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As countries in the world review interventions for containing the pandemic of coronavirus disease 2019 (COVID-19), important lessons can be drawn from the study of the full transmission dynamics of its causative agent—severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)— in Wuhan (China), where vigorous non-pharmaceutical interventions have suppressed the local outbreak of this disease 1 . Here we use a modelling approach to reconstruct the full-spectrum dynamics of COVID-19 in Wuhan between 1 January and 8 March 2020 across 5 periods defined by events and interventions, on the basis of 32,583 laboratory-confirmed cases 1 . Accounting for presymptomatic infectiousness 2 , time-varying ascertainment rates, transmission rates and population movements 3 , we identify two key features of the outbreak: high covertness and high transmissibility. We estimate 87% (lower bound, 53%) of the infections before 8 March 2020 were unascertained (potentially including asymptomatic and mildly symptomatic individuals); and a basic reproduction number ( R 0 ) of 3.54 (95% credible interval 3.40–3.67) in the early outbreak, much higher than that of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) 4 , 5 . We observe that multipronged interventions had considerable positive effects on controlling the outbreak, decreasing the reproduction number to 0.28 (95% credible interval 0.23–0.33) and—by projection—reducing the total infections in Wuhan by 96.0% as of 8 March 2020. We also explore the probability of resurgence following the lifting of all interventions after 14 consecutive days of no ascertained infections; we estimate this probability at 0.32 and 0.06 on the basis of models with 87% and 53% unascertained cases, respectively—highlighting the risk posed by substantial covert infections when changing control measures. These results have important implications when considering strategies of continuing surveillance and interventions to eventually contain outbreaks of COVID-19. Analysis of the full-spectrum transmission dynamics of COVID-19 in Wuhan reveals that multipronged non-pharmaceutical interventions were effective in controlling the outbreak, and highlights that covert infections may pose risks of resurgence when reopening without intervention measures.

Asthma is a common chronic airway disease worldwide. Despite its large population size, China has had no comprehensive study of the national prevalence, risk factors, and management of asthma. We therefore aimed to estimate the national prevalence of asthma in a representative sample of the Chinese population. A representative sample of 57 779 adults aged 20 years or older was recruited for the national cross-sectional China Pulmonary Health (CPH) study using a multi-stage stratified sampling method with parameters derived from the 2010 census. Ten Chinese provinces, representative of all socioeconomic settings, from six geographical regions were selected, and all assessments were done in local health centres. Exclusion criteria were temporary residence, inability to take a spirometry test, hospital treatment of cardiovascular conditions or tuberculosis, and pregnancy and breastfeeding. Asthma was determined on the basis of a self-reported history of diagnosis by a physician or by wheezing symptoms in the preceding 12 months. All participants were assessed with a standard asthma questionnaire and were classed as having or not having airflow limitation through pulmonary function tests before and after the use of a bronchodilator (400 μg of salbutamol). Risk factors for asthma were examined by multivariable-adjusted analyses done in all participants for whom data on the variables of interest were available. Disease management was assessed by the self-reported history of physician diagnosis, treatments, and hospital visits in people with asthma. Between June 22, 2012, and May 25, 2015, 57 779 participants were recruited into the CPH study. 50 991 (21 446 men and 29 545 women) completed the questionnaire survey and had reliable post-bronchodilator pulmonary function test results and were thus included in the final analysis. The overall prevalence of asthma in our sample was 4·2% (95% CI 3·1–5·6), representing 45·7 million Chinese adults. The prevalence of asthma with airflow limitation was 1·1% (0·9–1·4), representing 13·1 million adults. Cigarette smoking (odds ratio [OR] 1·89, 95% CI 1·26–2·84; p=0·004), allergic rhinitis (3·06, 2·26–4·15; p<0·0001), childhood pneumonia or bronchitis (2·43, 1·44–4·10; p=0·002), parental history of respiratory disease (1·44, 1·02–2·04; p=0·040), and low education attainment (p=0·045) were associated with prevalent asthma. In 2032 people with asthma, only 28·8% (95% CI 19·7–40·0) reported ever being diagnosed by a physician, 23·4% (13·9–36·6) had a previous pulmonary function test, and 5·6% (3·1–9·9) had been treated with inhaled corticosteroids. Furthermore, 15·5% (11·4–20·8) people with asthma reported at least one emergency room visit and 7·2% (4·9–10·5) at least one hospital admission due to exacerbation of respiratory symptoms within the preceding year. Asthma is prevalent but largely undiagnosed and undertreated in China. It is crucial to increase the awareness of asthma and disseminate standardised treatment in clinical settings to reduce the disease burden. National Key R&D Program of China, Ministry of Science and Technology of China; the Special Research Foundation for Public Welfare of Health, Ministry of Health of China; the Chinese National Research Program for Key Issues in Air Pollution Control; and the National Natural Science Foundation of China.

Kidney stone disease (KSD) is a complex disorder with high heritability and prevalence. We performed a large genome-wide association study (GWAS) meta-analysis for KSD to date, including 720,199 individuals with 17,969 cases in European population. We identified 44 susceptibility loci, including 28 novel loci. Cell type-specific analysis pinpointed the proximal tubule as the most relevant cells where susceptibility variants might act through a tissue-specific fashion. By integrating kidney-specific omics data, we prioritized 223 genes which strengthened the importance of ion homeostasis, including calcium and magnesium in stone formation, and suggested potential target drugs for the treatment. The genitourinary and digestive diseases showed stronger genetic correlations with KSD. In this study, we generate an atlas of candidate genes, tissue and cell types involved in the formation of KSD. In addition, we provide potential drug targets for KSD treatment and insights into shared regulation with other diseases. Kidney stone disease is a complex disorder with high heritability and prevalence. Here, the authors perform a large genome-wide association study meta-analysis, identifying 28 new loci and genes potentially involved in disease etiology.

Background Coronary artery disease (CAD) remains the leading cause of mortality worldwide despite enormous efforts devoted to its prevention and treatment. While many genetic loci have been identified to associate with CAD, the intermediate causal risk factors and etiology have not been fully understood. This study assesses the causal effects of 37 heritable clinical factors on CAD in East Asian and European populations. Methods We collected genome-wide association summary statistics of 37 clinical factors from the Biobank Japan (42,793 to 191,764 participants) and the UK Biobank (314,658 to 442,817 participants), paired with summary statistics of CAD from East Asians (29,319 cases and 183,134 controls) and Europeans (91,753 cases and 311,344 controls). These clinical factors covered 12 cardiometabolic traits, 13 hematological indices, 7 hepatological and 3 renal function indices, and 2 serum electrolyte indices. We performed univariable and multivariable Mendelian randomization (MR) analyses in East Asians and Europeans separately, followed by meta-analysis. Results Univariable MR analyses identified reliable causal evidence ( P < 0.05/37) of 10 cardiometabolic traits (height, body mass index [BMI], blood pressure, glycemic and lipid traits) and 4 other clinical factors related to red blood cells (red blood cell count [RBC], hemoglobin, hematocrit) and uric acid (UA). Interestingly, while generally consistent, we identified population heterogeneity in the causal effects of BMI and UA, with higher effect sizes in East Asians than those in Europeans. After adjusting for cardiometabolic factors in multivariable MR analysis, red blood cell traits (RBC, meta-analysis odds ratio 1.07 per standard deviation increase, 95% confidence interval 1.02–1.13; hemoglobin, 1.10, 1.03–1.16; hematocrit, 1.10, 1.04–1.17) remained significant ( P < 0.05), while UA showed an independent causal effect in East Asians only (1.12, 1.06–1.19, P = 3.26×10 −5 ). Conclusions We confirmed the causal effects of 10 cardiometabolic traits on CAD and identified causal risk effects of RBC, hemoglobin, hematocrit, and UA independent of traditional cardiometabolic factors. We found no causal effects for 23 clinical factors, despite their reported epidemiological associations. Our findings suggest the physiology of red blood cells and the level of UA as potential intervention targets for the prevention of CAD.

Background Chronological age (CA) does not reflect individual variation in the aging process. However, existing biological age predictors are mostly based on European populations and overlook the widespread nonlinear effects of clinical biomarkers. Methods Using data from the prospective Dongfeng-Tongji (DFTJ) cohort of elderly Chinese, we propose a physiological aging index (PAI) based on 36 routine clinical biomarkers to measure aging progress. We first determined the optimal level of each biomarker by restricted cubic spline Cox models. For biomarkers with a U-shaped relationship with mortality, we derived new variables to model their distinct effects below and above the optimal levels. We defined PAI as a weighted sum of variables predictive of mortality selected by a LASSO Cox model. To measure aging acceleration, we defined ΔPAI as the residual of PAI after regressing on CA. We evaluated the predictive value of ΔPAI on cardiovascular diseases (CVD) in the DFTJ cohort, as well as nine major chronic diseases in the UK Biobank (UKB). Results In the DFTJ training set ( n  = 12,769, median follow-up: 10.38 years), we identified 25 biomarkers with significant nonlinear associations with mortality, of which 11 showed insignificant linear associations. By incorporating nonlinear effects, we selected CA and 17 clinical biomarkers to calculate PAI. In the DFTJ testing set ( n  = 15,904, 5.87 years), PAI predict mortality with a concordance index (C-index) of 0.816 (95% confidence interval, [0.796, 0.837]), better than CA (C-index = 0.771 [0.755, 0.788]) and PhenoAge (0.799 [0.784, 0.814]). ΔPAI was predictive of incident CVD and its subtypes, independent of traditional risk factors. In the external validation set of UKB ( n  = 296,931, 12.80 years), PAI achieved a C-index of 0.749 (0.746, 0.752) to predict mortality, remaining better than CA (0.706 [0.702, 0.709]) and PhenoAge (0.743 [0.739, 0.746]). In both DFTJ and UKB, PAI calibrated better than PhenoAge when comparing the predicted and observed survival probabilities. Furthermore, ΔPAI outperformed any single biomarker to predict incident risks of eight age-related chronic diseases. Conclusions Our results highlight the potential of PAI and ΔPAI as integrative biomarkers to evaluate aging acceleration and facilitate the development of targeted intervention strategies for healthy aging.

Venous thromboembolism is a life-threatening vascular event with high prevalence and genetic determinants. PWAS has become a popular strategy to identify therapeutic targets of complex diseases. However, the current PWAS model only considers the linear relationship between protein and disease. Here, we propose a novel non-linear PWAS pipeline and identify 43 proteins exhibiting non-linear associations with venous thromboembolism in the UK Biobank, of which eight proteins cannot be captured by linear PWAS. We further conduct prospective cohort replication in the UK Biobank Pharma Proteomics Project, and replicate eight proteins with similar non-linear trends, including ULBP2, IL18BP, MAN1A2, CCL25, ICAM2, LGALS4, VSIG2 and ABO. Pathway enrichment analysis suggests that the identified non-linear proteins are involved in endothelium development, fluid shear stress and atherosclerosis pathways. In summary, we develop a novel non-linear PWAS analysis pipeline, and identify 43 non-linear proteins with venous thromboembolism, highlighting the importance of incorporating non-linear analysis in PWAS. Venous thromboembolism is a serious condition influenced by genetics, but current protein-based analyses often miss complex patterns. Here, the authors show that a new non-linear analysis method reveals 43 associated proteins, including eight missed by traditional models, offering deeper insight into disease mechanisms.

Background The two-way communications along the gut-lung axis influence the immune function in both gut and lung. However, the shared genetic characteristics of lung function with gastrointestinal tract (GIT) diseases remain to be investigated. Methods We first investigated the genetic correlations between three lung function traits and four GIT diseases. Second, we illustrated the genetic overlap by genome-wide pleiotropic analysis (PLACO) and further pinpointed the relevant tissue and cell types by partitioning heritability. Furthermore, we proposed pleiotropic genes as potential drug targets by drug database mining. Finally, we evaluated the causal relationships by epidemiologic observational study and Mendelian randomization (MR) analysis. Results We found lung function and GIT diseases were genetically correlated. We identified 258 pleiotropic loci, which were enriched in gut- and lung-specific regions marked by H3K4me1. Among these, 16 pleiotropic genes were targets of drugs, such as tofacitinib and baricitinib targeting TYK2 for the treatment of ulcer colitis and COVID-19, respectively. We identified a missense variant in TYK2 , exhibiting a shared causal effect on FEV 1 /FVC and inflammatory bowel disease (rs12720356, P PLACO =1.38 × 10 − 8 ). These findings suggested TYK2 as a promising drug target. Although the epidemiologic observational study suggested the protective role of lung function in the development of GIT diseases, no causalities were found by MR analysis. Conclusions Our study suggested the shared genetic characteristics between lung function and GIT diseases. The pleiotropic variants could exert their effects by modulating gene expression marked by histone modifications. Finally, we highlighted the potential of pleiotropic analyses in drug repurposing.

Background Circulating levels of amino acids were associated with blood pressure (BP) in observational studies. However, the causation of such associations has been hypothesized but is difficult to prove in human studies. Here, we aimed to use two-sample Mendelian randomization analyses to evaluate the potential causal associations of circulating levels of amino acids with BP and risk of hypertension. Methods We generated genetic instruments for circulating levels of nine amino acids by conducting meta-analyses of genome-wide association study (GWAS) in UK Biobank participants with metabolomic data ( n  = 98,317) and another published metabolomics GWAS ( n  = 24,925). Data on the associations of the genetic variants with BP and hypertension were obtained in the UK Biobank participants without metabolomic data ( n  = 286,390). The causal effects were estimated using inverse-variance weighted method. Results Significant evidence consistently supported the causal effects of increased branched-chain amino acids (BCAAs, i.e., leucine, isoleucine, and valine) levels on higher BP and risk of hypertension (all P  < 0.006 after Bonferroni correction except for P leucine-on-diastolicBP  = 0.008). For example, per standard deviation higher of genetically predicted isoleucine levels were associated with 2.71 ± 0.78 mmHg higher systolic BP and 1.24 ± 0.34 mmHg higher diastolic BP, as well as with 7% higher risk of hypertension (odds ratio: 1.07, [95% CI: 1.04–1.10]). In addition, per standard deviation higher of genetically predicted glycine level was associated with lower systolic BP (− 0.70 ± 0.17 mmHg, P  = 4.04 × 10 −5 ) and a lower risk of hypertension (0.99 [0.98–0.99], P  = 6.46 × 10 −5 ). In the reverse direction, genetically predicted higher systolic BP was associated with lower circulating levels of glycine (− 0.025±0.008, P  = 0.001). Conclusions This study provides evidence for causal impacts of genetically predicted circulating BCAAs and glycine levels on BP. Meanwhile, genetically predicted higher BP was associated with lower glycine levels. Further investigations are warranted to clarify the underlying mechanisms.

Multivariate statistical techniques such as principal components analysis (PCA) and multidimensional scaling (MDS) have been widely used to summarize the structure of human genetic variation, often in easily visualized two-dimensional maps. Many recent studies have reported similarity between geographic maps of population locations and MDS or PCA maps of genetic variation inferred from single-nucleotide polymorphisms (SNPs). However, this similarity has been evident primarily in a qualitative sense; and, because different multivariate techniques and marker sets have been used in different studies, it has not been possible to formally compare genetic variation datasets in terms of their levels of similarity with geography. In this study, using genome-wide SNP data from 128 populations worldwide, we perform a systematic analysis to quantitatively evaluate the similarity of genes and geography in different geographic regions. For each of a series of regions, we apply a Procrustes analysis approach to find an optimal transformation that maximizes the similarity between PCA maps of genetic variation and geographic maps of population locations. We consider examples in Europe, Sub-Saharan Africa, Asia, East Asia, and Central/South Asia, as well as in a worldwide sample, finding that significant similarity between genes and geography exists in general at different geographic levels. The similarity is highest in our examples for Asia and, once highly distinctive populations have been removed, Sub-Saharan Africa. Our results provide a quantitative assessment of the geographic structure of human genetic variation worldwide, supporting the view that geography plays a strong role in giving rise to human population structure.