Objective:Neuroblastoma is the most common extracranial solid tumor in children and has complex genetic underpinnings.Previous genome-wide association studies(GWASs)have identified many loci associated with neuroblast...Objective:Neuroblastoma is the most common extracranial solid tumor in children and has complex genetic underpinnings.Previous genome-wide association studies(GWASs)have identified many loci associated with neuroblastoma susceptibility;however,their application in risk prediction for Chinese children has not been systematically explored.This study seeks to enhance neuroblastoma risk prediction by validating these loci and evaluating their performance in polygenic risk models.Methods:We validated 35 GWAS-identified neuroblastoma susceptibility loci in a cohort of Chinese children,consisting of 402 neuroblastoma patients and 473 healthy controls.Genotyping these polymorphisms was conducted via the TaqMan method.Univariable and multivariable logistic regression analyses revealed the genetic loci significantly associated with neuroblastoma risk.We constructed polygenic risk models by combining these loci and assessed their predictive performance via area under the curve(AUC)analysis.We also established a polygenic risk scoring(PRS)model for risk prediction by adopting the PLINK method.Results:Fourteen loci,including ten protective polymorphisms from CASC15,BARD1,LMO1,HSD17B12,and HACE1,and four risk variants from BARD1,RSRC1,CPZ and MMP20 were significantly associated with neuroblastoma risk.Compared with single-gene model,the 8-gene model(AUC=0.72)and 13-gene model(AUC=0.73)demonstrated superior predictive performance.Additionally,a PRS incorporating six significant loci achieved an AUC of 0.66,effectively stratifying individuals into distinct risk categories regarding neuroblastoma susceptibility.A higher PRS was significantly associated with advanced International Neuroblastoma Staging System(INSS)stages,suggesting its potential for clinical risk stratification.Conclusions:Our findings validate multiple loci as neuroblastoma risk factors in Chinese children and demonstrate the utility of polygenic risk models,particularly the PRS,in improving risk prediction.These results suggest that integrating multiple genetic variants into a PRS can enhance neuroblastoma risk stratification and potentially improve early diagnosis by guiding targeted screening programs for high-risk children.展开更多
The quantitative trait loci(QTL)-by-environment(Q × E) interaction effect is hard to detect because there are no effective ways to control the genomic background. In this study, we propose a linear mixed model th...The quantitative trait loci(QTL)-by-environment(Q × E) interaction effect is hard to detect because there are no effective ways to control the genomic background. In this study, we propose a linear mixed model that simultaneously analyzes data from multiple environments to detect Q × E interactions. This model incorporates two different kinship matrices derived from the genome-wide markers to control both main and interaction polygenic background effects. Simulation studies demonstrate that our approach is more powerful than the meta-analysis and inclusive composite interval mapping methods. We further analyze four agronomic traits of rice across four environments. A main effect QTL is identified for 1000-grain weight(KGW), while no QTL are found for tiller number. Additionally, a large QTL with a significant Q × E interaction is detected on chromosome 7 affecting grain number, yield, and KGW. This region harbors two important genes, PROG1 and Ghd7. Furthermore, we apply our mixed model to analyze lodging in barley across six environments. The six regions exhibiting Q × E interaction effects identified by our approach overlap with the SNPs previously identified using EM and MCMC-based Bayesian methods, further validating the robustness of our approach. Both simulation studies and empirical data analyses show that our method outperforms all other methods compared.展开更多
To evaluate whether the polygenic profile modifies the development of sporadic Alzheimer’s disease(sAD)and pathological biomarkers in cerebrospinal fluid(CSF),462 sAD patients and 463 age-matched cognitively normal(C...To evaluate whether the polygenic profile modifies the development of sporadic Alzheimer’s disease(sAD)and pathological biomarkers in cerebrospinal fluid(CSF),462 sAD patients and 463 age-matched cognitively normal(CN)controls were genotyped for 35 singlenucleotide polymorphisms(SNPs)that are significantly associated with sAD.Then,the alleles found to be associated with sAD were used to build polygenic risk score(PRS)models to represent the genetic risk.Receiver operating characteristic(ROC)analyses and the Cox proportional hazards model were used to evaluate the predictive value of PRS for the sAD risk and age at onset.We measured the CSF levels of Aβ42,Aβ42/Aβ40,total tau(T-tau),and phosphorylated tau(P-tau)in a subgroup(60 sAD and 200 CN participants),and analyzed their relationships with the PRSs.We found that 14 SNPs,including SNPs in the APOE,BIN1,CD33,EPHA1,SORL1,and TOMM40 genes,were associated with sAD risk in our cohort.The PRS models built with these SNPs showed potential for discriminating sAD patients from CN controls,and were able to predict the incidence rate of sAD and age at onset.Furthermore,the PRSs were correlated with the CSF levels of Aβ42,Aβ42/Aβ40,T-tau,and P-tau.Our study suggests that PRS models hold promise for assessing the genetic risk and development of AD.As genetic risk profiles vary among populations,large-scale genome-wide sequencing studies are urgently needed to identify the genetic risk loci of sAD in Chinese populations to build accurate PRS models for clinical practice.展开更多
Highly fecund marine species with dispersive life-history stages often display large population sizes and wide geographic distribution ranges. Consequently, they are expected to experience reduced genetic drift, effic...Highly fecund marine species with dispersive life-history stages often display large population sizes and wide geographic distribution ranges. Consequently, they are expected to experience reduced genetic drift, efficient selection fueled by frequent adaptive mutations, and high migration loads. This has important consequences for understanding how local adaptation proceeds in the sea. A key issue in this regard, relates to the genetic architecture underlying fitness traits. Theory predicts that adaptation may involve many genes but with a high variance in effect size. Therefore, the effect of selection on allele frequencies may be substantial for the largest effect size loci, but insignificant for small effect genes. In such a context, the performance of population genomic methods to unravel the genetic basis of adaptation depends on the fraction of adaptive genetic variance explained by the cumulative effect of outlier loci. Here, we address some methodological challenges associated with the detection of local adaptation using molecular approaches. We provide an overview of genome scan methods to detect selection, including those assuming complex demographic models that better describe spatial population structure. We then focus on quantitative genetics approaches that search for genotype-phenotype associations at different genomic scales, including genome-wide methods evaluating the cumulative effect of variants. We argue that the limited power of single locus tests can be alleviated by the use of polygenic scores to estimate the joint contribution of candidate variants to phenotypic variation.展开更多
BACKGROUND Genetic variants of Helicobacter pylori(H. pylori) are involved in gastric cancer occurrence. Single nucleotide polymorphisms(SNPs) of H. pylori that are associated with gastric cancer have been reported. T...BACKGROUND Genetic variants of Helicobacter pylori(H. pylori) are involved in gastric cancer occurrence. Single nucleotide polymorphisms(SNPs) of H. pylori that are associated with gastric cancer have been reported. The combined effect of H. pylori SNPs on the risk of gastric cancer remains unclear.AIM To assess the performance of a polygenic risk score(PRS) based on H. pylori SNPs in predicting the risk of gastric cancer.METHODS A total of 15 gastric cancer-associated H. pylori SNPs were selected. The associations between these SNPs and gastric cancer were further validated in 1022 global strains with publicly available genome sequences. The PRS model was established based on the validated SNPs. The performance of the PRS for predicting the risk of gastric cancer was assessed in global strains using quintiles and random forest(RF) methods. The variation in the performance of the PRS among different populations of H. pylori was further examined.RESULTS Analyses of the association between selected SNPs and gastric cancer in the global dataset revealed that the risk allele frequencies of six SNPs were significantly higher in gastric cancer cases than non-gastric cancer cases. The PRS model constructed subsequently with these validated SNPs produced significantly higher scores in gastric cancer. The odds ratio(OR) value for gastric cancer gradually increased from the first to the fifth quintile of PRS, with the fifth quintile having an OR value as high as 9.76(95% confidence interval: 5.84-16.29). The results of RF analyses indicated that the area under the curve(AUC) value for classifying gastric cancer and non-gastric cancer was 0.75, suggesting that the PRS based on H. pylori SNPs was capable of predicting the risk of gastric cancer. Assessing the performance of the PRS among different H. pylori populations demonstrated that it had good predictive power for cancer risk for hp Europe strains, with an AUC value of 0.78.CONCLUSION The PRS model based on H. pylori SNPs had a good performance for assessment of gastric cancer risk. It would be useful in the prediction of final consequences of the H. pylori infection and beneficial for the management of the infection in clinical settings.展开更多
Genetic variations are associated with individual susceptibility to gastric cancer.Recently,polygenic risk score(PRS)models have been established based on genetic variants to predict the risk of gastric cancer.To asse...Genetic variations are associated with individual susceptibility to gastric cancer.Recently,polygenic risk score(PRS)models have been established based on genetic variants to predict the risk of gastric cancer.To assess the accuracy of current PRS models in the risk prediction,a systematic review was conducted.A total of eight eligible studies consisted of 544842 participants were included for evaluation of the performance of PRS models.The overall accuracy was moderate with Area under the curve values ranging from 0.5600 to 0.7823.Incorporation of epidemiological factors or Helicobacter pylori(H.pylori)status increased the accuracy for risk prediction,while selection of single nucleotide polymorphism(SNP)and number of SNPs appeared to have little impact on the model performance.To further improve the accuracy of PRS models for risk prediction of gastric cancer,we summarized the association between gastric cancer risk and H.pylori genomic variations,cancer associated bacteria members in the gastric microbiome,discussed the potentials for performance improvement of PRS models with these microbial factors.Future studies on comprehensive PRS models established with human SNPs,epidemiological factors and microbial factors are indicated.展开更多
BACKGROUND John Henryism(JH)is a strategy for dealing with chronic psychological stress characterized by high levels of physical effort and work.Cynicism is a belief that people are motivated primarily by self-interes...BACKGROUND John Henryism(JH)is a strategy for dealing with chronic psychological stress characterized by high levels of physical effort and work.Cynicism is a belief that people are motivated primarily by self-interest.High scores on the JH scale and cynicism measures correlate with an increased risk of cardiovascular disease.High cynicism is also a hallmark of burnout syndrome,another known risk factor for heart disease.AIM To evaluate possible interactions between JH and cynicism hoping to clarify risk factors of burnout.METHODS We analyzed genetic and psychological data available from the Database of Genotypes and Phenotypes for genome-wide associations with these traits.We split the total available samples and used plink to perform the association studies on the discovery set(n=1852,80%)and tested for replication using the validation set(n=465).We used scikit-learn to perform supervised machine learning for developing genetic risk algorithms.RESULTS We identified 2,727,and 204 genetic associations for scores on the JH,cynicism and cynical distrust(CD)scales,respectively.We also found 173 associations with high cynicism,109 with high CD,but no associations with high JH.We also produced polygenic classifiers for high cynicism using machine learning with areas under the receiver operator characteristics curve greater than 0.7.CONCLUSION We found significant genetic components to these traits but no evidence of an interaction.Therefore,while there may be a genetic risk,JH is not likely a burnout risk factor.展开更多
Genetic dissection and breeding by design for polygenic traits remain substantial challenges.To ad-dress these challenges,it is important to identify as many genes as possible,including key regulatory genes.Here,we de...Genetic dissection and breeding by design for polygenic traits remain substantial challenges.To ad-dress these challenges,it is important to identify as many genes as possible,including key regulatory genes.Here,we developed a genome-wide scanning plus machine learning framework,integrated with advanced computational techniques,to propose a novel algorithm named Fast3VmrMLM.This algo-rithm aims to enhance the identification of abundant and key genes for polygenic traits in the era of big data and artificial intelligence.The algorithm was extended to identify haplotype(Fast3VmrMLM-Hap)and molecular(Fast3VmrMLM-mQTL)variants.In simulation studies,Fast3VmrMLM outperformed existing methods in detecting dominant,small,and rare variants,requiring only 3.30 and 5.43 h(20 threads)to analyze the 18K rice and UK Biobank-scale datasets,respectively.Fast3VmrMLM identified more known(211)and candidate(384)genes for 14 traits in the 18K rice dataset than FarmCPU(100 known genes).Additionally,it identified 26 known and 24 candidate genes for seven yield-related traits in a maize NC II design;Fast3VmrMLM-mQTL identified two known soybean genes near structural variants.We demonstrated that this novel two-step framework outperformed genome-wide scanning alone.In breeding by design,a genetic network constructed via machine learning using all known and candidate genes identified in this study revealed 21 key genes associated with rice yield-related traits.All associated markers yielded high prediction accuracies in rice(0.7443)and maize(0.8492),en-abling the development of superior hybrid combinations.A new breeding-by-design strategy based on the identified key genes was also proposed.This study provides an effective method for gene mining and breeding by design.展开更多
BACKGROUND Diabetic retinopathy(DR)is the leading cause of blindness among working-age adults,with an increasing prevalence due to the global burden of diabetes.AIM To develop a polygenic risk score(PRS)to identify hi...BACKGROUND Diabetic retinopathy(DR)is the leading cause of blindness among working-age adults,with an increasing prevalence due to the global burden of diabetes.AIM To develop a polygenic risk score(PRS)to identify high-risk groups for DR and evaluate its severity in patients with type 2 diabetes(T2D).METHODS This population-based study included 13335 patients with T2D,comprising 7295 patients with DR and 6040 without DR.Genetic data,duration of DR diagnosis,body mass index,systolic blood pressure,diastolic blood pressure,and glycated hemoglobin A1c levels were obtained from the study population.The PRS was constructed from a genome-wide association study conducted in a Taiwan region of China Han population.Electronic medical records were used to track patients with T2D and analyze the associations between PRS,timing of DR diagnosis,and therapeutic interventions.The hazard ratio(HR)of PRS for DR development and severity was estimated using multivariate Cox proportional hazards regression.RESULTS The results demonstrated that patients with T2D in the top PRS decile had a 1.21-fold greater risk of developing DR[HR=1.21;95%confidence interval(CI):1.01-1.45;P=0.041]over a 20-year follow-up period.Among patients with DR,those in the highest PRS decile exhibited a 4.81-fold increased risk of requiring more than four laser treatments(HR=4.81;95%CI:1.40-16.5;P=0.012)and a 1.38-fold increased risk of undergoing vitreoretinal surgery(HR=1.38;95%CI:1.01-1.90;P=0.044).CONCLUSION Patients with T2D with a higher PRS are at increased risk of developing DR and may experience more severe forms of the disease.展开更多
To investigate whether genetic variants may provide additional prognostic value to improve the existing clinical staging system for gastric cancer(GC),we performed two genome-wide association studies(GWASs)of GC survi...To investigate whether genetic variants may provide additional prognostic value to improve the existing clinical staging system for gastric cancer(GC),we performed two genome-wide association studies(GWASs)of GC survival in the Jiangsu(N=1049)and Shanghai(N=1405)cohorts.By using a TCGA dataset,we validated genetic markers identified from a meta-analysis of these two Chinese cohorts to determine GC survival-associated loci.Then,we constructed a weighted polygenic hazard score(PHS)and developed a nomogram in combination with clinical variables.We also evaluated prognostic accuracy with the time-dependent receiver operating characteristic(ROC)curve,net reclassification improvement(NRI)and integrated discrimination improvement(IDI).We identified a single nucleotide polymorphism(SNP)of rs1618332 at 15q15.1 that was associated with the survival of GC patients with a P value of 4.12×10^(-8),and we also found additional 25 SNPs having consistent associations among these two Chinese cohort and TCGA cohort.The PHS derived from these 26 SNPs(PHS-26)was an independent prognostic factor for GC survival(all P<0.001).The 5-year AUC of PHS-26 was 0.68,0.66 and 0.67 for Jiangsu,Shanghai and their pooled cohorts,respectively,which increased to 0.80,0.82 and 0.81,correspondingly,after being integrated into a nomogram together with variables of the clinical model.The PHS-26 could improve the NRIs by 16.20%,4.90%and 8.70%,respectively,and the IDIs by 11.90%,8.00%and 9.70%,respectively.The 26-SNP based PHS could substantially improve the accuracy of prognostic assessment and might facilitate precision medicine for GC patients.展开更多
Genome-wide association studies(GWASs)have identified 30 independent genetic variants associated with IgA nephropathy(IgAN).A genetic risk score(GRS)represents the number of risk alleles carried and thus captures an i...Genome-wide association studies(GWASs)have identified 30 independent genetic variants associated with IgA nephropathy(IgAN).A genetic risk score(GRS)represents the number of risk alleles carried and thus captures an individual's genetic risk.However,whether and which polygenic risk score crucial for the evaluation of any potential personal or clinical utility on risk and prognosis are still obscure.We constructed different GRS models based on different sets of variants,which were top single nucleotide polymorphisms(SNPs)reported in the previous GWASs.The case–control GRS analysis included 3365 IgAN patients and 8842 healthy individuals.The association between GRS and clinical variability,including age at diagnosis,clinical parameters,Oxford pathology classification,and kidney prognosis was further evaluated in a prospective cohort of 1747 patients.Three GRS models(15 SNPs,21 SNPs,and 55 SNPs)were constructed after quality control.The patients with the top 20%GRS had 2.42—(15 SNPs,p=8.12×10^(-40)),3.89—(21 SNPs,p=3.40×10^(-80))and 3.73—(55 SNPs,p=6.86×10^(-81))fold of risk to develop IgAN compared to the patients with the bottom 20%GRS,with area under the receiver operating characteristic curve(AUC)of 0.59,0.63,and 0.63 in group discriminations,respectively.A positive correlation between GRS and microhematuria,mesangial hypercellularity,segmental glomerulosclerosis and a negative correlation on the age at diagnosis,body mass index(BMI),mean arterial pressure(MAP),serum C3,triglycerides can be observed.Patients with the top 20%GRS also showed a higher risk of worse prognosis for all three models(1.36,1.42,and 1.36 fold of risk)compared to the remaining 80%,whereas 21 SNPs model seemed to show a slightly better fit in prediction.Collectively,a higher burden of risk variants is associated with earlier disease onset and a higher risk of a worse prognosis.This may be informational in translating knowledge on IgAN genetics into disease risk prediction and patient stratification.展开更多
Patients with immunoglobulin A nephropathy(IgAN)can present with diverse clinical manifestations from asympto-matic microscopic hematuria or proteinuria to rapid decline of renal function(Stamellou et al.2023).Many pa...Patients with immunoglobulin A nephropathy(IgAN)can present with diverse clinical manifestations from asympto-matic microscopic hematuria or proteinuria to rapid decline of renal function(Stamellou et al.2023).Many patients with IgAN progress to kidney failure within a span of 10-15 years and nearly all of the patients are at risk of progression to kidney failure over the course of their expected lifetimes(Pitcher et al.2023).However,early identification of IgAN patients at high risk of progression and those who would benefit from early and targeted intervention is a key chal-lenge in the clinical management of IgAN patients.展开更多
Deep phenotyping and genetic characterization of individuals are fundamental to assessing the metabolic status and determining nutrition-specific requirements.This study aimed to ascertain the utmost effectiveness of ...Deep phenotyping and genetic characterization of individuals are fundamental to assessing the metabolic status and determining nutrition-specific requirements.This study aimed to ascertain the utmost effectiveness of personalized interventions by aligning dietary adjustments with both the genotype and metabolotype of individuals.Therefore,we assessed here the usefulness of a polygenic score(PGS)characterizing a potential pro-inflammatory profile(PGSi)as a nutrigenetic tool to discern individuals from the Danish PREVENTOMICS cohort that could better respond to precision nutrition(PN)plans,specifically targeted at counteracting the low-grade inflammatory profile typically found in obesity.The cohort followed a PN plan to counteract the pro-inflammatory profile(PNi group)or generic dietary recommendations(Control)for 10 weeks.PGSi was applied for genetic stratification(Low/High).The effects of the intervention on anthropometrics and biomarkers related to inflammatory profile and carbohydrate metabolism were assessed.Around 30%of subjects had a high genetic predisposition to pro-inflammatory status(high-PGSi).These individuals demonstrated the most effective response to the dietary plan,experiencing improved body composition,with significant decreases in body weight(∆:-4.84%;P=0.039)and body fat(∆:-4.86%;P=0.007),and beneficial changes in pro-and anti-inflammatory biomarkers,with significant increases in IL-10(∆:71.3%;P=0.025)and decreases in TNF-α(∆:-3.0%;P=0.048),CRP(∆:-31.1%),ICAM1(∆:-5.8%),and MCP1(∆:-4.2%)circulating levels,compared to low-PGSi individuals.Both phenotypic and genetic stratification contributed to a better understanding of metabolic heterogeneity in response to diet.This approach allows for refinement of the prediction of individual requirements and potentially for better management of obesity.展开更多
Facial morphology,a complex trait influenced by genetics,holds great significance in evolutionary research.However,due to limited fossil evidence,the facial characteristics of Neanderthals and Denisovans have remained...Facial morphology,a complex trait influenced by genetics,holds great significance in evolutionary research.However,due to limited fossil evidence,the facial characteristics of Neanderthals and Denisovans have remained largely unknown.In this study,we conduct a large-scale multi-ethnic meta-analysis of the genome-wide association study(GWAS),including 9674 East Asians and 10,115 Europeans,quantitatively assessing 78 facial traits using 3D facial images.We identify 71 genomic loci associated with facial features,including 21 novel loci.We develop a facial polygenic score(FPS)that enables the prediction of facial features based on genetic information.Interestingly,the distribution of FPSs among populations from diverse continental groups exhibits relevant correlations with observed facial features.Furthermore,we apply the FPS to predict the facial traits of seven Neanderthals and one Denisovan using ancient DNA and align predictions with the fossil records.Our results suggest that Neanderthals and Denisovans likely share similar facial features,such as a wider but shorter nose and a wider endocanthion distance.The decreased mouth width is characterized specifically in Denisovans.The integration of genomic data and facial trait analysis provides valuable insights into the evolutionary history and adaptive changes in human facial morphology.展开更多
Attention deficit hyperactivity disorder(ADHD),a prevalent neurodevelopmental disorder influenced by both genetic and environmental factors,remains poorly understood regarding how its polygenic risk score(PRS)impacts ...Attention deficit hyperactivity disorder(ADHD),a prevalent neurodevelopmental disorder influenced by both genetic and environmental factors,remains poorly understood regarding how its polygenic risk score(PRS)impacts functional networks and symptomology.This study capitalized on data from 11,430 children in the Adolescent Brain Cognitive Development study to explore the interplay between PRSADHD,brain function,and behavioral problems,along with their interactive effects.The results showed that children with a higher PRSADHD exhibited more severe attention deficits and rule-breaking problems,and experienced sleep disturbances,particularly in initiating and maintaining sleep.We also identified the central executive network,default mode network,and sensory-motor network as the functional networks most associated with PRS and symptoms in ADHD cases,with potential mediating roles.Particularly,the impact of PRSADHD was enhanced in children experiencing heightened sleep disturbances,emphasizing the need for early intervention in sleep issues to potentially mitigate subsequent ADHD symptoms.展开更多
Objective To investigate the relationship between physical activity and genetic risk and their combined effects on the risk of developing chronic obstructive pulmonary disease.Methods This prospective cohort study inc...Objective To investigate the relationship between physical activity and genetic risk and their combined effects on the risk of developing chronic obstructive pulmonary disease.Methods This prospective cohort study included 318,085 biobank participants from the UK.Physical activity was assessed using the short form of the International Physical Activity Questionnaire.The participants were stratified into low-,intermediate-,and high-genetic-risk groups based on their polygenic risk scores.Multivariate Cox regression models and multiplicative interaction analyses were used.Results During a median follow-up period of 13 years,9,209 participants were diagnosed with chronic obstructive pulmonary disease.For low genetic risk,compared to low physical activity,the hazard ratios(HRs)for moderate and high physical activity were 0.853(95%confidence interval[CI]:0.748–0.972)and 0.831(95%CI:0.727–0.950),respectively.For intermediate genetic risk,the HRs were 0.829(95%CI:0.758–0.905)and 0.835(95%CI:0.764–0.914),respectively.For participants with high genetic risk,the HRs were 0.809(95%CI:0.746–0.877)and 0.818(95%CI:0.754–0.888),respectively.A significant interaction was observed between genetic risk and physical activity.Conclusion Moderate or high levels of physical activity were associated with a lower risk of developing chronic obstructive pulmonary disease across all genetic risk groups,highlighting the need to tailor activity interventions for genetically susceptible individuals.展开更多
The utility of the polygenic risk score(PRS)to identify individuals at higher risk of stroke beyond clinical risk remains unclear,and we clarified this using Chinese population-based prospective cohorts.Cox proportion...The utility of the polygenic risk score(PRS)to identify individuals at higher risk of stroke beyond clinical risk remains unclear,and we clarified this using Chinese population-based prospective cohorts.Cox proportional hazards models were used to estimate the 10-year risk,and Fine and Gray’s models were used for hazard ratios(HRs),their 95%confidence intervals(CIs),and the lifetime risk according to PRS and clinical risk categories.A total of 41,006 individuals aged 30–75 years with a mean follow-up of 9.0 years were included.Comparing the top versus bottom 5%of the PRS,the HR was 3.01(95%CI 2.03–4.45)in the total population,and similar findings were observed within clinical risk strata.Marked gradients in the 10-year and lifetime risk across PRS categories were also found within clinical risk categories.Notably,among individuals with intermediate clinical risk,the 10-year risk for those in the top 5%of the PRS(7.3%,95%CI 7.1%–7.5%)reached the threshold of high clinical risk(≥7.0%)for initiating preventive treatment,and this effect of the PRS on refining risk stratification was evident for ischemic stroke.Even among those in the top 10%and 20%of the PRS,the 10-year risk would also exceed this level when aged≥50 and≥60 years,respectively.Overall,the combination of the PRS with the clinical risk score improved the risk stratification within clinical risk strata and distinguished actual high-risk individuals with intermediate clinical risk.展开更多
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-...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.展开更多
Genome-wide association studies(GWASs)have shown that the genetic architecture of cancers are highly polygenic and enabled researchers to identify genetic risk loci for cancers.The genetic variants associated with a c...Genome-wide association studies(GWASs)have shown that the genetic architecture of cancers are highly polygenic and enabled researchers to identify genetic risk loci for cancers.The genetic variants associated with a cancer can be combined into a polygenic risk score(PRS),which captures part of an individual’s genetic susceptibility to cancer.Recently,PRSs have been widely used in cancer risk prediction and are shown to be capable of identifying groups of individuals who could benefit from the knowledge of their probabilistic susceptibility to cancer,which leads to an increased interest in understanding the potential utility of PRSs that might further refine the assessment and management of cancer risk.In this context,we provide an overview of the major discoveries from cancer GWASs.We then review the methodologies used for PRS construction,and describe steps for the development and evaluation of risk prediction models that include PRS and/or conventional risk factors.Potential utility of PRSs in cancer risk prediction,screening,and precision prevention are illustrated.Challenges and practical considerations relevant to the implementation of PRSs in health care settings are discussed.展开更多
Background:A polygenic risk score(PRS)derived from 112 single-nucleotide polymorphisms(SNPs)for gastric cancer has been reported in Chinese populations(PRS-112).However,its performance in other populations is unknown....Background:A polygenic risk score(PRS)derived from 112 single-nucleotide polymorphisms(SNPs)for gastric cancer has been reported in Chinese populations(PRS-112).However,its performance in other populations is unknown.A functional PRS(fPRS)using functional SNPs(fSNPs)may improve the generalizability of the PRS across populations with distinct ethnicities.Methods:We performed functional annotations on SNPs in strong linkage disequilibrium(LD)with the 112 previously reported SNPs to identify fSNPs that affect protein-coding or transcriptional regulation.Subsequently,we constructed an fPRS based on the fSNPs by using the LDpred2-infinitesimal model and then analyzed the performance of the PRS-112 and fPRS in the risk prediction of gastric cancer in 457,521 European participants of the UK Biobank cohort.Finally,the performance of the fPRS in combination with lifestyle factors were evaluated in predicting the risk of gastric cancer.Results:During 4,582,045 person-years of follow-up with a total of 623 incident gastric cancer cases,we found no significant association between the PRS-112 and gastric cancer risk in the European population(hazard ratio[HR]=1.00[95%confidence interval(CI)0.93–1.09],P=0.846).We identified 125 fSNPs,including seven deleterious protein-coding SNPs and 118 regulatory non-coding SNPs,and used them to construct the fPRS-125.Our result showed that the fPRS-125 was significantly associated with gastric cancer risk(HR=1.11[95%CI,1.03–1.20],P=0.009).Compared to participants with a low fPRS-125(bottom quintile),those with a high fPRS-125(top quintile)had a higher risk of incident gastric cancer(HR=1.43[95%CI,1.12–1.84],P=0.005).Moreover,we observed that participants with both an unfavorable lifestyle and a high genetic risk had the highest risk of incident gastric cancer(HR=4.99[95%CI,1.55–16.10],P=0.007)compared to those with both a favorable lifestyle and a low genetic risk.Conclusion:These results indicate that the fPRS-125 derived from fSNPs may act as an indicator to measure the genetic risk of gastric cancer in the European population.展开更多
基金supported by grants from the National Natural Science Foundation of China(No.82173593,32300473)Guangzhou Science and Technology Project(No.2025A04J4537,2025A04J4696)+1 种基金Guangdong Basic and Applied Basic Research Foundation(No.2023A1515220053)Postdoctoral Science Foundation of Jiangsu Province(No.2021K524C).
文摘Objective:Neuroblastoma is the most common extracranial solid tumor in children and has complex genetic underpinnings.Previous genome-wide association studies(GWASs)have identified many loci associated with neuroblastoma susceptibility;however,their application in risk prediction for Chinese children has not been systematically explored.This study seeks to enhance neuroblastoma risk prediction by validating these loci and evaluating their performance in polygenic risk models.Methods:We validated 35 GWAS-identified neuroblastoma susceptibility loci in a cohort of Chinese children,consisting of 402 neuroblastoma patients and 473 healthy controls.Genotyping these polymorphisms was conducted via the TaqMan method.Univariable and multivariable logistic regression analyses revealed the genetic loci significantly associated with neuroblastoma risk.We constructed polygenic risk models by combining these loci and assessed their predictive performance via area under the curve(AUC)analysis.We also established a polygenic risk scoring(PRS)model for risk prediction by adopting the PLINK method.Results:Fourteen loci,including ten protective polymorphisms from CASC15,BARD1,LMO1,HSD17B12,and HACE1,and four risk variants from BARD1,RSRC1,CPZ and MMP20 were significantly associated with neuroblastoma risk.Compared with single-gene model,the 8-gene model(AUC=0.72)and 13-gene model(AUC=0.73)demonstrated superior predictive performance.Additionally,a PRS incorporating six significant loci achieved an AUC of 0.66,effectively stratifying individuals into distinct risk categories regarding neuroblastoma susceptibility.A higher PRS was significantly associated with advanced International Neuroblastoma Staging System(INSS)stages,suggesting its potential for clinical risk stratification.Conclusions:Our findings validate multiple loci as neuroblastoma risk factors in Chinese children and demonstrate the utility of polygenic risk models,particularly the PRS,in improving risk prediction.These results suggest that integrating multiple genetic variants into a PRS can enhance neuroblastoma risk stratification and potentially improve early diagnosis by guiding targeted screening programs for high-risk children.
基金supported by the National Key Research and Development Programs of China(2024YFF1000100 and 2021YFD1301102)the National Natural Science Foundation of China (32172702)+3 种基金the State Key Laboratory of Animal Biotech Breeding (XQSWYZQZ-KFYX-4)Zaozhuang Elite Industrial Innovation ProgramAgricultural Science and Technology Innovation Program (ASTIP-IAS-TS-6)supported by the United States National Science Foundation (NSF) Collaborative Research Grant (DBI-1458515)
文摘The quantitative trait loci(QTL)-by-environment(Q × E) interaction effect is hard to detect because there are no effective ways to control the genomic background. In this study, we propose a linear mixed model that simultaneously analyzes data from multiple environments to detect Q × E interactions. This model incorporates two different kinship matrices derived from the genome-wide markers to control both main and interaction polygenic background effects. Simulation studies demonstrate that our approach is more powerful than the meta-analysis and inclusive composite interval mapping methods. We further analyze four agronomic traits of rice across four environments. A main effect QTL is identified for 1000-grain weight(KGW), while no QTL are found for tiller number. Additionally, a large QTL with a significant Q × E interaction is detected on chromosome 7 affecting grain number, yield, and KGW. This region harbors two important genes, PROG1 and Ghd7. Furthermore, we apply our mixed model to analyze lodging in barley across six environments. The six regions exhibiting Q × E interaction effects identified by our approach overlap with the SNPs previously identified using EM and MCMC-based Bayesian methods, further validating the robustness of our approach. Both simulation studies and empirical data analyses show that our method outperforms all other methods compared.
基金supported by the National Basic Research Development Programof Ministry of Science and Technology of China (2016YFC1306401)the National Natural Science Foundation of China (91749206)。
文摘To evaluate whether the polygenic profile modifies the development of sporadic Alzheimer’s disease(sAD)and pathological biomarkers in cerebrospinal fluid(CSF),462 sAD patients and 463 age-matched cognitively normal(CN)controls were genotyped for 35 singlenucleotide polymorphisms(SNPs)that are significantly associated with sAD.Then,the alleles found to be associated with sAD were used to build polygenic risk score(PRS)models to represent the genetic risk.Receiver operating characteristic(ROC)analyses and the Cox proportional hazards model were used to evaluate the predictive value of PRS for the sAD risk and age at onset.We measured the CSF levels of Aβ42,Aβ42/Aβ40,total tau(T-tau),and phosphorylated tau(P-tau)in a subgroup(60 sAD and 200 CN participants),and analyzed their relationships with the PRSs.We found that 14 SNPs,including SNPs in the APOE,BIN1,CD33,EPHA1,SORL1,and TOMM40 genes,were associated with sAD risk in our cohort.The PRS models built with these SNPs showed potential for discriminating sAD patients from CN controls,and were able to predict the incidence rate of sAD and age at onset.Furthermore,the PRSs were correlated with the CSF levels of Aβ42,Aβ42/Aβ40,T-tau,and P-tau.Our study suggests that PRS models hold promise for assessing the genetic risk and development of AD.As genetic risk profiles vary among populations,large-scale genome-wide sequencing studies are urgently needed to identify the genetic risk loci of sAD in Chinese populations to build accurate PRS models for clinical practice.
文摘Highly fecund marine species with dispersive life-history stages often display large population sizes and wide geographic distribution ranges. Consequently, they are expected to experience reduced genetic drift, efficient selection fueled by frequent adaptive mutations, and high migration loads. This has important consequences for understanding how local adaptation proceeds in the sea. A key issue in this regard, relates to the genetic architecture underlying fitness traits. Theory predicts that adaptation may involve many genes but with a high variance in effect size. Therefore, the effect of selection on allele frequencies may be substantial for the largest effect size loci, but insignificant for small effect genes. In such a context, the performance of population genomic methods to unravel the genetic basis of adaptation depends on the fraction of adaptive genetic variance explained by the cumulative effect of outlier loci. Here, we address some methodological challenges associated with the detection of local adaptation using molecular approaches. We provide an overview of genome scan methods to detect selection, including those assuming complex demographic models that better describe spatial population structure. We then focus on quantitative genetics approaches that search for genotype-phenotype associations at different genomic scales, including genome-wide methods evaluating the cumulative effect of variants. We argue that the limited power of single locus tests can be alleviated by the use of polygenic scores to estimate the joint contribution of candidate variants to phenotypic variation.
基金Supported by the National Natural Science Foundation of China,No. 31870777。
文摘BACKGROUND Genetic variants of Helicobacter pylori(H. pylori) are involved in gastric cancer occurrence. Single nucleotide polymorphisms(SNPs) of H. pylori that are associated with gastric cancer have been reported. The combined effect of H. pylori SNPs on the risk of gastric cancer remains unclear.AIM To assess the performance of a polygenic risk score(PRS) based on H. pylori SNPs in predicting the risk of gastric cancer.METHODS A total of 15 gastric cancer-associated H. pylori SNPs were selected. The associations between these SNPs and gastric cancer were further validated in 1022 global strains with publicly available genome sequences. The PRS model was established based on the validated SNPs. The performance of the PRS for predicting the risk of gastric cancer was assessed in global strains using quintiles and random forest(RF) methods. The variation in the performance of the PRS among different populations of H. pylori was further examined.RESULTS Analyses of the association between selected SNPs and gastric cancer in the global dataset revealed that the risk allele frequencies of six SNPs were significantly higher in gastric cancer cases than non-gastric cancer cases. The PRS model constructed subsequently with these validated SNPs produced significantly higher scores in gastric cancer. The odds ratio(OR) value for gastric cancer gradually increased from the first to the fifth quintile of PRS, with the fifth quintile having an OR value as high as 9.76(95% confidence interval: 5.84-16.29). The results of RF analyses indicated that the area under the curve(AUC) value for classifying gastric cancer and non-gastric cancer was 0.75, suggesting that the PRS based on H. pylori SNPs was capable of predicting the risk of gastric cancer. Assessing the performance of the PRS among different H. pylori populations demonstrated that it had good predictive power for cancer risk for hp Europe strains, with an AUC value of 0.78.CONCLUSION The PRS model based on H. pylori SNPs had a good performance for assessment of gastric cancer risk. It would be useful in the prediction of final consequences of the H. pylori infection and beneficial for the management of the infection in clinical settings.
基金Supported by the National Natural Science Foundation of China,No.31870777.
文摘Genetic variations are associated with individual susceptibility to gastric cancer.Recently,polygenic risk score(PRS)models have been established based on genetic variants to predict the risk of gastric cancer.To assess the accuracy of current PRS models in the risk prediction,a systematic review was conducted.A total of eight eligible studies consisted of 544842 participants were included for evaluation of the performance of PRS models.The overall accuracy was moderate with Area under the curve values ranging from 0.5600 to 0.7823.Incorporation of epidemiological factors or Helicobacter pylori(H.pylori)status increased the accuracy for risk prediction,while selection of single nucleotide polymorphism(SNP)and number of SNPs appeared to have little impact on the model performance.To further improve the accuracy of PRS models for risk prediction of gastric cancer,we summarized the association between gastric cancer risk and H.pylori genomic variations,cancer associated bacteria members in the gastric microbiome,discussed the potentials for performance improvement of PRS models with these microbial factors.Future studies on comprehensive PRS models established with human SNPs,epidemiological factors and microbial factors are indicated.
文摘BACKGROUND John Henryism(JH)is a strategy for dealing with chronic psychological stress characterized by high levels of physical effort and work.Cynicism is a belief that people are motivated primarily by self-interest.High scores on the JH scale and cynicism measures correlate with an increased risk of cardiovascular disease.High cynicism is also a hallmark of burnout syndrome,another known risk factor for heart disease.AIM To evaluate possible interactions between JH and cynicism hoping to clarify risk factors of burnout.METHODS We analyzed genetic and psychological data available from the Database of Genotypes and Phenotypes for genome-wide associations with these traits.We split the total available samples and used plink to perform the association studies on the discovery set(n=1852,80%)and tested for replication using the validation set(n=465).We used scikit-learn to perform supervised machine learning for developing genetic risk algorithms.RESULTS We identified 2,727,and 204 genetic associations for scores on the JH,cynicism and cynical distrust(CD)scales,respectively.We also found 173 associations with high cynicism,109 with high CD,but no associations with high JH.We also produced polygenic classifiers for high cynicism using machine learning with areas under the receiver operator characteristics curve greater than 0.7.CONCLUSION We found significant genetic components to these traits but no evidence of an interaction.Therefore,while there may be a genetic risk,JH is not likely a burnout risk factor.
基金supported by the National Natural Science Foundation of China,China(32470657 and 32270673).
文摘Genetic dissection and breeding by design for polygenic traits remain substantial challenges.To ad-dress these challenges,it is important to identify as many genes as possible,including key regulatory genes.Here,we developed a genome-wide scanning plus machine learning framework,integrated with advanced computational techniques,to propose a novel algorithm named Fast3VmrMLM.This algo-rithm aims to enhance the identification of abundant and key genes for polygenic traits in the era of big data and artificial intelligence.The algorithm was extended to identify haplotype(Fast3VmrMLM-Hap)and molecular(Fast3VmrMLM-mQTL)variants.In simulation studies,Fast3VmrMLM outperformed existing methods in detecting dominant,small,and rare variants,requiring only 3.30 and 5.43 h(20 threads)to analyze the 18K rice and UK Biobank-scale datasets,respectively.Fast3VmrMLM identified more known(211)and candidate(384)genes for 14 traits in the 18K rice dataset than FarmCPU(100 known genes).Additionally,it identified 26 known and 24 candidate genes for seven yield-related traits in a maize NC II design;Fast3VmrMLM-mQTL identified two known soybean genes near structural variants.We demonstrated that this novel two-step framework outperformed genome-wide scanning alone.In breeding by design,a genetic network constructed via machine learning using all known and candidate genes identified in this study revealed 21 key genes associated with rice yield-related traits.All associated markers yielded high prediction accuracies in rice(0.7443)and maize(0.8492),en-abling the development of superior hybrid combinations.A new breeding-by-design strategy based on the identified key genes was also proposed.This study provides an effective method for gene mining and breeding by design.
基金Supported by China Medical University Hospital,No.DMR-113-105.
文摘BACKGROUND Diabetic retinopathy(DR)is the leading cause of blindness among working-age adults,with an increasing prevalence due to the global burden of diabetes.AIM To develop a polygenic risk score(PRS)to identify high-risk groups for DR and evaluate its severity in patients with type 2 diabetes(T2D).METHODS This population-based study included 13335 patients with T2D,comprising 7295 patients with DR and 6040 without DR.Genetic data,duration of DR diagnosis,body mass index,systolic blood pressure,diastolic blood pressure,and glycated hemoglobin A1c levels were obtained from the study population.The PRS was constructed from a genome-wide association study conducted in a Taiwan region of China Han population.Electronic medical records were used to track patients with T2D and analyze the associations between PRS,timing of DR diagnosis,and therapeutic interventions.The hazard ratio(HR)of PRS for DR development and severity was estimated using multivariate Cox proportional hazards regression.RESULTS The results demonstrated that patients with T2D in the top PRS decile had a 1.21-fold greater risk of developing DR[HR=1.21;95%confidence interval(CI):1.01-1.45;P=0.041]over a 20-year follow-up period.Among patients with DR,those in the highest PRS decile exhibited a 4.81-fold increased risk of requiring more than four laser treatments(HR=4.81;95%CI:1.40-16.5;P=0.012)and a 1.38-fold increased risk of undergoing vitreoretinal surgery(HR=1.38;95%CI:1.01-1.90;P=0.044).CONCLUSION Patients with T2D with a higher PRS are at increased risk of developing DR and may experience more severe forms of the disease.
基金supported by National Natural Science Foundation of China(82125033,81872702,82103932,82003534)Natural Science Foundation of Jiangsu Province(BK20200674).
文摘To investigate whether genetic variants may provide additional prognostic value to improve the existing clinical staging system for gastric cancer(GC),we performed two genome-wide association studies(GWASs)of GC survival in the Jiangsu(N=1049)and Shanghai(N=1405)cohorts.By using a TCGA dataset,we validated genetic markers identified from a meta-analysis of these two Chinese cohorts to determine GC survival-associated loci.Then,we constructed a weighted polygenic hazard score(PHS)and developed a nomogram in combination with clinical variables.We also evaluated prognostic accuracy with the time-dependent receiver operating characteristic(ROC)curve,net reclassification improvement(NRI)and integrated discrimination improvement(IDI).We identified a single nucleotide polymorphism(SNP)of rs1618332 at 15q15.1 that was associated with the survival of GC patients with a P value of 4.12×10^(-8),and we also found additional 25 SNPs having consistent associations among these two Chinese cohort and TCGA cohort.The PHS derived from these 26 SNPs(PHS-26)was an independent prognostic factor for GC survival(all P<0.001).The 5-year AUC of PHS-26 was 0.68,0.66 and 0.67 for Jiangsu,Shanghai and their pooled cohorts,respectively,which increased to 0.80,0.82 and 0.81,correspondingly,after being integrated into a nomogram together with variables of the clinical model.The PHS-26 could improve the NRIs by 16.20%,4.90%and 8.70%,respectively,and the IDIs by 11.90%,8.00%and 9.70%,respectively.The 26-SNP based PHS could substantially improve the accuracy of prognostic assessment and might facilitate precision medicine for GC patients.
基金supported by National Science Foundation of China(82022010,82370709,81970613,82070733,82000680)Beijing Natural Science Foundation(Z190023)+3 种基金Academy of Medical Sciences–Newton Advanced Fellowship(NAFR13\1033)Fok Ying Tung Education Foundation(171030)Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2019-I2M-5–046,2020-JKCS-009)National High Level Hospital Clinical Research Funding(Interdisciplinary Clinical Research Project of Peking University First Hospital,2022CR41)。
文摘Genome-wide association studies(GWASs)have identified 30 independent genetic variants associated with IgA nephropathy(IgAN).A genetic risk score(GRS)represents the number of risk alleles carried and thus captures an individual's genetic risk.However,whether and which polygenic risk score crucial for the evaluation of any potential personal or clinical utility on risk and prognosis are still obscure.We constructed different GRS models based on different sets of variants,which were top single nucleotide polymorphisms(SNPs)reported in the previous GWASs.The case–control GRS analysis included 3365 IgAN patients and 8842 healthy individuals.The association between GRS and clinical variability,including age at diagnosis,clinical parameters,Oxford pathology classification,and kidney prognosis was further evaluated in a prospective cohort of 1747 patients.Three GRS models(15 SNPs,21 SNPs,and 55 SNPs)were constructed after quality control.The patients with the top 20%GRS had 2.42—(15 SNPs,p=8.12×10^(-40)),3.89—(21 SNPs,p=3.40×10^(-80))and 3.73—(55 SNPs,p=6.86×10^(-81))fold of risk to develop IgAN compared to the patients with the bottom 20%GRS,with area under the receiver operating characteristic curve(AUC)of 0.59,0.63,and 0.63 in group discriminations,respectively.A positive correlation between GRS and microhematuria,mesangial hypercellularity,segmental glomerulosclerosis and a negative correlation on the age at diagnosis,body mass index(BMI),mean arterial pressure(MAP),serum C3,triglycerides can be observed.Patients with the top 20%GRS also showed a higher risk of worse prognosis for all three models(1.36,1.42,and 1.36 fold of risk)compared to the remaining 80%,whereas 21 SNPs model seemed to show a slightly better fit in prediction.Collectively,a higher burden of risk variants is associated with earlier disease onset and a higher risk of a worse prognosis.This may be informational in translating knowledge on IgAN genetics into disease risk prediction and patient stratification.
基金supported,in part,by funding from NIH/NIDDK through the George M.O’Brien Michigan Kidney Translational Core Center,grant:U54 DK137314supported by a grant from the University of Michigan Health System and Peking University Health Sciences Center Joint Institute for Translational and Clinical Research.
文摘Patients with immunoglobulin A nephropathy(IgAN)can present with diverse clinical manifestations from asympto-matic microscopic hematuria or proteinuria to rapid decline of renal function(Stamellou et al.2023).Many patients with IgAN progress to kidney failure within a span of 10-15 years and nearly all of the patients are at risk of progression to kidney failure over the course of their expected lifetimes(Pitcher et al.2023).However,early identification of IgAN patients at high risk of progression and those who would benefit from early and targeted intervention is a key chal-lenge in the clinical management of IgAN patients.
基金supported through the European Union’s Horizon 2020 Research and Innovation Program(818318)。
文摘Deep phenotyping and genetic characterization of individuals are fundamental to assessing the metabolic status and determining nutrition-specific requirements.This study aimed to ascertain the utmost effectiveness of personalized interventions by aligning dietary adjustments with both the genotype and metabolotype of individuals.Therefore,we assessed here the usefulness of a polygenic score(PGS)characterizing a potential pro-inflammatory profile(PGSi)as a nutrigenetic tool to discern individuals from the Danish PREVENTOMICS cohort that could better respond to precision nutrition(PN)plans,specifically targeted at counteracting the low-grade inflammatory profile typically found in obesity.The cohort followed a PN plan to counteract the pro-inflammatory profile(PNi group)or generic dietary recommendations(Control)for 10 weeks.PGSi was applied for genetic stratification(Low/High).The effects of the intervention on anthropometrics and biomarkers related to inflammatory profile and carbohydrate metabolism were assessed.Around 30%of subjects had a high genetic predisposition to pro-inflammatory status(high-PGSi).These individuals demonstrated the most effective response to the dietary plan,experiencing improved body composition,with significant decreases in body weight(∆:-4.84%;P=0.039)and body fat(∆:-4.86%;P=0.007),and beneficial changes in pro-and anti-inflammatory biomarkers,with significant increases in IL-10(∆:71.3%;P=0.025)and decreases in TNF-α(∆:-3.0%;P=0.048),CRP(∆:-31.1%),ICAM1(∆:-5.8%),and MCP1(∆:-4.2%)circulating levels,compared to low-PGSi individuals.Both phenotypic and genetic stratification contributed to a better understanding of metabolic heterogeneity in response to diet.This approach allows for refinement of the prediction of individual requirements and potentially for better management of obesity.
基金funded by the following grants and contracts:Strategic Priority Research Program of the Chinese Academy of Sciences(XDB38020400 to S.W.)the National Natural Science Foundation of China(32325013 to S.W.,32271186 to J.T.,31900408 to M.Z.)+5 种基金the CAS Project for Young Scientists in Basic Research(YSBR-077 to S.W.)Shanghai Science and Technology Commission Excellent Academic Leaders Program(22XD1424700 to S.W.)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-066 to L.J.and J.W.)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01 to L.J.and S.W.)the National Science and Technology Basic Research Project(2015FY111700 to L.J.)the 111 Project(B13016 to L.J.).
文摘Facial morphology,a complex trait influenced by genetics,holds great significance in evolutionary research.However,due to limited fossil evidence,the facial characteristics of Neanderthals and Denisovans have remained largely unknown.In this study,we conduct a large-scale multi-ethnic meta-analysis of the genome-wide association study(GWAS),including 9674 East Asians and 10,115 Europeans,quantitatively assessing 78 facial traits using 3D facial images.We identify 71 genomic loci associated with facial features,including 21 novel loci.We develop a facial polygenic score(FPS)that enables the prediction of facial features based on genetic information.Interestingly,the distribution of FPSs among populations from diverse continental groups exhibits relevant correlations with observed facial features.Furthermore,we apply the FPS to predict the facial traits of seven Neanderthals and one Denisovan using ancient DNA and align predictions with the fossil records.Our results suggest that Neanderthals and Denisovans likely share similar facial features,such as a wider but shorter nose and a wider endocanthion distance.The decreased mouth width is characterized specifically in Denisovans.The integration of genomic data and facial trait analysis provides valuable insights into the evolutionary history and adaptive changes in human facial morphology.
基金supported by the National Natural Science Foundation of China(62373062,82022035,and 82001450)the Scientific and Technological Innovation 2030-The Major Project of the Brain Science and Brain-Inspired Intelligence Technology(2021ZD0200500)the Startup Funds for Talents at Beijing Normal University,and the China Postdoctoral Science Foundation(2022M710434).
文摘Attention deficit hyperactivity disorder(ADHD),a prevalent neurodevelopmental disorder influenced by both genetic and environmental factors,remains poorly understood regarding how its polygenic risk score(PRS)impacts functional networks and symptomology.This study capitalized on data from 11,430 children in the Adolescent Brain Cognitive Development study to explore the interplay between PRSADHD,brain function,and behavioral problems,along with their interactive effects.The results showed that children with a higher PRSADHD exhibited more severe attention deficits and rule-breaking problems,and experienced sleep disturbances,particularly in initiating and maintaining sleep.We also identified the central executive network,default mode network,and sensory-motor network as the functional networks most associated with PRS and symptoms in ADHD cases,with potential mediating roles.Particularly,the impact of PRSADHD was enhanced in children experiencing heightened sleep disturbances,emphasizing the need for early intervention in sleep issues to potentially mitigate subsequent ADHD symptoms.
基金supported by the Construction of High-level University of Guangdong(G624330242)the National Natural Science Foundation of China (82425052) to Dr. Chen Maothe Postdoctoral Fellowship Program of CPSF(GZC20231052) to Dr. Jin Yang
文摘Objective To investigate the relationship between physical activity and genetic risk and their combined effects on the risk of developing chronic obstructive pulmonary disease.Methods This prospective cohort study included 318,085 biobank participants from the UK.Physical activity was assessed using the short form of the International Physical Activity Questionnaire.The participants were stratified into low-,intermediate-,and high-genetic-risk groups based on their polygenic risk scores.Multivariate Cox regression models and multiplicative interaction analyses were used.Results During a median follow-up period of 13 years,9,209 participants were diagnosed with chronic obstructive pulmonary disease.For low genetic risk,compared to low physical activity,the hazard ratios(HRs)for moderate and high physical activity were 0.853(95%confidence interval[CI]:0.748–0.972)and 0.831(95%CI:0.727–0.950),respectively.For intermediate genetic risk,the HRs were 0.829(95%CI:0.758–0.905)and 0.835(95%CI:0.764–0.914),respectively.For participants with high genetic risk,the HRs were 0.809(95%CI:0.746–0.877)and 0.818(95%CI:0.754–0.888),respectively.A significant interaction was observed between genetic risk and physical activity.Conclusion Moderate or high levels of physical activity were associated with a lower risk of developing chronic obstructive pulmonary disease across all genetic risk groups,highlighting the need to tailor activity interventions for genetically susceptible individuals.
基金supported by the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2021-I2M-1-010,2019-I2M-2-003,and 2017-I2M-1-004)the National High Level Hospital Clinical Research Funding(2022-GSP-GG-1,2022-GSPGG-2)+5 种基金Research Unit of Prospective Cohort of Cardiovascular Diseases and Cancers,CAMS(2019RU038)the National Key Research and Development Program of China(2018YFE0115300 and 2017YFC0211700)the National Natural Science Foundation of China(82030102,1212660291857118)Taikang Yicai Public Health and Epidemic Control Fund(TKYC-GW-2020)the National Clinical Research Center for Cardiovascular Diseases,Fuwai Hospital,Chinese Academy of Medical Sciences(NCRC2020006)。
文摘The utility of the polygenic risk score(PRS)to identify individuals at higher risk of stroke beyond clinical risk remains unclear,and we clarified this using Chinese population-based prospective cohorts.Cox proportional hazards models were used to estimate the 10-year risk,and Fine and Gray’s models were used for hazard ratios(HRs),their 95%confidence intervals(CIs),and the lifetime risk according to PRS and clinical risk categories.A total of 41,006 individuals aged 30–75 years with a mean follow-up of 9.0 years were included.Comparing the top versus bottom 5%of the PRS,the HR was 3.01(95%CI 2.03–4.45)in the total population,and similar findings were observed within clinical risk strata.Marked gradients in the 10-year and lifetime risk across PRS categories were also found within clinical risk categories.Notably,among individuals with intermediate clinical risk,the 10-year risk for those in the top 5%of the PRS(7.3%,95%CI 7.1%–7.5%)reached the threshold of high clinical risk(≥7.0%)for initiating preventive treatment,and this effect of the PRS on refining risk stratification was evident for ischemic stroke.Even among those in the top 10%and 20%of the PRS,the 10-year risk would also exceed this level when aged≥50 and≥60 years,respectively.Overall,the combination of the PRS with the clinical risk score improved the risk stratification within clinical risk strata and distinguished actual high-risk individuals with intermediate clinical risk.
基金supported by grants from the National Natural Science Foundation of China(Nos.82192904,82192901,82192900,and 91846303)The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong.The long-term follow-up is supported by grants from the UK Wellcome Trust(Nos.212946/Z/18/Z,202922/Z/16/Z,104085/Z/14/Z,and 088158/Z/09/Z)+2 种基金the National Key Research and Development Program of China(No.2016 YFC0900500)National Natural Science Foundation of China(No.81390540)Chinese Ministry of Science and Technology(No.2011BAI09B01).
文摘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.
基金the National Natural Science Foundation of China(81820108028,81922061,82003530).
文摘Genome-wide association studies(GWASs)have shown that the genetic architecture of cancers are highly polygenic and enabled researchers to identify genetic risk loci for cancers.The genetic variants associated with a cancer can be combined into a polygenic risk score(PRS),which captures part of an individual’s genetic susceptibility to cancer.Recently,PRSs have been widely used in cancer risk prediction and are shown to be capable of identifying groups of individuals who could benefit from the knowledge of their probabilistic susceptibility to cancer,which leads to an increased interest in understanding the potential utility of PRSs that might further refine the assessment and management of cancer risk.In this context,we provide an overview of the major discoveries from cancer GWASs.We then review the methodologies used for PRS construction,and describe steps for the development and evaluation of risk prediction models that include PRS and/or conventional risk factors.Potential utility of PRSs in cancer risk prediction,screening,and precision prevention are illustrated.Challenges and practical considerations relevant to the implementation of PRSs in health care settings are discussed.
基金supported by grants from the National Natural Science Foundation of China(Nos.82125033,82230110,81872702,82003534,and 82273714)the Natural Science Foundation of Jiangsu Province(No.BK20200674)CAMS Innovation Fund for Medical Sciences(No.2019RU038).
文摘Background:A polygenic risk score(PRS)derived from 112 single-nucleotide polymorphisms(SNPs)for gastric cancer has been reported in Chinese populations(PRS-112).However,its performance in other populations is unknown.A functional PRS(fPRS)using functional SNPs(fSNPs)may improve the generalizability of the PRS across populations with distinct ethnicities.Methods:We performed functional annotations on SNPs in strong linkage disequilibrium(LD)with the 112 previously reported SNPs to identify fSNPs that affect protein-coding or transcriptional regulation.Subsequently,we constructed an fPRS based on the fSNPs by using the LDpred2-infinitesimal model and then analyzed the performance of the PRS-112 and fPRS in the risk prediction of gastric cancer in 457,521 European participants of the UK Biobank cohort.Finally,the performance of the fPRS in combination with lifestyle factors were evaluated in predicting the risk of gastric cancer.Results:During 4,582,045 person-years of follow-up with a total of 623 incident gastric cancer cases,we found no significant association between the PRS-112 and gastric cancer risk in the European population(hazard ratio[HR]=1.00[95%confidence interval(CI)0.93–1.09],P=0.846).We identified 125 fSNPs,including seven deleterious protein-coding SNPs and 118 regulatory non-coding SNPs,and used them to construct the fPRS-125.Our result showed that the fPRS-125 was significantly associated with gastric cancer risk(HR=1.11[95%CI,1.03–1.20],P=0.009).Compared to participants with a low fPRS-125(bottom quintile),those with a high fPRS-125(top quintile)had a higher risk of incident gastric cancer(HR=1.43[95%CI,1.12–1.84],P=0.005).Moreover,we observed that participants with both an unfavorable lifestyle and a high genetic risk had the highest risk of incident gastric cancer(HR=4.99[95%CI,1.55–16.10],P=0.007)compared to those with both a favorable lifestyle and a low genetic risk.Conclusion:These results indicate that the fPRS-125 derived from fSNPs may act as an indicator to measure the genetic risk of gastric cancer in the European population.
