCR U24 CA199461; GDAN U24 CA210949; GDAN U24 CA210950Funder: European Commission's H2020 Programme, project SOUND, Grant Agreement no 633974Funder: Spanish Government (SEV 2015-0493) BSC-Lenovo Master Collaboration Agreement (2015)The Pan-Cancer Analysis of Whole Genomes (PCAWG) project generated a vast amount of whole-genome cancer sequencing resource data. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumor types, we provide a user's guide to the five publicly available online data exploration and visualization tools introduced in the PCAWG marker paper. These tools are ICGC Data Portal, UCSC Xena, Chromothripsis Explorer, Expression Atlas, and PCAWG-Scout. We detail use cases and analyses for each tool, show how they incorporate outside resources from the larger genomics ecosystem, and demonstrate how the tools can be used together to understand the biology of cancers more deeply. Together, the tools enable researchers to query the complex genomic PCAWG data dynamically and integrate external information, enabling and enhancing interpretation

High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations

The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. TERT-associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non-amplified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements

Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts

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