{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:25:50Z","timestamp":1790835950811,"version":"4.1.0"},"reference-count":56,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,7,22]],"date-time":"2020-07-22T00:00:00Z","timestamp":1595376000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,7,22]],"date-time":"2020-07-22T00:00:00Z","timestamp":1595376000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004794","name":"Centre National de la Recherche Scientifique","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004794","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Lithium (Li) is the cornerstone maintenance treatment for bipolar disorders (BD), but response rates are highly variable. To date, no clinical or biological marker is available to reliably define eligibility criteria for a maintenance treatment with Li. We examined whether the prophylactic response to Li (assessed retrospectively) is associated with distinct blood DNA methylation profiles. Bisulfite-treated total blood DNA samples from individuals with BD type 1 (15 excellent-responders (LiERs) versus 11 non-responders (LiNRs)) were used for targeted enrichment of CpG rich genomic regions followed by high-resolution next-generation sequencing to identify differentially methylated regions (DMRs). After controlling for potential confounders we identified 111 DMRs that significantly differ between LiERs and LiNRs with a significant enrichment in neuronal cell components. Logistic regression and receiver operating curves identified a combination of 7 DMRs with a good discriminatory power for response to Li (Area Under the Curve 0.806). Annotated genes associated with these DMRs include Eukaryotic Translation Initiation Factor 2B Subunit Epsilon (<jats:italic>EIF2B5<\/jats:italic>), Von Willebrand Factor A Domain Containing 5B2 (<jats:italic>VWA5B2<\/jats:italic>), Ral GTPase Activating Protein Catalytic Alpha Subunit 1 (<jats:italic>RALGAPA1<\/jats:italic>). Although preliminary and deserving replication, these results suggest that biomarkers of response to Li may be identified through peripheral epigenetic measures.<\/jats:p>","DOI":"10.1038\/s41598-020-69073-0","type":"journal-article","created":{"date-parts":[[2020,7,22]],"date-time":"2020-07-22T06:07:35Z","timestamp":1595398055000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["A DNA methylation signature discriminates between excellent and non-response to lithium in patients with bipolar disorder type 1"],"prefix":"10.1038","volume":"10","author":[{"given":"C.","family":"Marie-Claire","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F. X.","family":"Lejeune","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Mundwiller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Ulveling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.","family":"Moszer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Bellivier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Etain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,22]]},"reference":[{"key":"69073_CR1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/475027a","volume":"475","author":"PY Collins","year":"2011","unstructured":"Collins, P. Y. et al. Grand challenges in global mental health. Nature 475, 27\u201330 (2011).","journal-title":"Nature"},{"key":"69073_CR2","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1016\/S0140-6736(11)60512-6","volume":"377","author":"FM Gore","year":"2011","unstructured":"Gore, F. M. et al. Global burden of disease in young people aged 10\u201324 years: A systematic analysis. Lancet 377, 2093\u20132102 (2011).","journal-title":"Lancet"},{"key":"69073_CR3","unstructured":"Goodwin, G.M. et al. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology. J. Psychopharmacol. 30, 495\u2013553 (2016)."},{"key":"69073_CR4","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1016\/S0140-6736(11)60873-8","volume":"378","author":"A Cipriani","year":"2011","unstructured":"Cipriani, A. et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: A multiple-treatments meta-analysis. Lancet (London, England) 378, 1306\u20131315 (2011).","journal-title":"Lancet (London, England)"},{"key":"69073_CR5","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S2215-0366(14)70314-1","volume":"1","author":"T Miura","year":"2014","unstructured":"Miura, T. et al. Comparative efficacy and tolerability of pharmacological treatments in the maintenance treatment of bipolar disorder: A systematic review and network meta-analysis. Lancet Psychiatry 1, 351\u2013359 (2014).","journal-title":"Lancet Psychiatry"},{"key":"69073_CR6","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s40345-014-0015-8","volume":"2","author":"E Severus","year":"2014","unstructured":"Severus, E. et al. Lithium for prevention of mood episodes in bipolar disorders: Systematic review and meta-analysis. Int. J. Bipolar Disord. 2, 15 (2014).","journal-title":"Int. J. Bipolar Disord."},{"key":"69073_CR7","doi-asserted-by":"crossref","first-page":"120","DOI":"10.2741\/E696","volume":"6","author":"PA Geoffroy","year":"2014","unstructured":"Geoffroy, P. A., Bellivier, F., Leboyer, M. & Etain, B. Can the response to mood stabilizers be predicted in bipolar disorder?. Front. Biosci. (Elite Ed) 6, 120\u2013138 (2014).","journal-title":"Front. Biosci. (Elite Ed)"},{"key":"69073_CR8","doi-asserted-by":"crossref","first-page":"e65636","DOI":"10.1371\/journal.pone.0065636","volume":"8","author":"M Manchia","year":"2013","unstructured":"Manchia, M. et al. Assessment of response to lithium maintenance treatment in bipolar disorder: A consortium on lithium genetics (ConLiGen) report. PLoS ONE 8, e65636 (2013).","journal-title":"PLoS ONE"},{"key":"69073_CR9","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1001\/archpsyc.57.2.187","volume":"57","author":"RJ Baldessarini","year":"2000","unstructured":"Baldessarini, R. J. & Tondo, L. Does lithium treatment still work? Evidence of stable responses over three decades. Arch. Gen. Psychiatry 57, 187\u2013190 (2000).","journal-title":"Arch. Gen. Psychiatry"},{"key":"69073_CR10","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.jad.2007.03.003","volume":"104","author":"J Garnham","year":"2007","unstructured":"Garnham, J. et al. Prophylactic treatment response in bipolar disorder: results of a naturalistic observation study. J. Affect. Disord. 104, 185\u2013190 (2007).","journal-title":"J. Affect. Disord."},{"key":"69073_CR11","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1177\/0004867416664794","volume":"51","author":"S Sportiche","year":"2017","unstructured":"Sportiche, S. et al. Clinical factors associated with lithium response in bipolar disorders. Aust. N. Z. J. Psychiatry 51, 524\u2013530 (2017).","journal-title":"Aust. N. Z. J. Psychiatry"},{"key":"69073_CR12","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1111\/acps.13062","volume":"140","author":"TP Hui","year":"2019","unstructured":"Hui, T. P. et al. A systematic review and meta-analysis of clinical predictors of lithium response in bipolar disorder. Acta Psychiatr. Scand. 140, 94\u2013115 (2019).","journal-title":"Acta Psychiatr. Scand."},{"key":"69073_CR13","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.neubiorev.2016.06.010","volume":"68","author":"GR Fries","year":"2016","unstructured":"Fries, G. R. et al. The role of DNA methylation in the pathophysiology and treatment of bipolar disorder. Neurosci. Biobehav. Rev. 68, 474\u2013488 (2016).","journal-title":"Neurosci. Biobehav. Rev."},{"key":"69073_CR14","doi-asserted-by":"crossref","first-page":"129","DOI":"10.2217\/pgs-2017-0111","volume":"19","author":"C Pisanu","year":"2018","unstructured":"Pisanu, C., Katsila, T., Patrinos, G. P. & Squassina, A. Recent trends on the role of epigenomics, metabolomics and noncoding RNAs in rationalizing mood stabilizing treatment. Pharmacogenomics 19, 129\u2013143 (2018).","journal-title":"Pharmacogenomics"},{"key":"69073_CR15","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1017\/S1461145713001569","volume":"17","author":"AA Huzayyin","year":"2014","unstructured":"Huzayyin, A. A. et al. Decreased global methylation in patients with bipolar disorder who respond to lithium. Int. J. Neuropsychopharmacol. 17, 561\u2013569 (2014).","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"69073_CR16","first-page":"76","volume":"1","author":"L Backlund","year":"2015","unstructured":"Backlund, L. et al. Mood stabilizers and the influence on global leukocyte DNA methylation in bipolar disorder. Mol. Neuropsychiatry 1, 76\u201381 (2015).","journal-title":"Mol. Neuropsychiatry"},{"key":"69073_CR17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2014.05.020","author":"B Dellosso","year":"2014","unstructured":"Dellosso, B. et al. Epigenetic modulation of BDNF gene: Differences in DNA methylation between unipolar and bipolar patients. J. Affect. Disord. https:\/\/doi.org\/10.1016\/j.jad.2014.05.020 (2014).","journal-title":"J. Affect. Disord."},{"key":"69073_CR18","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1038\/npp.2012.10","volume":"37","author":"C D\u2019Addario","year":"2012","unstructured":"D\u2019Addario, C. et al. Selective DNA methylation of BDNF promoter in bipolar disorder: Differences among patients with BDI and BDII. Neuropsychopharmacology 37, 1647\u20131655 (2012).","journal-title":"Neuropsychopharmacology"},{"key":"69073_CR19","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.pnpbp.2017.08.011","volume":"82","author":"C D\u2019Addario","year":"2018","unstructured":"D\u2019Addario, C. et al. Regulation of gene transcription in bipolar disorders: Role of DNA methylation in the relationship between prodynorphin and brain derived neurotrophic factor. Prog. Neuropsychopharmacol. Biol. Psychiatry 82, 314\u2013321 (2018).","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"69073_CR20","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1017\/S1461145713000710","volume":"16","author":"T Asai","year":"2013","unstructured":"Asai, T. et al. Effect of mood stabilizers on DNA methylation in human neuroblastoma cells. Int. J. Neuropsychopharmacol. 16, 2285\u20132294 (2013).","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"69073_CR21","doi-asserted-by":"crossref","first-page":"197","DOI":"10.2217\/epi.15.98","volume":"8","author":"LC Houtepen","year":"2016","unstructured":"Houtepen, L. C., van Bergen, A. H., Vinkers, C. H. & Boks, M. P. M. DNA methylation signatures of mood stabilizers and antipsychotics in bipolar disorder. Epigenomics 8, 197\u2013208 (2016).","journal-title":"Epigenomics"},{"key":"69073_CR22","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1016\/j.pnpbp.2008.08.012","volume":"32","author":"F Marmol","year":"2008","unstructured":"Marmol, F. Lithium: bipolar disorder and neurodegenerative diseases Possible cellular mechanisms of the therapeutic effects of lithium. Prog. Neuropsychopharmacol. Biol. Psychiatry 32, 1761\u20131771 (2008).","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"69073_CR23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1017\/S1462399404008385","volume":"6","author":"MK Rowe","year":"2004","unstructured":"Rowe, M. K. & Chuang, D.-M. Lithium neuroprotection: molecular mechanisms and clinical implications. Expert Rev. Mol. Med. 6, 1\u201318 (2004).","journal-title":"Expert Rev. Mol. Med."},{"key":"69073_CR24","first-page":"457","volume":"8","author":"T Dwivedi","year":"2014","unstructured":"Dwivedi, T. & Zhang, H. Lithium-induced neuroprotection is associated with epigenetic modification of specific BDNF gene promoter and altered expression of apoptotic-regulatory proteins. Front. Neurosci. 8, 457 (2014).","journal-title":"Front. Neurosci."},{"key":"69073_CR25","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.tig.2015.03.002","volume":"31","author":"G Lev Maor","year":"2015","unstructured":"Lev Maor, G., Yearim, A. & Ast, G. The alternative role of DNA methylation in splicing regulation. Trends Genet. 31, 274\u2013280 (2015).","journal-title":"Trends Genet."},{"key":"69073_CR26","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.ygeno.2014.08.020","volume":"104","author":"L Wen","year":"2014","unstructured":"Wen, L. & Tang, F. Genomic distribution and possible functions of DNA hydroxymethylation in the brain. Genomics 104, 341\u2013346 (2014).","journal-title":"Genomics"},{"key":"69073_CR27","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.ccr.2014.07.028","volume":"26","author":"X Yang","year":"2014","unstructured":"Yang, X. et al. Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer Cell 26, 577\u2013590 (2014).","journal-title":"Cancer Cell"},{"key":"69073_CR28","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1042\/BST20150164","volume":"43","author":"NC Wortham","year":"2015","unstructured":"Wortham, N. C. & Proud, C. G. eIF2B: Recent structural and functional insights into a key regulator of translation. Biochem. Soc. Trans. 43, 1234\u20131240 (2015).","journal-title":"Biochem. Soc. Trans."},{"key":"69073_CR29","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S0304-3940(02)00354-3","volume":"327","author":"F Bosetti","year":"2002","unstructured":"Bosetti, F., Seemann, R. & Rapoport, S. I. Chronic lithium chloride administration to rats decreases brain protein level of epsilon (\u03f5) subunit of eukaryotic initiation factor-2B. Neurosci. Lett. 327, 71\u201373 (2002).","journal-title":"Neurosci. Lett."},{"key":"69073_CR30","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.14887","author":"M Terumitsu-Tsujita","year":"2019","unstructured":"Terumitsu-Tsujita, M. et al. Glial pathology in a novel spontaneous mutant mouse of the Eif2b5 gene: A vanishing white matter disease model. J. Neurochem. https:\/\/doi.org\/10.1111\/jnc.14887 (2019).","journal-title":"J. Neurochem."},{"key":"69073_CR31","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/978-3-319-53889-1_11","volume":"978","author":"R Lin","year":"2017","unstructured":"Lin, R. & Turecki, G. Noncoding RNAs in depression. Adv. Exp. Med. Biol. 978, 197\u2013210 (2017).","journal-title":"Adv. Exp. Med. Biol."},{"key":"69073_CR32","doi-asserted-by":"crossref","first-page":"5240","DOI":"10.12659\/MSM.899372","volume":"22","author":"X Cui","year":"2016","unstructured":"Cui, X. et al. Long non-coding RNA: Potential diagnostic and therapeutic biomarker for major depressive disorder. Med. Sci. Monit. 22, 5240\u20135248 (2016).","journal-title":"Med. Sci. Monit."},{"key":"69073_CR33","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1097\/YPG.0000000000000129","volume":"26","author":"L Zuo","year":"2016","unstructured":"Zuo, L. et al. Long noncoding RNAs in psychiatric disorders. Psychiatr. Genet. 26, 109\u2013116 (2016).","journal-title":"Psychiatr. Genet."},{"key":"69073_CR34","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1016\/S0140-6736(16)00143-4","volume":"387","author":"L Hou","year":"2016","unstructured":"Hou, L. et al. Genetic variants associated with response to lithium treatment in bipolar disorder: A genome-wide association study. Lancet (London, England) 387, 1085\u20131093 (2016).","journal-title":"Lancet (London, England)"},{"key":"69073_CR35","first-page":"1","volume":"178","author":"IA Akkouh","year":"2019","unstructured":"Akkouh, I. A. et al. Exploring lithium\u2019s transcriptional mechanisms of action in bipolar disorder: a multi-step study. Neuropsychopharmacology 178, 1\u20139 (2019).","journal-title":"Neuropsychopharmacology"},{"key":"69073_CR36","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.ygeno.2009.08.015","volume":"94","author":"K Shimojima","year":"2009","unstructured":"Shimojima, K. et al. TULIP1 (RALGAPA1) haploinsufficiency with brain development delay. Genomics 94, 414\u2013422 (2009).","journal-title":"Genomics"},{"key":"69073_CR37","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.2217\/epi.15.64","volume":"7","author":"DL Walker","year":"2015","unstructured":"Walker, D. L. et al. DNA methylation profiling: comparison of genome-wide sequencing methods and the Infinium Human Methylation 450 Bead Chip. Epigenomics 7, 1287\u20131302 (2015).","journal-title":"Epigenomics"},{"key":"69073_CR38","doi-asserted-by":"crossref","first-page":"813","DOI":"10.2217\/epi.15.21","volume":"7","author":"Z Sun","year":"2015","unstructured":"Sun, Z., Cunningham, J., Slager, S. & Kocher, J.-P. Base resolution methylome profiling: Considerations in platform selection, data preprocessing and analysis. Epigenomics 7, 813\u2013828 (2015).","journal-title":"Epigenomics"},{"key":"69073_CR39","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1111\/acps.12684","volume":"135","author":"B Etain","year":"2017","unstructured":"Etain, B. et al. Childhood trauma and mixed episodes are associated with poor response to lithium in bipolar disorders. Acta Psychiatr. Scand. 135, 319\u2013327 (2017).","journal-title":"Acta Psychiatr. Scand."},{"key":"69073_CR40","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2018.1725","author":"O Story Jovanova","year":"2018","unstructured":"Story Jovanova, O. et al. DNA methylation signatures of depressive symptoms in middle-aged and elderly persons. JAMA Psychiatry https:\/\/doi.org\/10.1001\/jamapsychiatry.2018.1725 (2018).","journal-title":"JAMA Psychiatry"},{"key":"69073_CR41","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1002\/da.22480","volume":"33","author":"N Sadeh","year":"2016","unstructured":"Sadeh, N. et al. Epigenetic variation at SKA2 predicts suicide phenotypes and internalizing psychopathology. Depress. Anxiety 33, 308\u2013315 (2016).","journal-title":"Depress. Anxiety"},{"key":"69073_CR42","doi-asserted-by":"crossref","first-page":"e1187","DOI":"10.1038\/tp.2017.171","volume":"7","author":"RD Edgar","year":"2017","unstructured":"Edgar, R. D., Jones, M. J., Meaney, M. J., Turecki, G. & Kobor, M. S. BECon: a tool for interpreting DNA methylation findings from blood in the context of brain. Transl. Psychiatry 7, e1187\u2013e1187 (2017).","journal-title":"Transl. Psychiatry"},{"key":"69073_CR43","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1192\/bjp.134.4.382","volume":"134","author":"SA Montgomery","year":"1979","unstructured":"Montgomery, S. A. & Asberg, M. A new depression scale designed to be sensitive to change. Br. J. Psychiatry 134, 382\u2013389 (1979).","journal-title":"Br. J. Psychiatry"},{"key":"69073_CR44","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1192\/bjp.133.5.429","volume":"133","author":"RC Young","year":"1978","unstructured":"Young, R. C., Biggs, J. T., Ziegler, V. E. & Meyer, D. A. A rating scale for mania: Reliability, validity and sensitivity. Br. J. Psychiatry 133, 429\u2013435 (1978).","journal-title":"Br. J. Psychiatry"},{"key":"69073_CR45","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1001\/archpsyc.1994.03950110009002","volume":"51","author":"JI Nurnberger","year":"1994","unstructured":"Nurnberger, J. I. et al. Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Arch. Gen. Psychiatry 51, 849\u2013859 (1994).","journal-title":"Arch. Gen. Psychiatry"},{"key":"69073_CR46","doi-asserted-by":"crossref","first-page":"942","DOI":"10.4088\/JCP.v63n1013","volume":"63","author":"P Grof","year":"2002","unstructured":"Grof, P. et al. Is response to prophylactic lithium a familial trait?. J. Clin. Psychiatry 63, 942\u2013947 (2002).","journal-title":"J. Clin. Psychiatry"},{"key":"69073_CR47","first-page":"31","volume-title":"Considerations for Design and Analysis of DNA Methylation Studies","author":"KB Michels","year":"2018","unstructured":"Michels, K. B. & Binder, A. M. Considerations for Design and Analysis of DNA Methylation Studies 31\u201346 (Humana Press, New York, 2018). ."},{"key":"69073_CR48","first-page":"383","volume-title":"Methods in Molecular Biology","author":"J Wendt","year":"2018","unstructured":"Wendt, J., Rosenbaum, H., Richmond, T. A., Jeddeloh, J. A. & Burgess, D. L. Targeted bisulfite sequencing using the SeqCap epi enrichment system. In Methods in Molecular Biology 383\u2013405 (Humana Press Inc., New York, 2018)."},{"key":"69073_CR49","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1101\/gr.196394.115","volume":"26","author":"F J\u00fchling","year":"2016","unstructured":"J\u00fchling, F. et al. metilene: fast and sensitive calling of differentially methylated regions from bisulfite sequencing data. Genome Res. 26, 256\u2013262 (2016).","journal-title":"Genome Res."},{"key":"69073_CR50","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/1471-2105-13-86","volume":"13","author":"EA Houseman","year":"2012","unstructured":"Houseman, E. A. et al. DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinform. 13, 86 (2012).","journal-title":"BMC Bioinform."},{"key":"69073_CR51","doi-asserted-by":"crossref","first-page":"e41361","DOI":"10.1371\/journal.pone.0041361","volume":"7","author":"LE Reinius","year":"2012","unstructured":"Reinius, L. E. et al. Differential DNA methylation in purified human blood cells: implications for cell lineage and studies on disease susceptibility. PLoS ONE 7, e41361 (2012).","journal-title":"PLoS ONE"},{"key":"69073_CR52","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1093\/bioinformatics\/btu049","volume":"30","author":"MJ Aryee","year":"2014","unstructured":"Aryee, M. J. et al. Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics 30, 1363\u20131369 (2014).","journal-title":"Bioinformatics"},{"key":"69073_CR53","doi-asserted-by":"crossref","first-page":"R31","DOI":"10.1186\/gb-2014-15-2-r31","volume":"15","author":"AE Jaffe","year":"2014","unstructured":"Jaffe, A. E. & Irizarry, R. A. Accounting for cellular heterogeneity is critical in epigenome-wide association studies. Genome Biol. 15, R31 (2014).","journal-title":"Genome Biol."},{"key":"69073_CR54","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2008.211","volume":"4","author":"DW Huang","year":"2009","unstructured":"Huang, D. W., Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44\u201357 (2009).","journal-title":"Nat. Protoc."},{"key":"69073_CR55","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/nar\/gkn923","volume":"37","author":"DW Huang","year":"2009","unstructured":"Huang, D. W., Sherman, B. T. & Lempicki, R. A. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 37, 1\u201313 (2009).","journal-title":"Nucleic Acids Res."},{"key":"69073_CR56","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1186\/1471-2105-12-253","volume":"12","author":"K-A L\u00ea Cao","year":"2011","unstructured":"L\u00ea Cao, K.-A., Boitard, S. & Besse, P. Sparse PLS discriminant analysis: biologically relevant feature selection and graphical displays for multiclass problems. BMC Bioinform. 12, 253 (2011).","journal-title":"BMC Bioinform."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-69073-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-69073-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-69073-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T10:00:28Z","timestamp":1670320828000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-69073-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,22]]},"references-count":56,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["69073"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-69073-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,22]]},"assertion":[{"value":"10 January 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 July 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 July 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"F. Bellivier has received honoraria and financial compensation as an independent symposium speaker from Sanofi-Aventis, Lundbeck, AstraZeneca, Eli Lilly, Bristol-Myers Squibb and Servier. B. Etain has received honoraria form Sanofi-Aventis. All other authors have no conflicts of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12239"}}