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Gene-environment (GE) interactions are essential in understanding human complex traits. Identifying these interactions is necessary for deciphering the biological basis of such traits. In this study, we review state-of-art methods for estimating the proportion of phenotypic variance explained by genome-wide GE interactions and introduce a novel statistical method Linkage-Disequilibrium Eigenvalue Regression for Gene-Environment interactions (LDER-GE). LDER-GE improves the accuracy of estimating the phenotypic variance component explained by genome-wide GE interactions using large-scale biobank association summary statistics. LDER-GE leverages the complete Linkage Disequilibrium (LD) matrix, as opposed to only the diagonal squared LD matrix utilized by LDSC (Linkage Disequilibrium Score)-based methods. Our extensive simulation studies demonstrate that LDER-GE performs better than LDSC-based approaches by enhancing statistical efficiency by ~23%. This improvement is equivalent to a sample size increase of around 51%. Additionally, LDER-GE effectively controls type-I error rate and produces unbiased results. We conducted an analysis using UK Biobank data, comprising 307 259 unrelated European-Ancestry subjects and 966 766 variants, across 217 environmental covariate-phenotype (E-Y) pairs. LDER-GE identified 34 significant E-Y pairs while LDSC-based method only identified 23 significant E-Y pairs with 22 overlapped with LDER-GE. Furthermore, we employed LDER-GE to estimate the aggregated variance component attributed to multiple GE interactions, leading to an increase in the explained phenotypic variance with GE interactions compared to considering main genetic effects only. Our results suggest the importance of impacts of GE interactions on human complex traits.
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Interação Gene-Ambiente , Desequilíbrio de Ligação , Fenótipo , Humanos , Herança Multifatorial , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Modelos GenéticosRESUMO
Finding disease-relevant tissues and cell types can facilitate the identification and investigation of functional genes and variants. In particular, cell type proportions can serve as potential disease predictive biomarkers. In this manuscript, we introduce a novel statistical framework, cell-type Wide Association Study (cWAS), that integrates genetic data with transcriptomics data to identify cell types whose genetically regulated proportions (GRPs) are disease/trait-associated. On simulated and real GWAS data, cWAS showed good statistical power with newly identified significant GRP associations in disease-associated tissues. More specifically, GRPs of endothelial and myofibroblasts in lung tissue were associated with Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease, respectively. For breast cancer, the GRP of blood CD8+ T cells was negatively associated with breast cancer (BC) risk as well as survival. Overall, cWAS is a powerful tool to reveal cell types associated with complex diseases mediated by GRPs.
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Neoplasias da Mama , Doença Pulmonar Obstrutiva Crônica , Humanos , Feminino , Predisposição Genética para Doença , Pulmão , Perfilação da Expressão Gênica , Doença Pulmonar Obstrutiva Crônica/genética , Neoplasias da Mama/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Identification of pleiotropy at the single nucleotide polymorphism (SNP) level provides valuable insights into shared genetic signals among phenotypes. One approach to study these signals is through mediation analysis, which dissects the total effect of a SNP on the outcome into a direct effect and an indirect effect through a mediator. However, estimated effects from mediation analysis can be confounded by the genetic correlation between phenotypes, leading to inaccurate results. To address this confounding effect in the context of genetic mediation analysis, we propose a restricted-maximum-likelihood (REML)-based mediation analysis framework called REML-mediation, which can be applied to either individual-level or summary statistics data. Simulations demonstrated that REML-mediation provides unbiased estimates of the true cross-trait causal effect, assuming certain assumptions, albeit with a slightly inflated standard error compared to traditional linear regression. To validate the effectiveness of REML-mediation, we applied it to UK Biobank data and analyzed several mediator-outcome trait pairs along with their corresponding sets of pleiotropic SNPs. REML-mediation successfully identified and corrected for genetic confounding effects in these trait pairs, with correction magnitudes ranging from 7% to 39%. These findings highlight the presence of genetic confounding effects in cross-trait epidemiological studies and underscore the importance of accounting for them in data analysis.
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Pleiotropia Genética , Análise de Mediação , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único , Humanos , Estudo de Associação Genômica Ampla/métodos , Simulação por Computador , Funções VerossimilhançaRESUMO
China has over 100 million people living with type 2 diabetes mellitus (T2DM). Interventions framed around pre-existing personal beliefs in the supernatural may improve T2DM self-management, but such interventions are lacking in China. This pilot randomized controlled trial (RCT) assessed the feasibility of a full-scale RCT to evaluate the efficacy of a supernatural beliefs-based intervention on T2DM management self-efficacy in China. In 2019, 62 T2DM patients were enrolled at two hospitals in Suzhou, China. Participants were randomly assigned to view a 30-s control or intervention video at baseline. The control video showed general diabetes self-management information. The intervention video showed identical information, but also indicated that some diabetics with supernatural beliefs (chao ziran xinnian) have lower glycemic levels, because their beliefs enhance their confidence in diabetes self-management. Development of the intervention was guided by the theory of planned behavior and literature on spiritual framing health interventions. Baseline and follow-up measures after two weeks were assessed by interviewer administered surveys in-person and by telephone, respectively. Diabetes management self-efficacy was assessed with the diabetes management self-efficacy scale. Randomization of intervention allocation appeared to be successful. However, follow-up retention was low, especially for the intervention group (3% vs. 31%). A full-size efficacy RCT using the current study design is unlikely to succeed. T2DM patients shown the supernatural beliefs-based intervention had significantly higher loss to follow-up that was insurmountable. T2DM patients in Suzhou, China may not be receptive to brief, non-tailored supernatural beliefs-based interventions delivered to a general population in clinical settings.
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We report the fabrication and characterization of a five-tube nested hollow-core anti-resonant fiber (Nested HC-ARF), which exhibits outstanding optical performance in terms of a record attenuation value of 0.85â dB/km at 2 µm wavelength range with a 200â nm bandwidth below 2â dB/km and excellent modal purity. The power handling capability of the Nested HC-ARF is also demonstrated in this work. Pulses of 75 W, 160 ps from the thulium-doped fiber laser are delivered using a 6-m-long fabricated Nested HC-ARF. The tested fiber is coiled into a 20â cm bending radius and achieves a coupling efficiency of 86.7%. The maximum average power of 60.5 W is transmitted through our Nested HC-ARF in a robust single-mode fashion without introducing any damage to the input and output fiber end-faces, which demonstrates the superior ability of such a fiber for high-power laser delivery.
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The study area is a part of the North China Plain, where groundwater is heavily abstracted for drinking and irrigation purposes. Groundwater quality is adversely affected due to rapid economic development and urbanization. Therefore, the purposes of this study were to evaluate the suitability of groundwater for drinking and irrigation purposes and to quantify the associated human health risks in the southern part of Gu'an County, North China Plain. The matter-element extension method based on entropy weight was used to evaluate the water quality for drinking, while sodium adsorption ratio, sodium percentage (%Na), residual sodium carbonate and magnesium hazard were used to evaluate the water quality for irrigation. Non-carcinogenic and carcinogenic health risks via different exposure ways were evaluated for different age groups. The study found that the quality of both deep and shallow groundwater in this area was generally suitable for drinking. Deep water quality has better quality than the shallow water. However, 8.70% and 73.92% of water samples pose non-carcinogenic health risks on adults and children, respectively. Children and adults are also at cancer risk due to Cr6+ and As in drinking groundwater in this area. The main responsible parameters for non-carcinogenic risk are Cr6+, F- and Fe, and Cr6+ is also responsible for carcinogenic risk. These toxic elements are mainly from industries. Therefore, deterioration of groundwater quality can be prevented by strengthening the sewage management of various industries.
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Irrigação Agrícola , Água Potável , Monitoramento Ambiental/métodos , Água Subterrânea/química , Poluentes Químicos da Água/toxicidade , Qualidade da Água , Adulto , Criança , China , Humanos , Medição de Risco , Esgotos , Poluentes Químicos da Água/análiseRESUMO
Micro/nanostructures with high aspect ratios in silicon wafers obtained by plasma etching are of great significance in device fabrication. In most cases, the scallop nanostructure in deep silicon etching should be suppressed. However, the scallop nanostructure could be applied in electronic device fabrication as characteristic information, which indicates the balance between deposition and etching. In this work, the applications of scallop nanostructures in etching process optimization and environmental protection are demonstrated. In addition, the minimum effect of the cycle time on the scallop size is reported for the first time. These results could bring new thoughts to the electronic devices related fields, such as micro-electro-mechanical systems (MEMS), silicon capacitors and advanced packaging.
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In tight oil reservoirs, nanopore throat acting as the narrowest section of fluidic channel determines the oil transport performance; injecting CO2 is found to significantly promote the oil flow. Despite substantial efforts, the underlying transport mechanism of above phenomenon remains unclear. Employing molecular dynamics simulation, the oil transport through a nanopore throat is studied. A high energy barrier derived of conformation deformation, oil/pore interaction and Jamin effect is found to impede the oil transport. The CO2 activating effect for oil transport is present, and a dependence on CO2 amount is observed. The underlying mechanism was well documented from the aspects of oil swelling, interfacial tension and surface sliding. Our study provides fundamental insight into the oil transport across nanopore throat and CO2 activating effect; the results have promising applications in enhanced oil recovery in CO2 flooding.
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OBJECTIVES: The objectives of this study are to study the risk of developing cardiac arrhythmia and its subtypes over time in patients with systemic sclerosis (SSc), to assess potential risk factors for arrhythmia in SSc and to explore whether arrhythmia is associated with mortality. METHODS: We used nationwide Swedish registers to identify patients with incident SSc 2004-2019 and matched general population comparators (1:10). The primary outcome was incident arrhythmia. Follow-up started at the date of SSc diagnosis and ended at the primary outcome, death, emigration or 31 December 2019. We estimated the incidence of arrhythmia overall and stratified by subtype and explored the relative risk in relation to time since diagnosis using flexible parametric models. We used Cox regression to study risk factors for arrhythmia and the association of arrhythmia with mortality. RESULTS: We identified 1565 patients and 16 009 comparators. The overall incidence of arrhythmia was 255 (95% CI 221 to 295) and 119 (95% CI 112 to 127) per 10 000 person years in patients with SSc and comparators, respectively, corresponding to an IRR of 2.1 (95% CI 1.8 to 2.5). The greatest hazard difference between patients with SSc compared with the comparators was seen in the first year of follow-up (HR for arrhythmia 3.0; 95% CI 2.3 to 3.8). Atrial fibrillation and flutter were the most common arrhythmia subtypes. Male sex, index age and pulmonary arterial hypertension were significant risk factors for arrhythmia in SSc. Incident arrhythmia was significantly associated with mortality (HR 2.2; 95% CI 1.6 to 3.0). CONCLUSION: SSc is associated with higher incidence of cardiac arrhythmia compared with general population. Arrhythmia seems to be an early manifestation of SSc and is associated with higher mortality.
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Arritmias Cardíacas , Sistema de Registros , Escleroderma Sistêmico , Humanos , Escleroderma Sistêmico/mortalidade , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/epidemiologia , Suécia/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Incidência , Fatores de Risco , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/mortalidade , Arritmias Cardíacas/complicações , Arritmias Cardíacas/etiologia , Idoso , Adulto , Modelos de Riscos Proporcionais , Flutter Atrial/epidemiologia , Flutter Atrial/complicações , Flutter Atrial/mortalidadeRESUMO
Background: Asthma, type 2 diabetes (T2D), and anthropometric measures are correlated complex traits that all have a major genetic component. Objective: To investigate the overlap in genetic variants associated with these complex traits. Methods: Using United Kingdom Biobank data, we performed univariate association analysis, fine-mapping, and mediation analysis to identify and dissect shared genomic regions associated with asthma, T2D, height, weight, body mass index (BMI), and waist circumference (WC). Results: We found several genome-wide significant variants in and around the JAZF1 gene that are associated with asthma, T2D, or height with two of these variants shared by the three phenotypes. We also observed an association in this region with WC when adjusted for BMI. However, there was no association with WC when it was not adjusted for BMI or weight. Additionally, only suggestive associations between variants in this region and BMI were observed. Fine-mapping analyses suggested that within JAZF1 there are non-overlapping regions harboring causal susceptibility variants for asthma, T2D, and height. Mediation analyses supported the conclusion that these are independent associations. Conclusion: Our findings indicate that variants in the JAZF1 are associated with asthma, T2D, and height, but the associated causal variant(s) are different for each of the three phenotypes.
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Background: Genome-wide association studies of asthma have identified associations with variants in type-2 related genes. Also, specific interactions between genetic variants and viral bronchiolitis in the development of asthma has been suggested. Objective: To conduct a gene-based analysis of genetic variants in type 2 cytokine related genes as risk factors for allergic asthma at school age, and further, to study their interaction with specific viral infections in early childhood. Methods: A prospectively investigated cohort of children with previous bronchiolitis and controls came for follow-up at school age. The research visit, blinded to viral exposure, included detailed lung function tests, laboratory investigation, and questionnaires. Allergic asthma was defined as typical symptoms plus objective variable airway obstruction, in addition to laboratory verified atopy (elevated eosinophil count or sensitization to an allergen). Targeted and complete sequencing was performed for nine type 2 cytokine candidate genes: IL4, 5, 13, 25, 33 and 37, IL17RB, CRLF2 and TSLP. Results: At follow-up, there were 109 children with genetic data, 91 with a history of bronchiolitis (46% respiratory syncytial virus, 24% human rhinovirus, 15% human metapneumovirus and 14% mixed viral etiology) and 18 without. The median age was 9.4 years (range 6-13) and 41 (38%) had laboratory verified atopy. Twenty-one children (19%) met the definition of allergic asthma. After adjusting for age, sex and five viral categories, IL33 achieved nominal significance (p = 0.017) for a positive association with allergic asthma development. In the gene-virus interaction analysis, the variant set in IL17RB demonstrated a nominally significant positive interaction with human metapneumovirus infection (p=0.05). Conclusion: The results highlight the multifactorial nature of allergic asthma risk, with both viral infection and inherited genetic variants contributing to increasing risk. Results for IL33 and IL17RB were nominally significant and are potential candidate targets for designing therapeutics and early screening, but these results must be replicated in an independent study.
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Asma , Bronquiolite Viral , Bronquiolite , Hipersensibilidade Imediata , Vírus Sincicial Respiratório Humano , Criança , Humanos , Pré-Escolar , Adolescente , Bronquiolite Viral/genética , Estudo de Associação Genômica Ampla , Interleucina-33/genética , Asma/etiologia , Fatores de Risco , Vírus Sincicial Respiratório Humano/genéticaRESUMO
Lack of iodine knowledge might be a risk factor for inadequate iodine intake in populations. Therefore, we aimed to determine the relationship between iodine knowledge and intake in young Chinese adults. A cross-sectional study was conducted in Suzhou, China. Iodine intake was assessed using a validated 33-item iodine-specific Chinese food frequency questionnaire (FFQ) and iodine knowledge was determined using a Chinese iodine knowledge questionnaire. A total of 150 participants (mean age 20.3 years) completed the study. The median iodine intake plus iodized salt was 260 µg/d, indicating iodine sufficiency (>150 µg/d). The median iodine knowledge score was 16/24, suggesting a medium level of knowledge. The majority of participants correctly recognized fish and seafood (95%) and iodized salt (83%) as the most important dietary iodine sources. After adjusting for age and sex, studying in the science cluster and having received iodine education were the predictors of having a higher iodine knowledge score, with adjusted odd ratios (OR) of 4.33 (1.49, 12.61) and 2.73 (1.21, 6.14), respectively. In conclusion, young Chinese adults had an adequate iodine intake despite a medium iodine knowledge score. This study provides support that iodine fortification in China has been successful, but further research is required to more fully substantiate this finding.
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Goji berries (Lycium fruits) are usually found in Asia, particularly in northwest regions of China. Traditionally, dried goji berries are cooked before they are consumed. They are commonly used in Chinese soups and as herbal tea. Moreover, goji berries are used for the production of tincture, wine, and juice. Goji berries are high antioxidant potential fruits which alleviate oxidative stress to confer many health protective benefits such as preventing free radicals from damaging DNA, lipids, and proteins. Therefore, the aim of the review was to focus on the bioactive compounds and pharmacological properties of goji berries including their molecular mechanisms of action. The health benefits of goji berries include enhancing hemopoiesis, antiradiation, antiaging, anticancer, improvement of immunity, and antioxidation. There is a better protection through synergistic and additive effects in fruits and herbal products from a complex mixture of phytochemicals when compared to one single phytochemical.