Genetic-algorithm-based waveguide display system with a multiplexed volume holographic grating.

Most of the current holographic waveguide display systems are designed based on the center beam. When the incident beam consists of rays with different angles, the field of view and optical efficiency would greatly reduce. The heavy angular dependence of the volume holographic grating (VHG) and the back-coupling loss are two main reasons. This paper proposes a design method of the waveguide display system with multiplexed VHG, which is based on a genetic algorithm to optimize and calculate the parameters both of the VHG and the waveguide. The simulation results show that the diagonal field of view of the holographic waveguide system is increased to 28°, and its optical efficiency is improved by 30%. The design method of the waveguide system with the multiplexed grating proposed in this paper can effectively expand the field of view and improve the optical efficiency.

Megafossils of Betulaceae from the Oligocene of Qaidam Basin and their paleoenvironmental and phytogeographic implications.

Understanding the paleoenvironment and phytogeographical history of the Tibetan Plateau, China relies on discovering new plant fossils. The Qaidam Basin has long been regarded as an ideal 'field laboratory' to investigate the paleoclimate and paleobiological evolution of the northern Tibetan Plateau. However, fossil angiosperms from the Qaidam Basin are rare, and our knowledge of its paleovegetation is poor. Here, we report fossil leaves and fruits of Betulaceae found from the Oligocene Shangganchaigou Formation of northwestern Qaidam Basin (Huatugou area). Comparative morphological analysis led us to assign the fruits to the Betula subgenus Betula and the leaves to Carpinus grandis. These findings, together with other reported fossil plants from the same locality, reveal a close floristic linkage between the Qaidam Basin and Europe during the Oligocene. The northern pathway of this floristic exchange may have crossed through the Qaidam Basin during the late Paleogene. This floristic linkage may have been facilitated by the continuous narrowing of the Turgai Strait and stronger westerlies, which transported moisture and provided favorable climatic conditions. Indeed, fossil plants collected from the Qaidam Basin suggest that during the Oligocene this region had warm and humid deciduous broad-leaf forest, which differs from the region's modern vegetation and indicates that the Qaidam Basin may have been a suitable region for these plants to flourish and spread during the Oligocene.

Levetiracetam may be an unsuitable choice for patients with PRRT2-associated self-limited infantile epilepsy.

INTRODUCTION: Self-limited infantile epilepsy (SeLIE) is a benign epilepsy. Previous studies have shown that monotherapy with most antiseizure medications can effectively relieve seizures in patients with SeLIE, but the efficacy of levetiracetam has not been investigated. OBJECTIVE: This study aimed to investigate the efficacy of levetiracetam in the treatment of SeLIE patients with PRRT2 mutations. METHODS: The clinical data of 39 SeLIE patients (21 males and 18 females, aged 4.79 ± 1.60 months) with pathogenic variants in PRRT2 or 16p11.2 microdeletion were retrospectively analyzed. Based on the use of initial antiseizure medication (ASM), the patients were classified into two groups: Levetiracetam group (LEG) and Other ASMs group (OAG). The difference of efficacy between the two groups was compared. RESULTS: Among the 39 SeLIE patients, 16 were LEG (10 males and 6 females, aged 5.25 ± 2.07 months), with whom two obtained a seizure-free status (12.50%) and 14 ineffective or even deteriorated (87.50%). Among the 14 ineffective or deteriorated cases, 13 were seizure-controlled after replacing levetiracetam with other ASMs including topiramate, oxcarbazepine, lamotrigine, and valproate, and the remaining one finally achieved remission at age 3. Of the 39 patients, 23 were OAG (11 males and 12 females; aged 4.48 ± 1.12 months), of whom 22 achieved seizure remission, except for one patient who was ineffective with topiramate initially and relieved by oxcarbazepine instead. Although there were no significant differences in gender and age of onset between the two groups, the effective rate was significantly different (12.50% in LEG vs. 95.65% in OAG) (P < 0.01). CONCLUSION: The findings showed that patients with SeLIE caused by the PRRT2 mutations did not benefit from the use of levetiracetam, but could benefit from other ASMs.

[Genetic analysis of a child with developmental disorder and epilepsy due to a homozygous variant of PIGW gene].

OBJECTIVE: To explore the genetic basis for a child featuring global developmental disorder with epilepsy. METHODS: A child who had presented at Guangzhou Women and Children's Medical Center in July 2022 was selected as the study subject. Clinical data was collected. Potential variant was detected by whole exome sequencing (WES). Candidate variant was validated by Sanger sequencing and bioinformatic analysis. RESULTS: The child, a three-year-old ethnic Zhuang Chinese girl, had presented with global developmental disorder and epilepsy, for which rehabilitation therapy was ineffective. Genetic testing revealed that she has harbored a homozygous c.821T>C (p.Leu274Pro) missense variant of the PIGW gene, for which both of her parents and sister were heterozygous carriers. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as variant of uncertain significance. CONCLUSION: The homozygous c.821T>C (p.Leu274Pro) variant of the PIGW gene probably underlay the onset of disease in this child. Above finding has enriched the mutational spectrum of the PIGW gene.

[Analysis of NR2F1 gene variant in a child with optic atrophy and global developmental delay].

OBJECTIVE: To explore the genetic basis for a child with optic atrophy and global developmental delay. METHODS: A child who had presented at the Guangzhou Women and Children's Medical Center in January 2022 was selected as the study subject. Clinical data were collected. Whole exome sequencing (WES) was carried out for the child. Candidate variant was validated by Sanger sequencing and bioinformatic analysis. RESULTS: The child, a nine-month-old female, had manifested dysopia and global developmental delay. Genetic testing revealed that she has harbored a de novo c.425G>C (p.Arg142Pro) variant of the NR2F1 gene, which has been associated with Bosch-Boonstra-Schaaf syndrome. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PS2+PM1+PM2_Supporting+PM5+PP3+PP4). CONCLUSION: The c.425G>C (p.Arg142Pro) variant of the NR2F1 gene probably underlay the pathogenesis in this child. Above finding has enriched the genotypic and phenotypic spectrum of the NR2F1 gene.

The mitophagy pathway and its implications in human diseases.

Mitochondria are dynamic organelles with multiple functions. They participate in necrotic cell death and programmed apoptotic, and are crucial for cell metabolism and survival. Mitophagy serves as a cytoprotective mechanism to remove superfluous or dysfunctional mitochondria and maintain mitochondrial fine-tuning numbers to balance intracellular homeostasis. Growing evidences show that mitophagy, as an acute tissue stress response, plays an important role in maintaining the health of the mitochondrial network. Since the timely removal of abnormal mitochondria is essential for cell survival, cells have evolved a variety of mitophagy pathways to ensure that mitophagy can be activated in time under various environments. A better understanding of the mechanism of mitophagy in various diseases is crucial for the treatment of diseases and therapeutic target design. In this review, we summarize the molecular mechanisms of mitophagy-mediated mitochondrial elimination, how mitophagy maintains mitochondrial homeostasis at the system levels and organ, and what alterations in mitophagy are related to the development of diseases, including neurological, cardiovascular, pulmonary, hepatic, renal disease, etc., in recent advances. Finally, we summarize the potential clinical applications and outline the conditions for mitophagy regulators to enter clinical trials. Research advances in signaling transduction of mitophagy will have an important role in developing new therapeutic strategies for precision medicine.

Silver Nanoparticles Cause Neural and Vascular Disruption by Affecting Key Neuroactive Ligand-Receptor Interaction and VEGF Signaling Pathways.

Introduction: Silver nanoparticles (AgNP) are widely used as coating materials. However, the potential risks of AgNP to human health, especially for neural and vascular systems, are still poorly understood. Methods: The vascular and neurotoxicity of various concentrations of AgNP in zebrafish were examined using fluorescence microscopy. In addition, Illumina high-throughput global transcriptome analysis was performed to explore the transcriptome profiles of zebrafish embryos after exposure to AgNP. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to elucidate the top 3000 differentially expressed genes (DEGs) between AgNP-exposed and control groups. Results: We systematically investigated the neural and vascular developmental toxicities of AgNP exposure in zebrafish. The results demonstrated that AgNP exposure could cause neurodevelopmental anomalies, including a small-eye phenotype, neuronal morphology defects, and inhibition of athletic abilities. In addition, we found that AgNP exposure induces angiogenesis malformation in zebrafish embryos. Further RNA-seq revealed that DEGs were mainly enriched in the neuroactive ligand-receptor interaction and vascular endothelial growth factor (Vegf) signaling pathways in AgNP-treated zebrafish embryos. Specifically, the mRNA levels of the neuroactive ligand-receptor interaction pathway and Vegf signaling pathway-related genes, including si:ch73-55i23.1, nfatc2a, prkcg, si:ch211-132p1.2, lepa, mchr1b, pla2g4aa, rac1b, p2ry6, adrb2, chrnb1, and chrm1b, were significantly regulated in AgNP-treated zebrafish embryos. Conclusion: Our findings indicate that AgNP exposure transcriptionally induces developmental toxicity in neural and vascular development by disturbing neuroactive ligand-receptor interactions and the Vegf signaling pathway in zebrafish embryos.

Age at menarche and polycystic ovary syndrome: A Mendelian randomization study.

OBJECTIVE: The authors aimed to use a large two-sample Mendelian randomization (MR) study to reveal the causality between age at menarche (AAM) and polycystic ovary syndrome (PCOS) incidence. METHODS: The authors collected summary statistics from the hitherto largest genome-wide association studies conducted in AAM and PCOS in the same ancestry. MR with inverse variance weighting was conducted as the main analysis method, while weighted median and MR-Egger regression were used for comprehensive analysis. As for pleiotropy detection, inverse variance weighting, MR-Egger regression, Mendelian Randomization Pleiotropy Residual Sum and Outlier, as well as leave-one-out analysis were used to detect pleiotropy. Risk factor analysis was conducted to investigate the underlying mechanisms linking AAM to PCOS. RESULTS: Each standard deviation increment in AAM was associated with a significantly lower incidence of PCOS (odds ratio, 0.86 [95% confidence interval, 0.75-0.98]). After adjustment in horizontal pleiotropy by eliminating four outliers, this pathogenic association was still statistically detected. All pleiotropy indexes were without statistical differences, which suggested the conclusions were robust. It showed the causal association between later AAM and lower body mass index, lower fasting insulin level and insulin resistance. CONCLUSION: Our MR analysis verified that a slightly later onset age (15 to 18 years) at menarche could reduce the risk of PCOS. A more comprehensive investigation in a prospective setting is strongly advised.

Causal effects of gut microbiota on the risk of chronic kidney disease: a Mendelian randomization study.

Background: Previous studies have reported that gut microbiota is associated with an increased risk of chronic kidney disease (CKD) progression. However, whether gut microbiota has a causal effect on the development of CKD has not been revealed. Thus, we aimed to analyze the potential causal effect of gut microbiota on the risk of CKD using mendelian randomization (MR) study. Materials and Methods: Independent single nucleotide polymorphisms closely associated with 196 gut bacterial taxa (N = 18340) were identified as instrumental variables. Two-sample MR was performed to evaluate the causal effect of gut microbiota on CKD (N = 480698), including inverse-variance-weighted (IVW) method, weighted median method, MR-Egger, mode-based estimation and MR-PRESSO. The robustness of the estimation was tested by a series of sensitivity analyses including Cochran's Q test, MR-Egger intercept analysis, leave-one-out analysis and funnel plot. Statistical powers were also calculated. Results: The genetically predicted higher abundance of order Desulfovibrionales was causally associated with an increased risk of CKD (odds ratio = 1.15, 95% confidence interval: 1.05-1.26; p = 0.0026). Besides, we also detected potential causalities between nine other taxa (Eubacterium eligens group, Desulfovibrionaceae, Ruminococcaceae UCG-002, Deltaproteobacteria, Lachnospiraceae UCG-010, Senegalimassilia, Peptostreptococcaceae, Alcaligenaceae and Ruminococcus torques group) and CKD (p < 0.05). No heterogeneity or pleiotropy was detected for significant estimates. Conclusion: We found that Desulfovibrionales and nine other taxa are associated with CKD, thus confirming that gut microbiota plays an important role in the pathogenesis of CKD. Our work also provides new potential indicators and targets for screening and prevention of CKD.

Hierarchical Nanospheres with Polycrystalline Ir&Cu and Amorphous Cu2 O toward Energy-Efficient Nitrate Electrolysis to Ammonia.

Electrochemical reduction reaction of nitrate (NITRR) provides a sustainable route toward the green synthesis of ammonia. Nevertheless, it remains challenging to achieve high-performance electrocatalysts for NITRR especially at low overpotentials. In this work, hierarchical nanospheres consisting of polycrystalline Iridium&copper (Ir&Cu) and amorphous Cu2 O (Cux Iry Oz NS) have been fabricated. The optimal species Cu0.86 Ir0.14 Oz delivers excellent catalytic performance with a desirable NH3 yield rate (YR) up to 0.423 mmol h-1  cm-2 (or 4.8 mg h-1  mgcat -1 ) and a high NH3 Faradaic efficiency (FE) over 90% at a low overpotential of 0.69 V (or 0 VRHE ), where hydrogen evolution reaction (HER) is almost negligible. The electrolyzer toward NITRR and hydrazine oxidation (HzOR) is constructed for the first time with an electrode pair of Cu0.86 Ir0.14 Oz //Cu0.86 Ir0.14 Oz , yielding a high energy efficiency (EE) up to 87%. Density functional theory (DFT) calculations demonstrate that the dispersed Ir atom provides active site that not only promotes the NO3 - adsorption but also modulates the H adsorption/desorption to facilitate the proton supply for the hydrogenation of *N, hence boosting the NITRR. This work thus points to the importance of both morphological/structural and compositional engineering for achieving the highly efficient catalysts toward NITRR.

A Mendelian randomization study on causal effects of leisure sedentary behaviour on the risk of rheumatoid arthritis.

BACKGROUND: The causal inference between leisure sedentary behaviour (LSB) and rheumatoid arthritis (RA) is still controversial because of potential residual confounding and reverse causality. METHODS: The present study used publicly available large-scale genome-wide association studies (GWAS) of LSB (television watching, computer use, and driving) and RA to perform a two-sample Mendelian randomization (MR) study to evaluate the causal effect of LSB on the risk of RA. We detected significant causal associations using the multiplicative random effects-inverse variance weighted (MRE-IVW) method, the maximum likelihood, robust adjusted profile scores, the weighted median, MR-Egger regression, and several complementary sensitivity analyses. Risk factor analysis was also conducted to further investigate potential mediators linking causal inference. RESULTS: Increased genetic liability to leisure television watching was significantly associated with a higher risk of RA (MRE-IVW method; OR = 2.46, 95% CI 1.77-3.41; p = 8.35 × 10-8 ). MR estimates indicated that prolonged leisure computer use was causally associated with a lower risk of RA (MRE-IVW method; OR = 0.23, 95% CI 0.12-0.46; p = 2.19 × 10-5 ). However, we found no evidence for a causal effect of leisure driving on the risk of RA (MRE-IVW method; OR = 0.59, 95% CI 0.10-3.41; p = 0.557). No pleiotropy was detected by the sensitivity analysis. CONCLUSIONS: This study supports a causal association between prolonged leisure television watching and an increased risk of RA. Additionally, prolonged computer use might be a protective factor for RA.

Assessing the causal association between human blood metabolites and the risk of epilepsy.

BACKGROUND: Metabolic disturbance has been reported in patients with epilepsy. Still, the evidence about the causal role of metabolites in facilitating or preventing epilepsy is lacking. Systematically investigating the causality between blood metabolites and epilepsy would help provide novel targets for epilepsy screening and prevention. METHODS: We conducted two-sample Mendelian randomization (MR) analysis. Data for 486 human blood metabolites came from a genome-wide association study (GWAS) comprising 7824 participants. GWAS data for epilepsy were obtained from the International League Against Epilepsy (ILAE) consortium for primary analysis and the FinnGen consortium for replication and meta-analysis. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. RESULTS: 482 out of 486 metabolites were included for MR analysis following rigorous genetic variants selection. After IVW and sensitivity analysis filtration, six metabolites with causal effects on epilepsy were identified from the ILAE consortium. Only four metabolites remained significant associations with epilepsy when combined with the FinnGen consortium [uridine: odds ratio (OR) = 2.34, 95% confidence interval (CI) = 1.48-3.71, P = 0.0003; 2-hydroxystearate: OR = 1.61, 95% CI = 1.19-2.18, P = 0.002; decanoylcarnitine: OR = 0.82, 95% CI = 0.72-0.94, P = 0.004; myo-inositol: OR = 0.77, 95% CI = 0.62-0.96, P = 0.02]. CONCLUSION: The evidence that the four metabolites mentioned above are associated with epilepsy in a causal way provides a novel insight into the underlying mechanisms of epilepsy by integrating genomics with metabolism, and has an implication for epilepsy screening and prevention.

An Augmented Neural Network for Sentiment Analysis Using Grammar.

Understanding human sentiment from their expressions is very important in human-robot interaction. But deep learning models are hard to represent grammatical changes for natural language processing (NLP), especially for sentimental analysis, which influence the robot's judgment of sentiment. This paper proposed a novel sentimental analysis model named MoLeSy, which is an augmentation of neural networks incorporating morphological, lexical, and syntactic knowledge. This model is constructed from three concurrently processed classical neural networks, in which output vectors are concatenated and reduced with a single dense neural network layer. The models used in the three grammatical channels are convolutional neural networks (CNNs), long short-term memory (LSTM) networks, and fully connected dense neural networks. The corresponding output in the three channels is morphological, lexical, and syntactic results, respectively. Experiments are conducted on four different sentimental analysis corpuses, namely, hotel, NLPCC2014, Douban movie reviews dataset, and Weibo. MoLeSy can achieve the best performance over previous state-of-art models. It indicated that morphological, lexical, and syntactic grammar can augment the neural networks for sentimental analysis.

Causal relationship between physical activity, leisure sedentary behaviors and COVID-19 risk: a Mendelian randomization study.

BACKGROUND: The 2019 coronavirus disease pandemic (COVID-19) poses an enormous threat to public health worldwide, and the ensuing management of social isolation has greatly decreased opportunities for physical activity (PA) and increased opportunities for leisure sedentary behaviors (LSB). Given that both PA and LSB have been established as major influencing factors for obesity, diabetes and cardiometabolic syndrome, whether PA/LSB in turn affects the susceptibility to COVID-19 by disrupting metabolic homeostasis remains to be explored. In this study, we aimed to systematically evaluate the causal relationship between PA/LSB and COVID-19 susceptibility, hospitalization and severity using a Mendelian randomization study. METHODS: Data were obtained from a large-scale PA dataset (N = 377,000), LSB dataset (N = 422,218) and COVID-19 Host Genetics Initiative (N = 2,586,691). The causal effects were estimated with inverse variance weighted, MR-Egger, weighted median and MR-PRESSO. Sensitivity analyses were implemented with Cochran's Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis and the funnel plot. Risk factor analyses were further conducted to investigate the potential mediators. RESULTS: Genetically predicted accelerometer-assessed PA decreased the risk for COVID-19 hospitalization (OR = 0.93, 95% CI 0.88-0.97; P = 0.002), while leisure television watching significantly increased the risk of COVID-19 hospitalization (OR = 1.55, 95% CI 1.29-1.88; P = 4.68 × 10-6) and disease severity (OR = 1.85, 95% CI 1.33-2.56; P = 0.0002) after Bonferroni correction. No causal effects of self-reported moderate to vigorous physical activity (MVPA), accelerometer fraction of accelerations > 425 milligravities, computer use or driving on COVID-19 progression were observed. Risk factor analyses indicated that the above causal associations might be mediated by several metabolic risk factors, including smoking, high body mass index, elevated serum triglyceride levels, insulin resistance and the occurrence of type 2 diabetes. CONCLUSION: Our findings supported a causal effect of accelerometer-assessed PA on the reduced risk of COVID-19 hospitalization as well as television watching on the increased risk of COVID-19 hospitalization and severity, which was potentially mediated by smoking, obesity and type 2 diabetes-related phenotypes. Particular attention should be given to reducing leisure sedentary behaviors and encouraging proper exercise during isolation and quarantine for COVID-19.

Socioeconomic status, individual behaviors and risk for mental disorders: A Mendelian randomization study.

BACKGROUND: There is increasing attention on the association of socioeconomic status and individual behaviors (SES/IB) with mental health. However, the impacts of SES/IB on mental disorders are still unclear. To provide evidence for establishing feasible strategies on disease screening and prevention, we implemented Mendelian randomization (MR) design to appraise causality between SES/IB and mental disorders. METHODS: We conducted a two-sample MR study to assess the causal effects of SES and IB (dietary habits, habitual physical activity, smoking behaviors, drinking behaviors, sleeping behaviors, leisure sedentary behaviors, risky behaviors, and reproductive behaviors) on three mental disorders, including bipolar disorder, major depressive disorder and schizophrenia. A series of filtering steps were taken to select eligible genetic instruments robustly associated with each of the traits. Inverse variance weighted was used for primary analysis, with alternative MR methods including MR-Egger, weighted median, and weighted mode estimate. Complementary methods were further used to detect pleiotropic bias. RESULTS: After Bonferroni correction and rigorous quality control, we identified that SES (educational attainment), smoking behaviors (smoking initiation, number of cigarettes per day), risky behaviors (adventurousness, number of sexual partners, automobile speeding propensity) and reproductive behavior (age at first birth) were causally associated with at least one of the mental disorders. CONCLUSIONS: MR study provides robust evidence that SES/IB play broad impacts on mental disorders.

Generation of an induced pluripotent stem cell line (GWCMCi005-A) from a patient with Lennox-Gastaut syndrome carrying TANC2 Gln1441Ter mutation.

Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy, which may arise from genetic etiologies. TANC2 mutation may cause the neurodevelopmental disorders and epilepsy such as LGS. By reprogramming with SOX2, KLF4, c-MYC and OCT3/4, we generated an induced pluripotent stem cell (iPSC) line from peripheral blood mononuclear cells (PBMCs) collected from a two-year-old Chinese boy individual to be used as a disease model with TANC2 mutation. By fully examination, the resulting iPSCs expressed pluripotency-associated stem cell markers, maintained the normal karyotype and proliferative potential for three-germ layer differentiation.

Causal relationship between 14 site-specific cancers and venous thromboembolism.

Background: It has been observed that cancer and venous thromboembolism (VTE) are associated, but anticancer therapy may violate the causality. Therefore, this study aimed to elucidate the causal relationship of various cancers to VTE using Mendelian randomization (MR). Methods: Three MR methods were used to estimate causal effects: Inverse variance weighted (IVW), MR-Egger and weighted median. Sensitivity analyses included Cochran's Q-test, MR-Egger intercept test and MR-PRESSO. Gene ontology enrichment analysis was performed to elucidate the underlying mechanisms of VTE development in cancer patients. Results: The primary IVW approach showed that non-Hodgkin's lymphoma (NHL) might increase the risk of VTE (odds ratio [OR]: 1.20, 95% confidence interval [95% CI]: 1.00-1.44, p = 0.045), while melanoma possibly reduced the risk of VTE (OR: 0.89, 95% CI: 0.82-0.97, p = 0.006), although there was no significance after adjustment for multiple testing. No association was observed between VTE risk and other site-specific cancers. Gene ontology enrichment analysis revealed that vitamin D played an important role in the development of VTE in cancer patients. Conclusions: Our findings suggested that genetically predicted NHL was associated with higher VTE risk, whereas melanoma had lower VTE risk compared with other site-specific cancers. Moreover, this study suggested that anticancer therapy and increased extensive examination might play a more important role in VTE development than the nature of cancer.

Genetic liability for prescription opioid use and risk of cardiovascular diseases: a multivariable Mendelian randomization study.

BACKGROUND AND AIMS: Observational studies have yielded conflicting results on the association of prescription opioid use (POU) with the risk of cardiovascular diseases (CVD). Residual confounding and potential reverse causality are inevitable in such conventional observational studies. This study used Mendelian randomization (MR) design to estimate the causal effect of POU on the risk of CVD, including coronary heart disease (CHD), myocardial infarction (MI) and ischemic stroke (IS), as well as their common risk factors. DESIGN: We estimated the causal effect of genetic liability for POU on CVD in a two-sample MR framework. Complementary sensitivity analyses were conducted to test the robustness of our results. SETTING: Genome-wide association studies (GWAS) that were based on predominantly European ancestry. PARTICIPANTS: The sample sizes of the GWAS used in this study ranged from 69 033 to 757 601 participants. MEASUREMENTS: Genetic variants predictive of the POU and their corresponding summary-level information in the outcomes were retrieved and extracted from the respective GWAS. FINDINGS: Using univariable MR, we found evidence for a causal effect of genetic liability for POU on an increased risk of CHD [odds ratio (OR) = 1.09; 95% confidence interval (CI) = 1.02-1.16; P = 0.008] and MI (OR = 1.13; 95% CI = 1.04-1.22; P = 0.002). In multivariable MR, the association remained after accounting for comorbid pain conditions, but was attenuated with adjustment for potential mediators, including body mass index (BMI), waist circumference (WC) and type 2 diabetes (T2D). CONCLUSION: Mendelian randomization estimates provide robust evidence for the causal effects of genetic liability for prescription opioid use on an increased risk of coronary heart disease and myocardial infarction, which might be mediated by obesity-related traits.

Kidney damage causally affects the brain cortical structure: A Mendelian randomization study.

BACKGROUND: Alterations in the brain cortical structures of patients with chronic kidney disease (CKD) have been reported; however, the cause has not been determined yet. Herein, we used Mendelian randomization (MR) to reveal the causal effect of kidney damage on brain cortical structure. METHODS: Genome-wide association studies summary data of estimated glomerular filtration rate (eGFR) in 480,698 participants from the CKDGen Consortium were used to identify genetically predicted eGFR. Data from 567,460 individuals from the CKDGen Consortium were used to assess genetically determined CKD; 302,687 participants from the UK Biobank were used to evaluate genetically predicted albuminuria. Further, data from 51,665 patients from the ENIGMA Consortium were used to assess the relationship between genetic predisposition and reduced eGFR, CKD, and progressive albuminuria with alterations in cortical thickness (TH) or surficial area (SA) of the brain. Magnetic resonance imaging was used to measure the SA and TH globally and in 34 functional regions. Inverse-variance weighted was used as the primary estimate whereas MR Pleiotropy RESidual Sum and Outlier, MR-Egger and weighted median were used to detect heterogeneity and pleiotropy. FINDINGS: At the global level, albuminuria decreased TH (ß = -0.07 mm, 95% CI: -0.12 mm to -0.02 mm, P = 0.004); at the functional level, albuminuria reduced TH of pars opercularis gyrus without global weighted (ß = -0.11 mm, 95% CI: -0.16 mm to -0.07 mm, P = 3.74×10-6). No pleiotropy was detected. INTERPRETATION: Kidney damage causally influences the cortex structure which suggests the existence of a kidney-brain axis. FUNDING: This study was supported by the Science and Technology Planning Project of Guangdong Province (Grant No. 2020A1515111119 and 2017B020227007), the National Key Research and Development Program of China (Grant No. 2018YFA0902803), the National Natural Science Foundation of China (Grant No. 81825016, 81961128027, 81772719, 81772728), the Key Areas Research and Development Program of Guangdong (Grant No. 2018B010109006), Guangdong Special Support Program (2017TX04R246), Grant KLB09001 from the Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, and Grants from the Guangdong Science and Technology Department (2020B1212060018).

Causal relationship between educational attainment and the risk of rheumatoid arthritis: a Mendelian randomization study.

BACKGROUND: Educational attainment is moderately heritable and inversely associated with the risk of rheumatoid arthritis. However, the causality from educational attainment on rheumatoid arthritis remained unknown. Here, we aimed to determine whether educational attainment is causally associated with rheumatoid arthritis (RA) by using Mendelian randomization (MR) approach. METHODS: Summary statistics data for RA were obtained from an available, published meta-analysis of genome-wide association studies (GWAS) that included 14,361 RA cases and 43,923 controls of European ancestry. The instrumental variables for educational attainment were obtained from a GWAS meta-analysis that included over 1 million individuals (N = 1,131,881) of European ancestry. MR analyses were mainly performed using the inverse-variance weighted (IVW) method. Sensitivity analyses were further performed to test the robustness of the association using the weighted median method, MR-Egger, Cochran Q test, "leave-one-out" analysis and MR-PRESSO test. RESULTS: A total of 387 SNPs were employed as instrumental variables in our MR analysis. Genetically predicted higher educational attainment was associated with a significantly lower risk of RA using the IVW method (odds ratio [OR] = 0.42, 95% confidence interval [CI]: 0.34-0.52; p = 1.78 × 10- 14). The weighted median method and MR Egger regression analysis yielded consistent results. The effect estimate remained robust after the outlier variants and SNPs (associated with the confounding factors) were excluded. "Leave-one-out" analysis confirmed the stability of our results. Additionally, the results suggested the absence of the horizontal pleiotropy. CONCLUSIONS: The MR analysis supported a potential inverse causative relationship between educational attainment and the risk of RA.