{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T09:48:43Z","timestamp":1766137723332,"version":"3.37.3"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"22","license":[{"start":{"date-parts":[[2021,6,12]],"date-time":"2021-06-12T00:00:00Z","timestamp":1623456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01-CA178744","UH2-CA207101","P30-CA016672","R01-CA244845","P50-CA221707","1550088","UL1-TR001878"],"award-info":[{"award-number":["R01-CA178744","UH2-CA207101","P30-CA016672","R01-CA244845","P50-CA221707","1550088","UL1-TR001878"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Gastrointestinal Cancer Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,11,18]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Motivation<\/jats:title><jats:p>DNA methylation is a key epigenetic factor regulating gene expression. While promoter methylation has been well studied, recent publications have revealed that functionally important methylation also occurs in intergenic and distal regions, and varies across genes and tissue types. Given the growing importance of inter-platform integrative genomic analyses, there is an urgent need to develop methods to discover and characterize gene-level relationships between methylation and expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We introduce a novel sequential penalized regression approach to identify methylation-expression quantitative trait loci (methyl-eQTLs), a term that we have coined to represent, for each gene and tissue type, a sparse set of CpG loci best explaining gene expression and accompanying weights indicating direction and strength of association. Using TCGA and MD Anderson colorectal cohorts to build and validate our models, we demonstrate our strategy better explains expression variability than current commonly used gene-level methylation summaries. The methyl-eQTLs identified by our approach can be used to construct gene-level methylation summaries that are maximally correlated with gene expression for use in integrative models, and produce a tissue-specific summary of which genes appear to be strongly regulated by methylation. Our results introduce an important resource to the biomedical community for integrative genomics analyses involving DNA methylation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Availability and implementation<\/jats:title><jats:p>We produce an R Shiny app (https:\/\/rstudio-prd-c1.pmacs.upenn.edu\/methyl-eQTL\/) that interactively presents methyl-eQTL results for colorectal, breast and pancreatic cancer. The source R code for this work is provided in the Supplementary Material.<\/jats:p><\/jats:sec><jats:sec><jats:title>Supplementary information<\/jats:title><jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p><\/jats:sec>","DOI":"10.1093\/bioinformatics\/btab443","type":"journal-article","created":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T19:22:03Z","timestamp":1623439323000},"page":"4014-4022","source":"Crossref","is-referenced-by-count":6,"title":["Methylation-eQTL analysis in cancer research"],"prefix":"10.1093","volume":"37","author":[{"given":"Yusha","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Human Genetics, The University of Chicago , Chicago, IL 60637, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keith A","family":"Baggerly","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Computational Biology, M.D. Anderson Cancer Center , Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elias","family":"Orouji","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine, M.D. Anderson Cancer Center , Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ganiraju","family":"Manyam","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Computational Biology, M.D. Anderson Cancer Center , Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huiqin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Computational Biology, M.D. Anderson Cancer Center , Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Lam","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Medical Oncology, M.D. Anderson Cancer Center , Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer S","family":"Davis","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, M.D. Anderson Cancer Center , Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael S","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of North Carolina at Chapel Hill , Chapel Hill, NC 27599, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bradley M","family":"Broom","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Computational Biology, M.D. Anderson Cancer Center , Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David G","family":"Menter","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Medical Oncology, M.D. Anderson Cancer Center , Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kunal","family":"Rai","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine, M.D. Anderson Cancer Center , Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott","family":"Kopetz","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Medical Oncology, M.D. Anderson Cancer Center , Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8520-6088","authenticated-orcid":false,"given":"Jeffrey S","family":"Morris","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Epidemiology and Informatics, The University of Pennsylvania , Philadelphia, PA 19104-6021, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,6,12]]},"reference":[{"key":"2023051701223658800_btab443-B1","doi-asserted-by":"crossref","first-page":"R21","DOI":"10.1186\/gb-2013-14-3-r21","article-title":"DNA methylation of distal regulatory sites characterizes dysregulation of cancer genes","volume":"14","author":"Aran","year":"2013","journal-title":"Genome Biol"},{"key":"2023051701223658800_btab443-B2","doi-asserted-by":"crossref","first-page":"e14524","DOI":"10.1371\/journal.pone.0014524","article-title":"DNA methylation of the first exon is tightly linked to transcriptional silencing","volume":"6","author":"Brenet","year":"2011","journal-title":"PLoS One"},{"key":"2023051701223658800_btab443-B3","doi-asserted-by":"crossref","first-page":"i139","DOI":"10.1093\/bioinformatics\/btu293","article-title":"Graph-regularized dual lasso for robust eQTL mapping","volume":"30","author":"Cheng","year":"2014","journal-title":"Bioinformatics"},{"key":"2023051701223658800_btab443-B4","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s12859-016-0986-9","article-title":"Sparse regression models for unraveling group and individual associations in eQTL mapping","volume":"17","author":"Cheng","year":"2016","journal-title":"BMC Bioinformatics"},{"key":"2023051701223658800_btab443-B5","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1534\/genetics.109.100362","article-title":"Expression quantitative trait loci mapping with multivariate sparse partial least squares regression","volume":"182","author":"Chun","year":"2009","journal-title":"Genetics"},{"key":"2023051701223658800_btab443-B6","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1093\/bioinformatics\/btv653","article-title":"Evaluation of hierarchical models for integrative genomic analyses","volume":"32","author":"Denis","year":"2016","journal-title":"Bioinformatics"},{"key":"2023051701223658800_btab443-B7","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1080\/10618600.2019.1593179","article-title":"Simultaneous variable and covariance selection with the multivariate spike-and-slab lasso","volume":"28","author":"Deshpande","year":"2019","journal-title":"J. Comput. Graph. Stat"},{"key":"2023051701223658800_btab443-B8","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1038\/nbt.1662","article-title":"Discovery and characterization of chromatin states for systematic annotation of the human genome","volume":"28","author":"Ernst","year":"2010","journal-title":"Nat. Biotechnol"},{"key":"2023051701223658800_btab443-B9","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1038\/nm.3967","article-title":"The consensus molecular subtypes of colorectal cancer","volume":"21","author":"Guinney","year":"2015","journal-title":"Nat. Med"},{"key":"2023051701223658800_btab443-B10","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1038\/ng.298","article-title":"The human colon cancer methylome shows similar hypo-and hypermethylation at conserved tissue-specific CpG island shores","volume":"41","author":"Irizarry","year":"2009","journal-title":"Nat. Genet"},{"key":"2023051701223658800_btab443-B11","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1687-4153-2013-13","article-title":"Bayesian methods for expression-based integration of various types of genomics data","volume":"2013","author":"Jennings","year":"2013","journal-title":"EURASIP J. Bioinf. Syst. Biol"},{"key":"2023051701223658800_btab443-B12","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1111\/febs.13125","article-title":"DNA methylome profiling beyond promoters\u2013taking an epigenetic snapshot of the breast tumor microenvironment","volume":"282","author":"Jeschke","year":"2015","journal-title":"FEBS J"},{"key":"2023051701223658800_btab443-B13","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/nrg3230","article-title":"Functions of DNA methylation: islands, start sites, gene bodies and beyond","volume":"13","author":"Jones","year":"2012","journal-title":"Nat. Rev. Genet"},{"key":"2023051701223658800_btab443-B14","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1016\/j.bbagrm.2013.08.001","article-title":"Intragenic DNA methylation in transcriptional regulation, normal differentiation and cancer","volume":"1829","author":"Kulis","year":"2013","journal-title":"Biochim. Biophys. Acta Gene Regul. Mech"},{"key":"2023051701223658800_btab443-B15","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nature14248","article-title":"Integrative analysis of 111 reference human epigenomes","volume":"518","author":"Kundaje","year":"2015","journal-title":"Nature"},{"key":"2023051701223658800_btab443-B16","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1101\/gr.101907.109","article-title":"Dynamic changes in the human methylome during differentiation","volume":"20","author":"Laurent","year":"2010","journal-title":"Genome Res"},{"key":"2023051701223658800_btab443-B17","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1038\/bjc.2016.87","article-title":"Association of CpG island methylator phenotype and EREG\/AREG methylation and expression in colorectal cancer","volume":"114","author":"Lee","year":"2016","journal-title":"Br. J. Cancer"},{"key":"2023051701223658800_btab443-B18","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1186\/s13059-014-0408-0","article-title":"Whole-genome bisulfite sequencing of multiple individuals reveals complementary roles of promoter and gene body methylation in transcriptional regulation","volume":"15","author":"Lou","year":"2014","journal-title":"Genome Biol"},{"year":"2021","author":"Orouji","key":"2023051701223658800_btab443-B19"},{"key":"2023051701223658800_btab443-B20","doi-asserted-by":"crossref","first-page":"8464","DOI":"10.1093\/nar\/gkt643","article-title":"Integrated analysis of genome-wide DNA methylation and gene expression profiles in molecular subtypes of breast cancer","volume":"41","author":"Rhee","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"2023051701223658800_btab443-B21","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13072-016-0102-4","article-title":"Identification of activated enhancers and linked transcription factors in breast, prostate and kidney tumors by tracing enhancer networks using epigenetic traits","volume":"9","author":"Rhie","year":"2016","journal-title":"Epigenet. Chromatin"},{"key":"2023051701223658800_btab443-B22","doi-asserted-by":"crossref","first-page":"5100","DOI":"10.1093\/nar\/gkx078","article-title":"Modeling complex patterns of differential DNA methylation that associate with gene expression changes","volume":"45","author":"Schlosberg","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"2023051701223658800_btab443-B23","doi-asserted-by":"crossref","first-page":"2906","DOI":"10.1093\/bioinformatics\/btp543","article-title":"Integrative clustering of multiple genomic data types using a joint latent variable model with application to breast and lung cancer subtype analysis","volume":"25","author":"Shen","year":"2009","journal-title":"Bioinformatics"},{"key":"2023051701223658800_btab443-B24","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1534\/genetics.110.114280","article-title":"Genomewide multiple-loci mapping in experimental crosses by iterative adaptive penalized regression","volume":"185","author":"Sun","year":"2010","journal-title":"Genetics"},{"key":"2023051701223658800_btab443-B25","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/nrg.2017.86","article-title":"Statistical and integrative system-level analysis of DNA methylation data","volume":"19","author":"Teschendorff","year":"2018","journal-title":"Nat. Rev. Genet"},{"key":"2023051701223658800_btab443-B26","doi-asserted-by":"crossref","first-page":"2","DOI":"10.3389\/fgene.2016.00002","article-title":"Strategies for integrated analysis of genetic, epigenetic, and gene expression variation in cancer: addressing the challenges","volume":"7","author":"Thingholm","year":"2016","journal-title":"Front. Genet"},{"key":"2023051701223658800_btab443-B27","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1111\/j.2517-6161.1996.tb02080.x","article-title":"Regression shrinkage and selection via the lasso","volume":"58","author":"Tibshirani","year":"1996","journal-title":"J. R. Stat. Soc. Ser. B (Methodological)"},{"key":"2023051701223658800_btab443-B28","doi-asserted-by":"crossref","first-page":"6816","DOI":"10.1093\/nar\/gkt482","article-title":"Discovering high-resolution patterns of differential DNA methylation that correlate with gene expression changes","volume":"41","author":"VanderKraats","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"2023051701223658800_btab443-B29","doi-asserted-by":"crossref","first-page":"R37","DOI":"10.1186\/gb-2014-15-2-r37","article-title":"The relationship between DNA methylation, genetic and expression inter-individual variation in untransformed human fibroblasts","volume":"15","author":"Wagner","year":"2014","journal-title":"Genome Biol"},{"key":"2023051701223658800_btab443-B30","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1093\/bioinformatics\/bts655","article-title":"iBAG: integrative Bayesian analysis of high-dimensional multiplatform genomics data","volume":"29","author":"Wang","year":"2013","journal-title":"Bioinformatics"},{"key":"2023051701223658800_btab443-B31","doi-asserted-by":"crossref","DOI":"10.1201\/9781420010404","volume-title":"Generalized Additive Models: An Introduction with R","author":"Wood","year":"2006"},{"key":"2023051701223658800_btab443-B32","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1186\/s13059-015-0668-3","article-title":"Inferring regulatory element landscapes and transcription factor networks from cancer methylomes","volume":"16","author":"Yao","year":"2015","journal-title":"Genome Biol"},{"key":"2023051701223658800_btab443-B33","doi-asserted-by":"crossref","first-page":"e6757","DOI":"10.7717\/peerj.6757","article-title":"Predicting gene expression using DNA methylation in three human populations","volume":"7","author":"Zhong","year":"2019","journal-title":"PeerJ"},{"key":"2023051701223658800_btab443-B34","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1198\/016214506000000735","article-title":"The adaptive lasso and its oracle properties","volume":"101","author":"Zou","year":"2006","journal-title":"J. Am. Stat. Assoc"},{"key":"2023051701223658800_btab443-B35","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1111\/j.1467-9868.2005.00503.x","article-title":"Regularization and variable selection via the elastic net","volume":"67","author":"Zou","year":"2005","journal-title":"J. R. Stat. Soc. Ser. B (Stat. Methodol.)"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btab443\/39510899\/btab443.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/37\/22\/4014\/50335197\/btab443.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/37\/22\/4014\/50335197\/btab443.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,1]],"date-time":"2024-09-01T17:47:46Z","timestamp":1725212866000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/37\/22\/4014\/6297392"}},"subtitle":[],"editor":[{"given":"Pier","family":"Luigi Martelli","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,6,12]]},"references-count":35,"journal-issue":{"issue":"22","published-print":{"date-parts":[[2021,11,18]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btab443","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"type":"print","value":"1367-4803"},{"type":"electronic","value":"1367-4811"}],"subject":[],"published-other":{"date-parts":[[2021,11,15]]},"published":{"date-parts":[[2021,6,12]]}}}