Pelvic organ prolapse (POP), whose etiology is influenced by genetic and clinical risk factors, considerably impacts women's quality of life. However, the genetic underpinnings in non-European populations and comprehensive risk models integrating genetic and clinical factors remain underexplored. This study constructed the first polygenic risk score (PRS) for POP in the Chinese population by utilizing 20 disease-associated variants from the largest existing genome-wide association study. We analyzed a discovery cohort of 576 cases and 623 controls and a validation cohort of 264 cases and 200 controls. Results showed that the case group exhibited a significantly higher PRS than the control group. Moreover, the odds ratio of the top 10% risk group was 2.6 times higher than that of the bottom 10%. A high PRS was significantly correlated with POP occurrence in women older than 50 years old and in those with one or no childbirths. As far as we know, the integrated prediction model, which combined PRS and clinical risk factors, demonstrated better predictive accuracy than other existing PRS models. This combined risk assessment model serves as a robust tool for POP risk prediction and stratification, thereby offering insights into individualized preventive measures and treatment strategies in future clinical practice.
Humans ; Female ; Pelvic Organ Prolapse/epidemiology* ; Middle Aged ; Risk Assessment/methods* ; China/epidemiology* ; Multifactorial Inheritance ; Aged ; Risk Factors ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Case-Control Studies ; Adult ; Polymorphism, Single Nucleotide ; Genetic Risk Score ; East Asian People

BACKGROUND: Several studies have reported that polygenic risk scores (PRSs) can enhance risk prediction of coronary artery disease (CAD) in European populations. However, research on this topic is far from sufficient in non-European countries, including China. We aimed to evaluate the potential of PRS for predicting CAD for primary prevention in the Chinese population. METHODS: Participants with genome-wide genotypic data from the China Kadoorie Biobank were divided into training ( n = 28,490) and testing sets ( n = 72,150). Ten previously developed PRSs were evaluated, and new ones were developed using clumping and thresholding or LDpred method. The PRS showing the strongest association with CAD in the training set was selected to further evaluate its effects on improving the traditional CAD risk-prediction model in the testing set. Genetic risk was computed by summing the product of the weights and allele dosages across genome-wide single-nucleotide polymorphisms. Prediction of the 10-year first CAD events was assessed using hazard ratios (HRs) and measures of model discrimination, calibration, and net reclassification improvement (NRI). Hard CAD (nonfatal I21-I23 and fatal I20-I25) and soft CAD (all fatal or nonfatal I20-I25) were analyzed separately. RESULTS: In the testing set, 1214 hard and 7201 soft CAD cases were documented during a mean follow-up of 11.2 years. The HR per standard deviation of the optimal PRS was 1.26 (95% CI:1.19-1.33) for hard CAD. Based on a traditional CAD risk prediction model containing only non-laboratory-based information, the addition of PRS for hard CAD increased Harrell's C index by 0.001 (-0.001 to 0.003) in women and 0.003 (0.001 to 0.005) in men. Among the different high-risk thresholds ranging from 1% to 10%, the highest categorical NRI was 3.2% (95% CI: 0.4-6.0%) at a high-risk threshold of 10.0% in women. The association of the PRS with soft CAD was much weaker than with hard CAD, leading to minimal or no improvement in the soft CAD model. CONCLUSIONS In this Chinese population sample, the current PRSs minimally changed risk discrimination and offered little improvement in risk stratification for soft CAD. Therefore, this may not be suitable for promoting genetic screening in the general Chinese population to improve CAD risk prediction.
Male ; Humans ; Female ; Coronary Artery Disease/genetics* ; Biological Specimen Banks ; East Asian People ; Risk Assessment/methods* ; Genetic Predisposition to Disease/genetics* ; Risk Factors ; Genome-Wide Association Study

Objective: To explore the causal effects of the serum Vitamin D levels on the risk of systemic lupus erythematosus (SLE). Methods: A two-sample Mendelian randomization (MR) study was performed to infer the causality. Three Genome-wide association studies (GWAS) for circulating Vitamin D levels, including 25-hydroxyvitamin D [25(OH)D], 25-hydroxyvitamin D₃ [25(OH)D₃] and C3-epimer of 25-hydroxyvitamin D₃ [C3-epi-25(OH)D₃] published in 2020, and one GWAS for SLE published in 2015 were utilized to analyze the causal effects of the serum Vitamin D levels on the risk of SLE. MR analyses were conducted using the inverse-variance weighted method (IVW), weighted median, MR-Egger methods, MR-pleiotropy residual sum and outlier (MR-PRESSO) method. Results: 34, 29 and 6 SNPs were respectively selected as instrumental variables to analyze the causal association of total 25 (OH) D level, 25 (OH) D₃ level and C3-epi-25 (OH) D₃ level with the risk of SLE. The MR results showed that each standard deviation decrease in the level of 25(OH)D₃ would result in 14.2% higher risk of SLE (OR, 0.858; 95%CI, 0.753-0.978; P=0.022). The levels of 25(OH)D and C3-epi-25(OH)D₃ had null associations with risk of SLE (OR, 0.849; 95%CI, 0.653-1.104; P=0.222; OR, 0.904; 95%CI, 0.695-1.176; P=0.452). Conclusion: This study have identified a causal effect of 25(OH)D₃ on increased risk of SLE. These findings highlighted the significance of active monitoring and prevention of SLE in population of low Vitamin D levels.
Humans ; Genome-Wide Association Study ; Vitamin D ; Lupus Erythematosus, Systemic/complications* ; Vitamins ; Causality ; Mendelian Randomization Analysis/methods* ; Polymorphism, Single Nucleotide

Objective: A Mendelian randomization (MR) analysis was performed to assess the relationship between tea consumption and cancer. Methods: There were 100 639 participants with the information of gene sequencing of whole genome in the China Kadoorie Biobank. After excluding those with cancer at baseline survey, a total of 100 218 participants were included in this study. The baseline information about tea consumption were analyzed, including daily tea consumption or not, cups of daily tea consumption, and grams of daily tea consumption. We used the two-stage least square method to evaluate the associations between three tea consumption variables and incidence of cancer and some subtypes, including stomach cancer, liver and intrahepatic bile ducts cancer, colorectal cancer, tracheobronchial and lung cancer, and female breast cancer. Multivariable MR and analysis only among nondrinkers were used to control the impact of alcohol consumption. Sensitivity analyses were also performed, including inverse variance weighting, weighted median, and MR-Egger. Results: We used 54, 42, and 28 SNPs to construct non-weighted genetic risk scores as instrumental variables for daily tea consumption or not, cups of daily tea consumption, and grams of daily tea consumption, respectively. During an average of (11.4±3.0) years of follow-up, 6 886 cases of cancer were recorded. After adjusting for age, age², sex, region, array type, and the first 12 genetic principal components, there were no significant associations of three tea consumption variables with the incidence of cancer and cancer subtypes. Compared with non-daily tea drinkers, the HR (95%CI) of daily tea drinkers for cancer and some subtypes, including stomach cancer, liver and intrahepatic bile ducts cancer, colorectal cancer, tracheobronchial and lung cancer, and female breast cancer, are respectively 0.99 (0.78-1.26), 1.17 (0.58-2.36), 0.86 (0.40-1.84), 0.85 (0.42-1.73), 1.39 (0.85-2.26) and 0.63 (0.28-1.38). After controlling the impact of alcohol consumption and performing multiple sensitivity analyses, the results were similar. Conclusion: There is no causal relationship between tea consumption and risk of cancer in population in China.
Humans ; Female ; Stomach Neoplasms/epidemiology* ; Mendelian Randomization Analysis/methods* ; Tea ; Breast Neoplasms ; Lung Neoplasms ; Colorectal Neoplasms ; Polymorphism, Single Nucleotide ; Genome-Wide Association Study

Mosaic chromosomal alteration (mCA) is referred to as large-scale somatic mutations on chromosomes, which results in diverse karyotypes in body. The mCA is regarded as one of the phenotypes of aging. Studies have revealed its associations with many chronic diseases such as hematopoietic cancers and cardiovascular diseases, but its genetic basis (e.g. genetic susceptibility variants) is still under-investigated. This paper reviews GWAS studies for mCA on autosomal chromosomes and sex chromosomes [mosaic loss of the Y chromosome (mLOY) and mosaic loss of the X chromosome (mLOX)] based on large population, respectively. Most of the genetic susceptibility loci found in studies for autosomal mCA were associated with copy-neutral loss of heterozygosity. The study of sex chromosome mCA focused on mosaic loss mutations. The number of genetic susceptibility loci for mLOY was high (up to 156), but it was relatively less for mLOX.
Humans ; Male ; Genome-Wide Association Study/methods* ; Mosaicism ; Genetic Predisposition to Disease ; Chromosomes, Human, Y ; Mutation

Chronic obstructive pulmonary disease (COPD) is a common and frequently-occurring disease in the department of respiratory medicine,the pathogenesis of which involves both environmental factors and genetic factors.In recent years,with the application of new methods such as genome-wide association study,researchers have discovered a large number of gene mutations associated with lung function and COPD,providing a new perspective on the pathogenesis of COPD and potential therapeutic targets.This article reviews the research achievements and application progress of genomics in COPD.
Genome-Wide Association Study/methods* ; Genomics ; Humans ; Pulmonary Disease, Chronic Obstructive/genetics*

Objective: Based on the Mendelian randomization analysis, to assess the causal relationship between DNA methylation levels of Janus kinase 2 (JAK2) and obesity. Methods: A case-control study was carried out, including 1 021 individuals [obesity (visceral fat index ≥10) vs. no obesity (visceral fat index <10) was 440 vs. 581] from the Henan Rural Cohort Study. MethylTarget^TM target region methylation sequencing technology was used for testing the DNA methylation level of JAK2. logistic regression models were used to assess the association between the DNA methylation level of JAK2 and obesity. With SNP as the instrumental variable, the association between the DNA methylation level of JAK2 and obesity was explored by using the Mendelian randomization analysis method. Results: There was a positive association between Chr9:4984943 (one DNA methylation site in the promoter of JAK2) and obesity, and the OR (95%CI) was 1.22(1.04-1.42). Methylation level of five sites in the exon of JAK2 (Chr9:4985378, Chr9:4985404, Chr9:4985407, Chr9:4985409 and Chr9:4985435) were negatively associated with obesity, the corresponding OR (95%CI) were 0.53 (0.29-0.95), 0.58(0.36-0.93), 0.69 (0.49-0.97), 0.72 (0.53-0.99) and 0.58 (0.35-0.98) , respectively. Mendelian randomization analysis showed that there was a causal relationship between the DNA methylation levels of JAK2 and obesity, and the corresponding β (95%CI) were -1.985 (-3.520 - -0.450),-3.547 (-6.301 - -0.792) and -3.900 (-6.328 - -1.472) for Mendelian randomization method of inverse variance weighted, Mendelian randomization method of median based and Maximum-likelihood method, respectively. Conclusion: This study supported there was a causal relationship between the DNA methylation level of JAK2 and obesity.
Case-Control Studies ; Cohort Studies ; DNA Methylation ; Genome-Wide Association Study ; Humans ; Janus Kinase 2/genetics* ; Mendelian Randomization Analysis/methods* ; Obesity/genetics* ; Polymorphism, Single Nucleotide

"Active health" has been emphasized in "Healthy China 2030" in dealing with the challenges of population aging, so the anti-aging strategies are requires to be more precise and effective at both individual and population levels. Aging is influenced by both genetic and environmental factors. In the recent 20 years, the research of genetics of human ageing has been greatly facilitated owning to the development of high-throughput sequencing techniques, statistical methodology for multi-omics data, as well as the growing qualified evidence of large-scale population-based genomic research. This paper provides a review of genome-wide association research of aging.
Aging/genetics* ; Genome-Wide Association Study/methods* ; Genomics/methods* ; High-Throughput Nucleotide Sequencing ; Humans ; Phenotype

Next-generation sequencing has revolutionized family-based association tests for rare variants. As the lower power of genome wide association study for detecting casual rare variants, methods aggregating effects of multiple variants have been proposed, such as burden tests and variance component tests. This paper summarizes the methods of rare variants association test that can be applied for family data, introduces their principles, characteristics and applicable conditions and discusses the shortcomings and the improvement of the present methods.
Computer Simulation ; Family Relations ; Genetic Association Studies ; Genetic Variation ; Genome-Wide Association Study/methods* ; Humans

Adult ; Female ; Genome-Wide Association Study ; Humans ; Leukocytes, Mononuclear ; metabolism ; Lupus Erythematosus, Systemic ; genetics ; Male ; Principal Component Analysis ; Sequence Analysis, RNA ; methods