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Association of polygenic risk score with Age at Onset and Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease in a Chinese Cohort

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Neuroscience Bulletin 2020年第7期36卷 696-704页

作者： Wei-Wei Li Zhen Wang Dong-Yu Fan Ying-Ying Shen Dong-Wan Chen Hui-Yun Li Ling Li Heng Yang Yu-Hui Liu Xian-Le Bu Wang-Sheng Jin Fan Zeng Zhi-Qiang Xu Jin-Tai Yu Li-Yong Chen Yan-Jiang Wang Department of Neurology and Centre for Clinical Neuroscience Duping HospitalThird Military Medical UniversityChongqing 400042China Department of Anaesthesiology Daping HospitalThird Military Medical UniversityChongqing 400042China Chongqing Key Laboratory of Aging and Diseases Chongqing 400042China Centre for Excellence in Brain Science and Intelligence Technology Chinese Academy of SciencesShanghai 200031China Department of Neurology Huashan HospitalFudan UniversityShanghai 200040China

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 ***,the alleles found to be associated with sAD were used to build polygenic risk score(PRS)models to represent the genetic *** 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 *** 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 *** found that 14 SNPs,including SNPs in the APOE,BIN1,CD33,EPHA1,SORL1,and TOMM40 genes,were associated with sAD risk in our *** 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 ***,the PRSs were correlated with the CSF levels of Aβ42,Aβ42/Aβ40,T-tau,and *** study suggests that PRS models hold promise for assessing the genetic risk and development of *** 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.

关键词： Alzheimer's disease Single nucleotide polymorphism polygenic risk score Cerebrospinal fluid Biomarker Amyloid-beta Tau

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Construction and evaluation of the functional polygenic risk score for gastric cancer in a prospective cohort of the European population

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Chinese Medical Journal 2023年第14期136卷 1671-1679页

作者： Yuanliang Gu Caiwang Yan Tianpei Wang Beiping Hu Meng Zhu Guangfu Jin Department of Epidemiology School of Public HealthSoutheast UniversityNanjingJiangsu 210009China Department of Epidemiology Center for Global HealthSchool of Public HealthNanjing Medical UniversityNanjingJiangsu 211166China Jiangsu Key Lab of Cancer Biomarkers Prevention and TreatmentCollaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human HealthNanjing Medical UniversityNanjingJiangsu 211166China Jiangsu Key Laboratory of Molecular and Translational Cancer Research Jiangsu Cancer HospitalJiangsu Institute of Cancer ResearchThe Affiliated Cancer Hospital of Nanjing Medical UniversityNanjingJiangsu 210009China

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 ***: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 ***,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 ***,the performance of the fPRS in combination with lifestyle factors were evaluated in predicting the risk of gastric ***: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 *** 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 ***:These results indicate that the fPRS-125 derived from fSNPs may act

关键词： polygenic risk score Gastric cancer Polymorphism,single nucleotide Cross ancestry

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Predictability of polygenic risk score for progression to dementia and its interaction with APOEε4 in mild cognitive impairment

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Translational Neurodegeneration 2021年第3期10卷 412-420页

作者： Jung‑Min Pyun Young Ho Park Keon‑Joo Lee SangYun Kim Andrew J.Saykin Kwangsik Nho Department of Neurology Uijeongbu Eulji Medical CenterEulji UniversityUijeongbuRepublic of Korea Department of Neurology Seoul National University Bundang Hospital and Seoul National University College of Medi‑cineSeongnamRepublic of Korea Department of Radiology and Imaging Sciences and the Indiana Alzheimer Disease CenterIndiana University School of MedicineIndianapolisINUSA Department of Medical and Molecular Genetics Indiana University School of MedicineIndianapolisINUSA Center for Computational Biology and Bioinformatics Indiana University School of MedicineIndianapolisINUSA.

Background:The combinatorial efect of multiple genetic factors calculated as a polygenic risk score(PRS)has been studied to predict disease progression to Alzheimer’s disease(AD)from mild cognitive impairment(MCI).Previous studies have investigated the performance of PRS in the prediction of disease progression to AD by including and excluding single nucleotide polymorphisms within the region surrounding the APOE *** studies may have missed the APOE genotype-specifc predictability of PRS for disease progression to ***:We analyzed 732 MCI from the Alzheimer’s Disease Neuroimaging Initiative cohort,including those who progressed to AD within 5 years post-baseline(n=270)and remained stable as MCI(n=462).The predictability of PRS including and excluding the APOE region(PRS_(+APOE) and PRS_(−APOE))on the conversion to AD and its interaction with the APOEε4 carrier status were assessed using Cox regression ***:PRS_(+APOE)(hazard ratio[HR]1.468,95%CI 1.335-1.615)and PRS_(−APOE)(HR 1.293,95%CI 1.157-1.445)were both associated with a signifcantly increased risk of MCI progression to *** interaction between PRS_(+APOE) and APOEε4 carrier status was signifcant with a P-value of *** association of PRSs with the progression risk was stronger in APOEε4 non-carriers(PRS_(+APOE):HR 1.710,95%CI 1.244-2.351;PRS_(−APOE):HR 1.429,95%CI 1.182-1.728)than in APOEε4 carriers(PRS_(+APOE):HR 1.167,95%CI 1.005-1.355;PRS_(−APOE):HR 1.172,95%CI 1.020-1.346).Conclusions:PRS could predict the conversion of MCI to dementia with a stronger association in APOEε4 noncarriers than APOEε4 *** indicates PRS as a potential genetic predictor particularly for MCI with no APOEε4 alleles.

关键词： polygenic risk score Mild cognitive impairment Alzheimer’s disease Disease progression APOEε4

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Effectiveness of colorectal cancer screening integrating non-genetic and genetic risk: a prospective study based on UK Biobank data

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Cancer Biology & Medicine 2024年第8期21卷 712-723页

作者： Yu Zhang Chao Sheng Zhangyan Lyu Hongji Dai Fangfang Song Fengju Song Yubei Huang Kexin Chen Department of Epidemiology and Biostatistics Key Laboratory of Molecular Cancer Epidemiology Key Laboratory of Prevention and Control of Human Major Diseases Ministry of Education National Clinical Research Center for Cancer Tianjin Medical University Cancer Institute and Hospital Tianjin Medical University

Objective: Few studies have evaluated the benefits of colorectal cancer(CRC) screening integrating both non-genetic and genetic risk factors. Here, we aimed to integrate an existing non-genetic risk model(QCancer-10) and a 139-variant polygenic risk score to evaluate the effectiveness of screening on CRC incidence and ***: We applied the integrated model to calculate 10-year CRC risk for 430,908 participants in the UK Biobank, and divided the participants into low-, intermediate-, and high-risk groups. We calculated the screening-associated hazard ratios(HRs) and absolute risk reductions(ARRs) for CRC incidence and mortality according to risk ***: During a median follow-up of 11.03 years and 12.60 years, we observed 5,158 CRC cases and 1,487 CRC deaths, respectively. CRC incidence and mortality were significantly lower among screened than non-screened participants in both the intermediateand high-risk groups [incidence: HR: 0.87, 95% confidence interval(CI): 0.81±0.94; 0.81, 0.73±0.90; mortality: 0.75, 0.64±0.87; 0.70, 0.58±0.85], which composed approximately 60% of the study population. The ARRs(95% CI) were 0.17(0.11±0.24) and 0.43(0.24±0.61), respectively, for CRC incidence, and 0.08(0.05±0.11) and 0.24(0.15±0.33), respectively, for mortality. Screening did not significantly reduce the relative or absolute risk of CRC incidence and mortality in the low-risk group. Further analysis revealed that screening was most effective for men and individuals with distal CRC among the intermediate to high-risk ***: After integrating both genetic and non-genetic factors, our findings provided priority evidence of risk-stratified CRC screening and valuable insights for the rational allocation of health resources.

关键词： Colorectal cancer incidence mortality polygenic risk score screening

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Deeprisk:A deep learning approach for genome-wide assessment of common disease risk

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Fundamental Research 2024年第4期4卷 752-760页

作者： Jiajie Peng Zhijie Bao Jingyi Lia Ruijiang Han Yuxian Wang Lu Han Jinghao Peng Tao Wang Jianye Hao Zhongyu Wei Xuequn Shang AI for Science Interdisciplinary Research Center Schoolof Computer ScienceNorthwestern Polyechnical UniversityXi'an 129China Key Laboratoryof Bg Data Sorage and Management Northwestern Polytechnical UniversityMinisty of Industy and Information TechnologyX'an 129Chin College of Intelligence and Computing Tianjin UniversityTianjin 300072China School of Data Science Fudan UniversityShanghai 200433China Research and Development Institute of Northwestern Polytechnical University in Shenzhen Shenzhen 518000China

The potential for being able to identify individuals at high disease risk solely based on genotype data has garnered significant *** widely applied,traditional polygenic risk scoring methods fall short,as they are built on additive models that fail to capture the intricate associations among single nucleotide polymorphisms(SNPs).This presents a limitation,as genetic diseases often arise from complex interactions between multiple *** address this challenge,we developed Deeprisk,a biological knowledge-driven deep learning method for modeling these complex,nonlinear associations among SNPs,to provide a more effective method for scoring the risk of common diseases with genome-wide genotype *** demonstrated that Deeprisk outperforms existing PRs-based methods in identifying individuals at high risk for four common diseases:Alzheimer's disease,inflammatory bowel disease,type 2diabetes,and breast cancer.

关键词： Disease risk prediction Deep learning polygenic risk score Common disease risk Disease prevention

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polygenic risk scores: effect estimation and model optimization

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Quantitative Biology 2021年第2期9卷 133-140页

作者： Zijie Zhao Jie Song Tuo Wang Qiongshi Lu Department of Biostatistics and Medical Informatics University of Wisconsin-MadisonMadison Wl 53726USA Department of Statistics University of Wisconsin-MadisonMadison Wl 53726USA Center for Demography of Health and Aging University of Wisconsin-MadisonMadison Wl 53726USA

Background:polygenic risk score(PRS)derived from summary statistics of genome-wide association studies(GWAS)is a useful tool to infer an individuaPs genetic risk for health outcomes and has gained increasing popularity in human genetics *** in its simplest form enjoys both computational efficiency and easy accessibility,yet the predictive performance of PRS remains moderate for diseases and ***:We provide an overview of recent advances in statistical methods to improve PRS's performance by incorporating information from linkage disequilibrium,functional annotation,and *** also introduce model validation methods that fine-tune PRS using GWAS summary ***:In this review,we showcase methodological advances and current limitations of PRS,and discuss several emerging issues in risk prediction research.

关键词： GWAS polygenic risk score summary statistics model selection

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Minimal improvement in coronary artery disease risk prediction in Chinese population using polygenic risk scores:evidence from the China Kadoorie Biobank

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Chinese Medical Journal 2023年第20期136卷 2476-2483页

作者： Songchun Yang Dong Sun Zhijia Sun Canqing Yu Yu Guo Jiahui Si Dianjianyi Sun Yuanjie Pang Pei Pei Ling Yang Iona YMillwood Robin GWalters Yiping Chen Huaidong Du Zengchang Pang Dan Schmidt Rebecca Stevens Robert Clarke Junshi Chen Zhengming Chen Jun Lv Liming Li On Behalf of the China Kadoorie Biobank Collaborative Group Department of Epidemiology and Biostatistics School of Public HealthPeking UniversityBeijing 100191China Department of Dermatology Xiangya HospitalCentral South UniversityChangshaHunan 410008China Peking University Center for Public Health and Epidemic Preparedness&Response Beijing 100191China Fuwai Hospital Chinese Academy of Medical Sciences Beijing 100730China Medical Research Council Population Health Research Unit at the University of Oxford Oxford OX37LFUK Clinical Trial Service Unit and Epidemiological Studies Unit(CTSU) Nuffield Department of Population HealthUniversity of OxfordOxford OX37LFUK Qingdao Center of Disease Control and Prevention QingdaoShandong 266033China China National Center for Food Safety risk Assessment Beijing 100738China 不详

Background:Several studies have reported that polygenic risk scores(PRSs)can enhance risk prediction of coronary artery disease(CAD)in European ***,research on this topic is far from sufficient in non-European countries,including *** aimed to evaluate the potential of PRS for predicting CAD for primary prevention in the Chinese ***: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 *** 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 *** risk was computed by summing the product of the weights and allele dosages across genome-wide single-nucleotide *** 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 ***:In the testing set,1214 hard and 7201 soft CAD cases were documented during a mean follow-up of 11.2 *** HR per standard deviation of the optimal PRS was 1.26(95%CI:1.19-1.33)for hard *** 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 *** 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 *** association of the PRS with soft CAD was much weaker than with hard CAD,leading to minimal or no improvement in the soft CAD ***:In this Chinese population sam

关键词： Coronary artery disease polygenic risk score risk prediction model Chinese population

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Evaluating the potential of(epi)genotype‑by‑low pass nanopore sequencing in dairy cattle:a study on direct genomic value and methylation analysis

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Journal of Animal Science and Biotechnology 2023年第6期14卷 2276-2289页

作者： Oscar Gonzalez‑Recio Adrian Lopez‑Catalina Ramon Peiro‑Pastor Alicia Nieto‑Valle Monica Castro Almudena Fernandez Dpt.Mejora Genetica Animal INIA-CSICCtra La Coruna Km 7.528040 MadridSpain. ETSIAAB Universidad Politecnica de Madrid.Ciudad Universitaria S/N28040 MadridSpain.

Background Genotype-by-sequencing has been proposed as an alternative to SNP genotyping arrays in genomic selection to obtain a high density of markers along the *** requires a low sequencing depth to be cost effective,which may increase the error at the genotype *** generation nanopore sequencing technology offers low cost sequencing and the possibility to detect genome methylation,which provides added value to *** aim of this study was to evaluate the performance of genotype-by-low pass nanopore sequencing for estimating the direct genomic value in dairy cattle,and the possibility to obtain methylation marks *** Latest nanopore chemistry(LSK14 and Q20)achieved a modal base calling accuracy of 99.55%,whereas previous kit(LSK109)achieved slightly lower accuracy(99.1%).The direct genomic value accuracy from genotype-by-low pass sequencing ranged between 0.79 and 0.99,depending on the trait(milk,fat or protein yield),with a sequencing depth as low as 2×and using the latest chemistry(LSK114).Lower sequencing depth led to biased estimates,yet with high rank *** LSK109 and Q20 achieved lower accuracies(0.57-0.93).More than one million high reliable methylated sites were obtained,even at low sequencing depth,located mainly in distal intergenic(87%)and promoter(5%)*** This study showed that the latest nanopore technology in useful in a LowPass sequencing framework to estimate direct genomic values with high *** may provide advantages in populations with no available SNP chip,or when a large density of markers with a wide range of allele frequencies is *** addition,low pass sequencing provided nucleotide methylation status of>1 million nucleotides at≥10×,which is an added value for epigenetic studies.

关键词： Genomic selection Genomic values Low pass sequencing Low sequencing imputation polygenic risk score

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Integrating polygenic and clinical risks to improve stroke risk stratification in prospective Chinese cohorts

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Science China(Life Sciences) 2023年第7期66卷 1626-1635页

作者： Qingmei Cui Fangchao Liu Jianxin Li Xiaoge Niu Zhongying Liu Chong Shen Dongsheng Hu Keyong Huang Shufeng Chen Jie Cao Xiaoqing Liu Ling Yu Fanghong Lu Xianping Wu Liancheng Zhao Jianfeng Huang Ying Li Zhibin Hu Hongbing Shen Dongfeng Gu Xiangfeng Lu Department of Epidemiology Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing100037China Key Laboratory of Cardiovascular Epidemiology Chinese Academy of Medical SciencesBeijing100037China Department of Nephrology Henan Provincial Key Laboratory of Kidney Disease and ImmunologyHenan Provincial Clinical Research Center for Kidney DiseaseHenan Provincial People’s Hospital and People’s Hospital of Zhengzhou UniversityZhengzhou450053China Department of Epidemiology and Biostatistics Center for Global HealthSchool of Public HealthNanjing Medical UniversityNanjing211166China Department of Epidemiology and Health Statistics College of Public HealthZhengzhou UniversityZhengzhou450001China Department of Prevention Medicine Shenzhen University School of MedicineShenzhen518060China Division of Epidemiology Guangdong Provincial People’s Hospital and Cardiovascular InstituteGuangzhou510080China Department of Cardiology Fujian Provincial People’s HospitalFuzhou350014China Cardio-Cerebrovascular Control and Research Center Institute of Basic MedicineShandong Academy of Medical SciencesJinan250062China Sichuan Center for Disease Control and Prevention Chengdu610041China Research Units of Cohort Study on Cardiovascular Diseases and Cancers Chinese Academy of Medical SciencesBeijing100730China School of Medicine Southern University of Science and TechnologyShenzhen518055China

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 *** 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 *** 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 *** gradients in the 10-year and lifetime risk across PRS categories were also found within clinical risk ***,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 *** 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,***,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.

关键词： stroke polygenic risk score clinical risk score utility stratification

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Impact of cognition-related single nucleotide polymorphisms on brain imaging phenotype in Parkinson’s disease

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Neural Regeneration Research 2023年第5期18卷 1154-1160页

作者： Ting Shen Jia-Li Pu Ya-Si Jiang Yu-Mei Yue Ting-Ting He Bo-Yi Qu Shuai Zhao Ya-Ping Yan Hsin-Yi Lai Bao-Rong Zhang Department of Neurology of the Second Affiliated Hospital Zhejiang University School of MedicineZhejiang UniversityHangzhouZhejiang ProvinceChina Department of Neurology of the Second Affiliated Hospital Interdisciplinary Institute of Neuroscience and TechnologyKey Laboratory of Medical Neurobiology of Zhejiang ProvinceZhejiang University School of MedicineHangzhouZhejiang ProvinceChina Department of Neurology of Sir Run Run Shaw Hospital Zhejiang University School of MedicineZhejiang UniversityHangzhouZhejiang ProvinceChina College of Biomedical Engineering and Instrument Science Key Laboratory for Biomedical Engineering of Ministry of EducationZhejiang UniversityHangzhouZhejiang ProvinceChina

Multiple single nucleotide polymorphisms may contribute to cognitive decline in Parkinson’s disease. However, the mechanism by which these single nucleotide polymorphisms modify brain imaging phenotype remains unclear. The aim of this study was to investigate the potential effects of multiple single nucleotide polymorphisms on brain imaging phenotype in Parkinson’s disease. Forty-eight Parkinson’s disease patients and 39 matched healthy controls underwent genotyping and 7 T magnetic resonance imaging. A cognitive-weighted polygenic risk score model was designed, in which the effect sizes were determined individually for 36 single nucleotide polymorphisms. The correlations between polygenic risk score, neuroimaging features, and clinical data were analyzed. Furthermore, individual single nucleotide polymorphism analysis was performed to explore the main effects of genotypes and their interactive effects with Parkinson’s disease diagnosis. We found that, in Parkinson’s disease, the polygenic risk score was correlated with the neural activity of the hippocampus, parahippocampus, and fusiform gyrus, and with hippocampal-prefrontal and fusiform-temporal connectivity, as well as with gray matter alterations in the orbitofrontal cortex. In addition, we found that single nucleotide polymorphisms in α-synuclein(SNCA) were associated with white matter microstructural changes in the superior corona radiata, corpus callosum, and external capsule. A single nucleotide polymorphism in catechol-O-methyltransferase was associated with the neural activities of the lingual, fusiform, and occipital gyri, which are involved in visual cognitive dysfunction. Furthermore, DRD3 was associated with frontal and temporal lobe function and structure. In conclusion, imaging genetics is useful for providing a better understanding of the genetic pathways involved in the pathophysiologic processes underlying Parkinson’s disease. This study provides evidence of an association between genetic factors

关键词： cognition imaging genetics magnetic resonance imaging multi-modality Parkinson’s disease polygenic risk score single nucleotide polymorphism ultra-high field

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