Genetic Epidemiology最新文献

{"title":"Hierarchical joint analysis of marginal summary statistics—Part I: Multipopulation fine mapping and credible set construction","authors":"Jiayi Shen,&nbsp;Lai Jiang,&nbsp;Kan Wang,&nbsp;Anqi Wang,&nbsp;Fei Chen,&nbsp;Paul J. Newcombe,&nbsp;Christopher A. Haiman,&nbsp;David V. Conti","doi":"10.1002/gepi.22562","DOIUrl":"10.1002/gepi.22562","url":null,"abstract":"<p>Recent advancement in genome-wide association studies (GWAS) comes from not only increasingly larger sample sizes but also the shift in focus towards underrepresented populations. Multipopulation GWAS increase power to detect novel risk variants and improve fine-mapping resolution by leveraging evidence and differences in linkage disequilibrium (LD) from diverse populations. Here, we expand upon our previous approach for single-population fine-mapping through Joint Analysis of Marginal SNP Effects (JAM) to a multipopulation analysis (mJAM). Under the assumption that true causal variants are common across studies, we implement a hierarchical model framework that conditions on multiple SNPs while explicitly incorporating the different LD structures across populations. The mJAM framework can be used to first select index variants using the mJAM likelihood with different feature selection approaches. In addition, we present a novel approach leveraging the ideas of mediation to construct credible sets for these index variants. Construction of such credible sets can be performed given any existing index variants. We illustrate the implementation of the mJAM likelihood through two implementations: mJAM-SuSiE (a Bayesian approach) and mJAM-Forward selection. Through simulation studies based on realistic effect sizes and levels of LD, we demonstrated that mJAM performs well for constructing concise credible sets that include the underlying causal variants. In real data examples taken from the most recent multipopulation prostate cancer GWAS, we showed several practical advantages of mJAM over other existing multipopulation methods.</p>","PeriodicalId":12710,"journal":{"name":"Genetic Epidemiology","volume":"48 6","pages":"241-257"},"PeriodicalIF":1.7,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/gepi.22562","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140603455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"OSCAA: A two-dimensional Gaussian mixture model for copy number variation association analysis","authors":"Xuanxuan Yu,&nbsp;Xizhi Luo,&nbsp;Guoshuai Cai,&nbsp;Feifei Xiao","doi":"10.1002/gepi.22558","DOIUrl":"10.1002/gepi.22558","url":null,"abstract":"<p>Copy number variants (CNVs) are prevalent in the human genome and are found to have a profound effect on genomic organization and human diseases. Discovering disease-associated CNVs is critical for understanding the pathogenesis of diseases and aiding their diagnosis and treatment. However, traditional methods for assessing the association between CNVs and disease risks adopt a two-stage strategy conducting quantitative CNV measurements first and then testing for association, which may lead to biased association estimation and low statistical power, serving as a major barrier in routine genome-wide assessment of such variation. In this article, we developed One-Stage CNV–disease Association Analysis (OSCAA), a flexible algorithm to discover disease-associated CNVs for both quantitative and qualitative traits. OSCAA employs a two-dimensional Gaussian mixture model that is built upon the PCs from copy number intensities, accounting for technical biases in CNV detection while simultaneously testing for their effect on outcome traits. In OSCAA, CNVs are identified and their associations with disease risk are evaluated simultaneously in a single step, taking into account the uncertainty of CNV identification in the statistical model. Our simulations demonstrated that OSCAA outperformed the existing one-stage method and traditional two-stage methods by yielding a more accurate estimate of the CNV–disease association, especially for short CNVs or CNVs with weak signals. In conclusion, OSCAA is a powerful and flexible approach for CNV association testing with high sensitivity and specificity, which can be easily applied to different traits and clinical risk predictions.</p>","PeriodicalId":12710,"journal":{"name":"Genetic Epidemiology","volume":"48 5","pages":"214-225"},"PeriodicalIF":1.7,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140293348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Breast and bowel cancers diagnosed in people ‘too young to have cancer’: A blueprint for research using family and twin studies","authors":"John L. Hopper,&nbsp;Shuai Li,&nbsp;Robert J. MacInnis,&nbsp;James G. Dowty,&nbsp;Tuong L. Nguyen,&nbsp;Minh Bui,&nbsp;Gillian S. Dite,&nbsp;Vivienne F. C. Esser,&nbsp;Zhoufeng Ye,&nbsp;Enes Makalic,&nbsp;Daniel F. Schmidt,&nbsp;Benjamin Goudey,&nbsp;Karen Alpen,&nbsp;Miroslaw Kapuscinski,&nbsp;Aung Ko Win,&nbsp;Pierre-Antoine Dugué,&nbsp;Roger L. Milne,&nbsp;Harindra Jayasekara,&nbsp;Jennifer D. Brooks,&nbsp;Sue Malta,&nbsp;Lucas Calais-Ferreira,&nbsp;Alexander C. Campbell,&nbsp;Jesse T. Young,&nbsp;Tu Nguyen-Dumont,&nbsp;Joohon Sung,&nbsp;Graham G. Giles,&nbsp;Daniel Buchanan,&nbsp;Ingrid Winship,&nbsp;Mary Beth Terry,&nbsp;Melissa C. Southey,&nbsp;Mark A. Jenkins","doi":"10.1002/gepi.22555","DOIUrl":"10.1002/gepi.22555","url":null,"abstract":"<p>Young breast and bowel cancers (e.g., those diagnosed before age 40 or 50 years) have far greater morbidity and mortality in terms of years of life lost, and are increasing in incidence, but have been less studied. For breast and bowel cancers, the familial relative risks, and therefore the familial variances in age-specific log(incidence), are much greater at younger ages, but little of these familial variances has been explained. Studies of families and twins can address questions not easily answered by studies of unrelated individuals alone. We describe existing and emerging family and twin data that can provide special opportunities for discovery. We present designs and statistical analyses, including novel ideas such as the VALID (Variance in Age-specific Log Incidence Decomposition) model for causes of variation in risk, the DEPTH (DEPendency of association on the number of Top Hits) and other approaches to analyse genome-wide association study data, and the within-pair, ICE FALCON (Inference about Causation from Examining FAmiliaL CONfounding) and ICE CRISTAL (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLysis) approaches to causation and familial confounding. Example applications to breast and colorectal cancer are presented. Motivated by the availability of the resources of the Breast and Colon Cancer Family Registries, we also present some ideas for future studies that could be applied to, and compared with, cancers diagnosed at older ages and address the challenges posed by young breast and bowel cancers.</p>","PeriodicalId":12710,"journal":{"name":"Genetic Epidemiology","volume":"48 8","pages":"433-447"},"PeriodicalIF":1.7,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/gepi.22555","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140169744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using parent-offspring pairs and trios to estimate indirect genetic effects in education","authors":"Victória Trindade Pons,&nbsp;Annique Claringbould,&nbsp;Priscilla Kamphuis,&nbsp;Albertine J. Oldehinkel,&nbsp;Hanna M. van Loo","doi":"10.1002/gepi.22554","DOIUrl":"10.1002/gepi.22554","url":null,"abstract":"<p>We investigated indirect genetic effects (IGEs), also known as genetic nurture, in education with a novel approach that uses phased data to include parent-offspring pairs in the transmitted/nontransmitted study design. This method increases the power to detect IGEs, enhances the generalizability of the findings, and allows for the study of effects by parent-of-origin. We validated and applied this method in a family-based subsample of adolescents and adults from the Lifelines Cohort Study in the Netherlands (<i>N</i> = 6147), using the latest genome-wide association study data on educational attainment to construct polygenic scores (PGS). Our results indicated that IGEs play a role in education outcomes in the Netherlands: we found significant associations of the nontransmitted PGS with secondary school level in youth between 13 and 24 years old as well as with education attainment and years of education in adults over 25 years old (<i>β</i> = 0.14, 0.17 and 0.26, respectively), with tentative evidence for larger maternal IGEs. In conclusion, we replicated previous findings and showed that including parent-offspring pairs in addition to trios in the transmitted/nontransmitted design can benefit future studies of parental IGEs in a wide range of outcomes.</p>","PeriodicalId":12710,"journal":{"name":"Genetic Epidemiology","volume":"48 4","pages":"190-199"},"PeriodicalIF":2.1,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/gepi.22554","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140109831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Causation and familial confounding as explanations for the associations of polygenic risk scores with breast cancer: Evidence from innovative ICE FALCON and ICE CRISTAL analyses","authors":"Shuai Li,&nbsp;Gillian S. Dite,&nbsp;Robert J. MacInnis,&nbsp;Minh Bui,&nbsp;Tuong L. Nguyen,&nbsp;Vivienne F. C. Esser,&nbsp;Zhoufeng Ye,&nbsp;James G. Dowty,&nbsp;Enes Makalic,&nbsp;Joohon Sung,&nbsp;Graham G. Giles,&nbsp;Melissa C. Southey,&nbsp;John L. Hopper","doi":"10.1002/gepi.22556","DOIUrl":"10.1002/gepi.22556","url":null,"abstract":"<p>A polygenic risk score (PRS) combines the associations of multiple genetic variants that could be due to direct causal effects, indirect genetic effects, or other sources of familial confounding. We have developed new approaches to assess evidence for and against causation by using family data for pairs of relatives (Inference about Causation from Examination of FAmiliaL CONfounding [ICE FALCON]) or measures of family history (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLyses [ICE CRISTAL]). Inference is made from the changes in regression coefficients of relatives' PRSs or PRS and family history before and after adjusting for each other. We applied these approaches to two breast cancer PRSs and multiple studies and found that (a) for breast cancer diagnosed at a young age, for example, &lt;50 years, there was no evidence that the PRSs were causal, while (b) for breast cancer diagnosed at later ages, there was consistent evidence for causation explaining increasing amounts of the PRS-disease association. The genetic variants in the PRS might be in linkage disequilibrium with truly causal variants and not causal themselves. These PRSs cause minimal heritability of breast cancer at younger ages. There is also evidence for nongenetic factors shared by first-degree relatives that explain breast cancer familial aggregation. Familial associations are not necessarily due to genes, and genetic associations are not necessarily causal.</p>","PeriodicalId":12710,"journal":{"name":"Genetic Epidemiology","volume":"48 8","pages":"401-413"},"PeriodicalIF":1.7,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/gepi.22556","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140109830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Are trait-associated genes clustered together in a gene network?","authors":"Hyun Jung Koo,&nbsp;Wei Pan","doi":"10.1002/gepi.22557","DOIUrl":"10.1002/gepi.22557","url":null,"abstract":"<p>Genome-wide association studies (GWAS) have provided an abundance of information about the genetic variants and their loci that are associated to complex traits and diseases. However, due to linkage disequilibrium (LD) and noncoding regions of loci, it remains a challenge to pinpoint the causal genes. Gene network-based approaches, paired with network diffusion methods, have been proposed to prioritize causal genes and to boost statistical power in GWAS based on the assumption that trait-associated genes are clustered in a gene network. Due to the difficulty in mapping trait-associated variants to genes in GWAS, this assumption has never been directly or rigorously tested empirically. On the other hand, whole exome sequencing (WES) data focuses on the protein-coding regions, directly identifying trait-associated genes. In this study, we tested the assumption by leveraging the recently available exome-based association statistics from the UK Biobank WES data along with two types of networks. We found that almost all trait-associated genes were significantly more proximal to each other than randomly selected genes within both networks. These results support the assumption that trait-associated genes are clustered in gene networks, which can be further leveraged to boost the power of GWAS such as by introducing less stringent <i>p</i> value thresholds.</p>","PeriodicalId":12710,"journal":{"name":"Genetic Epidemiology","volume":"48 5","pages":"203-213"},"PeriodicalIF":1.7,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/gepi.22557","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140109761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling challenges in Mendelian randomization for gene–environment interaction","authors":"Malka Gorfine,&nbsp;Conghui Qu,&nbsp;Ulrike Peters,&nbsp;Li Hsu","doi":"10.1002/gepi.22552","DOIUrl":"10.1002/gepi.22552","url":null,"abstract":"<p>Gene–environment (GxE) interactions play a crucial role in understanding the complex etiology of various traits, but assessing them using observational data can be challenging due to unmeasured confounders for lifestyle and environmental risk factors. Mendelian randomization (MR) has emerged as a valuable method for assessing causal relationships based on observational data. This approach utilizes genetic variants as instrumental variables (IVs) with the aim of providing a valid statistical test and estimation of causal effects in the presence of unmeasured confounders. MR has gained substantial popularity in recent years largely due to the success of genome-wide association studies. Many methods have been developed for MR; however, limited work has been done on evaluating GxE interaction. In this paper, we focus on two primary IV approaches: the two-stage predictor substitution and the two-stage residual inclusion, and extend them to accommodate GxE interaction under both the linear and logistic regression models for continuous and binary outcomes, respectively. Comprehensive simulation study and analytical derivations reveal that resolving the linear regression model is relatively straightforward. In contrast, the logistic regression model presents a considerably more intricate challenge, which demands additional effort.</p>","PeriodicalId":12710,"journal":{"name":"Genetic Epidemiology","volume":"48 4","pages":"164-189"},"PeriodicalIF":2.1,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139989797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Robust use of phenotypic heterogeneity at drug target genes for mechanistic insights: Application of cis-multivariable Mendelian randomization to GLP1R gene region","authors":"Ashish Patel,&nbsp;Dipender Gill,&nbsp;Dmitry Shungin,&nbsp;Christos S. Mantzoros,&nbsp;Lotte Bjerre Knudsen,&nbsp;Jack Bowden,&nbsp;Stephen Burgess","doi":"10.1002/gepi.22551","DOIUrl":"10.1002/gepi.22551","url":null,"abstract":"<p>Phenotypic heterogeneity at genomic loci encoding drug targets can be exploited by multivariable Mendelian randomization to provide insight into the pathways by which pharmacological interventions may affect disease risk. However, statistical inference in such investigations may be poor if overdispersion heterogeneity in measured genetic associations is unaccounted for. In this work, we first develop conditional <i>F</i> statistics for dimension-reduced genetic associations that enable more accurate measurement of phenotypic heterogeneity. We then develop a novel extension for two-sample multivariable Mendelian randomization that accounts for overdispersion heterogeneity in dimension-reduced genetic associations. Our empirical focus is to use genetic variants in the <i>GLP1R</i> gene region to understand the mechanism by which GLP1R agonism affects coronary artery disease (CAD) risk. Colocalization analyses indicate that distinct variants in the <i>GLP1R</i> gene region are associated with body mass index and type 2 diabetes (T2D). Multivariable Mendelian randomization analyses that were corrected for overdispersion heterogeneity suggest that bodyweight lowering rather than T2D liability lowering effects of GLP1R agonism are more likely contributing to reduced CAD risk. Tissue-specific analyses prioritized brain tissue as the most likely to be relevant for CAD risk, of the tissues considered. We hope the multivariable Mendelian randomization approach illustrated here is widely applicable to better understand mechanisms linking drug targets to diseases outcomes, and hence to guide drug development efforts.</p>","PeriodicalId":12710,"journal":{"name":"Genetic Epidemiology","volume":"48 4","pages":"151-163"},"PeriodicalIF":2.1,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/gepi.22551","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139912418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Making sense of breast cancer risk estimates","authors":"John O'Quigley","doi":"10.1002/gepi.22550","DOIUrl":"10.1002/gepi.22550","url":null,"abstract":"<p>Individual probabilistic assessments on the risk of cancer, primary or secondary, will not be understood by most patients. That is the essence of our arguments in this paper. Greater understanding can be achieved by extensive, intensive, and detailed counseling. But since probability itself is a concept that easily escapes our everyday intuition—consider the famous Monte Hall paradox—then it would also be wise to advise patients and potential patients, to not put undue weight on any probabilistic assessment. Such assessments can be of value to the epidemiologist in the investigation of different potential etiologies describing cancer evolution or to the clinical trialist as a way to maximize design efficiency. But to an ordinary individual we cannot anticipate that these assessments will be correctly interpreted.</p>","PeriodicalId":12710,"journal":{"name":"Genetic Epidemiology","volume":"48 3","pages":"141-147"},"PeriodicalIF":2.1,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139706548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revealing genomic heterogeneity and commonality: A penalized integrative analysis approach accounting for the adjacency structure of measurements","authors":"Xindi Wang,&nbsp;Yu Jiang,&nbsp;Yifan Sun","doi":"10.1002/gepi.22549","DOIUrl":"10.1002/gepi.22549","url":null,"abstract":"<p>Advancements in high-throughput genomic technologies have revolutionized the field of disease biomarker identification by providing large-scale genomic data. There is an increasing focus on understanding the relationships among diverse patient groups with distinct disease subtypes and characteristics. Complex diseases exhibit both heterogeneity and shared genomic factors, making it essential to investigate these patterns to accurately detect markers and comprehensively understand the diseases. Integrative analysis has emerged as a promising approach to address this challenge. However, existing studies have been limited by ignoring the adjacency structure of genomic measurements, such as single nucleotide polymorphisms (SNPs) and DNA methylations. In this study, we propose a structured integrative analysis method that incorporates a spline type penalty to accommodate this adjacency structure. We utilize a fused lasso type penalty to identify both heterogeneity and commonality across the groups. Extensive simulations demonstrate its superiority compared to several direct competing methods. The analysis of The Cancer Genome Atlas melanoma data with DNA methylation measurements and GENEVA diabetes data with SNP measurements exhibit that the proposed analysis lead to meaningful findings with better prediction performance and higher selection stability.</p>","PeriodicalId":12710,"journal":{"name":"Genetic Epidemiology","volume":"48 3","pages":"114-140"},"PeriodicalIF":2.1,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139691643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}