{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T06:07:03Z","timestamp":1784527623524,"version":"3.55.0"},"reference-count":87,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T00:00:00Z","timestamp":1638921600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hungarian Brain Research Program","award":["2017-1.2.1-NKP-2017-00002"],"award-info":[{"award-number":["2017-1.2.1-NKP-2017-00002"]}]},{"name":"Hungarian Brain Research Program","award":["KTIA_13_NAPA-II\/14"],"award-info":[{"award-number":["KTIA_13_NAPA-II\/14"]}]},{"name":"National Development Agency","award":["KTIA_NAP_13-1-2013-0001"],"award-info":[{"award-number":["KTIA_NAP_13-1-2013-0001"]}]},{"name":"National Development Agency","award":["KTIA_NAP_13-2-2015-0001"],"award-info":[{"award-number":["KTIA_NAP_13-2-2015-0001"]}]},{"DOI":"10.13039\/501100003549","name":"Hungarian Scientific Research Fund","doi-asserted-by":"publisher","award":["119866"],"award-info":[{"award-number":["119866"]}],"id":[{"id":"10.13039\/501100003549","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015498","name":"Ministry for Innovation and Technology","doi-asserted-by":"publisher","award":["\u00daNKP-20-4-II-SE-9"],"award-info":[{"award-number":["\u00daNKP-20-4-II-SE-9"]}],"id":[{"id":"10.13039\/501100015498","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015498","name":"Ministry for Innovation and Technology","doi-asserted-by":"publisher","award":["\u00daNKP-20-5-BME-92"],"award-info":[{"award-number":["\u00daNKP-20-5-BME-92"]}],"id":[{"id":"10.13039\/501100015498","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015498","name":"Ministry for Innovation and Technology","doi-asserted-by":"publisher","award":["\u00daNKP-21-4-II-SE-1"],"award-info":[{"award-number":["\u00daNKP-21-4-II-SE-1"]}],"id":[{"id":"10.13039\/501100015498","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015498","name":"Ministry for Innovation and Technology","doi-asserted-by":"publisher","award":["\u00daNKP-21-5-BME-362"],"award-info":[{"award-number":["\u00daNKP-21-5-BME-362"]}],"id":[{"id":"10.13039\/501100015498","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018818","name":"National Research, Development and Innovation Office","doi-asserted-by":"publisher","award":["2019-2.1.7-ERA-NET-2020-00005"],"award-info":[{"award-number":["2019-2.1.7-ERA-NET-2020-00005"]}],"id":[{"id":"10.13039\/501100018818","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Thematic Excellence Programme","award":["2020-4.1.1.-TKP2020"],"award-info":[{"award-number":["2020-4.1.1.-TKP2020"]}]},{"name":"Sixth Framework Program of the European Union","award":["LSHM-CT-2004-503474"],"award-info":[{"award-number":["LSHM-CT-2004-503474"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Past-oriented rumination and future-oriented worry are two aspects of perseverative negative thinking related to the neuroticism endophenotype and associated with depression and anxiety. Our present aim was to investigate the genomic background of these two aspects of perseverative negative thinking within separate groups of individuals with suboptimal versus optimal folate intake. We conducted a genome-wide association study in the UK Biobank database (n = 72,621) on the \u201crumination\u201d and \u201cworry\u201d items of the Eysenck Personality Inventory Neuroticism scale in these separate groups. Optimal folate intake was related to lower worry, but unrelated to rumination. In contrast, genetic associations for worry did not implicate specific biological processes, while past-oriented rumination had a more specific genetic background, emphasizing its endophenotypic nature. Furthermore, biological pathways leading to rumination appeared to differ according to folate intake: purinergic signaling and circadian regulator gene ARNTL emerged in the whole sample, blastocyst development, DNA replication, and C-C chemokines in the suboptimal folate group, and prostaglandin response and K+ channel subunit gene KCNH3 in the optimal folate group. Our results point to possible benefits of folate in anxiety disorders, and to the importance of simultaneously taking into account genetic and environmental factors to determine personalized intervention in polygenic and multifactorial disorders.<\/jats:p>","DOI":"10.3390\/nu13124396","type":"journal-article","created":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T23:30:00Z","timestamp":1639006200000},"page":"4396","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Biology of Perseverative Negative Thinking: The Role of Timing and Folate Intake"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4913-028X","authenticated-orcid":false,"given":"Nora","family":"Eszlari","sequence":"first","affiliation":[{"name":"Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, H-1089 Budapest, Hungary"},{"name":"NAP-2-SE New Antidepressant Target Research Group, Hungarian Brain Research Program, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, H-1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bence","family":"Bruncsics","sequence":"additional","affiliation":[{"name":"Department of Measurement and Information Systems, Budapest University of Technology and Economics, Magyar Tud\u00f3sok krt. 2, H-1521 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andras","family":"Millinghoffer","sequence":"additional","affiliation":[{"name":"NAP-2-SE New Antidepressant Target Research Group, Hungarian Brain Research Program, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, H-1089 Budapest, Hungary"},{"name":"Department of Measurement and Information Systems, Budapest University of Technology and Economics, Magyar Tud\u00f3sok krt. 2, H-1521 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabor","family":"Hullam","sequence":"additional","affiliation":[{"name":"Department of Measurement and Information Systems, Budapest University of Technology and Economics, Magyar Tud\u00f3sok krt. 2, H-1521 Budapest, Hungary"},{"name":"MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, H-1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Petschner","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, H-1089 Budapest, Hungary"},{"name":"MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, H-1089 Budapest, Hungary"},{"name":"Bioinformatics Center, Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9015-4203","authenticated-orcid":false,"given":"Xenia","family":"Gonda","sequence":"additional","affiliation":[{"name":"NAP-2-SE New Antidepressant Target Research Group, Hungarian Brain Research Program, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, H-1089 Budapest, Hungary"},{"name":"MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, H-1089 Budapest, Hungary"},{"name":"Department of Psychiatry and Psychotherapy, Semmelweis University, Gyulai P\u00e1l utca 2, H-1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerome","family":"Breen","sequence":"additional","affiliation":[{"name":"Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s 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Sciences, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, H-1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Francis William","family":"Deakin","sequence":"additional","affiliation":[{"name":"Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, The University of Manchester, Oxford Road, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5975-4267","authenticated-orcid":false,"given":"Gabriella","family":"Juhasz","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, H-1089 Budapest, Hungary"},{"name":"MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, H-1089 Budapest, Hungary"},{"name":"SE-NAP 2 Genetic Brain Imaging Migraine Research Group, Hungarian Brain Research Program, Semmelweis University, Nagyv\u00e1rad t\u00e9r 4, H-1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1017\/S1352465818000619","article-title":"Neuroticism and somatic complaints: Concomitant effects of rumination and worry","volume":"47","author":"Denovan","year":"2019","journal-title":"Behav. Cogn. Psychother."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1007\/s10862-013-9374-1","article-title":"Cognitive vulnerability to emotional symptoms: Reconsidering the role of worry and rumination","volume":"36","author":"Merino","year":"2014","journal-title":"J. Psychopathol. Behav. Assess."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s10826-010-9380-9","article-title":"The role of repetitive negative thoughts in the vulnerability for emotional problems in non-clinical children","volume":"20","author":"Broeren","year":"2011","journal-title":"J. Child Fam. Stud."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Merino, H., Senra, C., and Ferreiro, F. (2016). Are worry and rumination specific pathways linking neuroticism and symptoms of anxiety and depression in patients with generalized anxiety disorder, major depressive disorder and mixed anxiety-depressive disorder?. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0156169"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1016\/j.brat.2008.10.002","article-title":"Rumination and worrying as possible mediators in the relation between neuroticism and symptoms of depression and anxiety in clinically depressed individuals","volume":"46","author":"Roelofs","year":"2008","journal-title":"Behav. Res. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.jpsychores.2005.06.074","article-title":"The perseverative cognition hypothesis: A review of worry, prolonged stress-related physiological activation, and health","volume":"60","author":"Brosschot","year":"2006","journal-title":"J. Psychosom. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.cpr.2008.10.003","article-title":"A roadmap to rumination: A review of the definition, assessment, and conceptualization of this multifaceted construct","volume":"29","author":"Smith","year":"2009","journal-title":"Clin. Psychol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/psyp.13082","article-title":"Brain-heart interaction in perseverative cognition","volume":"55","author":"Ottaviani","year":"2018","journal-title":"Psychophysiology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"363","DOI":"10.5127\/jep.038813","article-title":"Are rumination and worry two sides of the same coin? A structural equation modelling approach","volume":"5","author":"Topper","year":"2014","journal-title":"J. Exp. Psychopathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1037\/abn0000430","article-title":"Are rumination and neuroticism genetically or environmentally distinct risk factors for psychopathology?","volume":"128","author":"Rhee","year":"2019","journal-title":"J. Abnorm. Psychol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/s41398-019-0454-1","article-title":"Genome-wide association analysis reveals KCTD12 and miR-383-binding genes in the background of rumination","volume":"9","author":"Eszlari","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3389\/fpsyt.2019.00394","article-title":"Childhood adversity moderates the effects of HTR2A epigenetic regulatory polymorphisms on rumination","volume":"10","author":"Eszlari","year":"2019","journal-title":"Front. Psychiatry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"101780","DOI":"10.1016\/j.cpr.2019.101780","article-title":"The developmental origins of ruminative response style: An integrative review","volume":"74","author":"Shaw","year":"2019","journal-title":"Clin. Psychol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e745","DOI":"10.1038\/tp.2016.19","article-title":"Distinct effects of folate pathway genes MTHFR and MTHFD1L on ruminative response style: A potential risk mechanism for depression","volume":"6","author":"Eszlari","year":"2016","journal-title":"Transl. Psychiatry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1136\/bmj.324.7352.1512","article-title":"Folic acid, ageing, depression, and dementia","volume":"324","author":"Reynolds","year":"2002","journal-title":"BMJ"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1111\/j.1365-277X.2012.01283.x","article-title":"Diet and the risk of unipolar depression in adults: Systematic review of cohort studies","volume":"26","author":"Sanhueza","year":"2013","journal-title":"J. Hum. Nutr. Diet."},{"key":"ref_17","first-page":"vii","article-title":"Folate augmentation of treatment\u2014Evaluation for depression (FolATED): Randomised trial and economic evaluation","volume":"18","author":"Bedson","year":"2014","journal-title":"Health Technol. Assess."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1176\/appi.ajp.2012.11071114","article-title":"L-methylfolate as adjunctive therapy for SSRI-resistant major depression: Results of two randomized, double-blind, parallel-sequential trials","volume":"169","author":"Papakostas","year":"2012","journal-title":"Am. J. Psychiatry"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1177\/0269881104042630","article-title":"Folate for depressive disorders: Systematic review and meta-analysis of randomized controlled trials","volume":"18","author":"Taylor","year":"2004","journal-title":"J. Psychopharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1177\/0269881118756060","article-title":"Caveat emptor: Folate in unipolar depressive illness, a systematic review and meta-analysis","volume":"32","author":"Roberts","year":"2018","journal-title":"J. Psychopharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.neurobiolaging.2005.01.003","article-title":"Folate and the methylenetetrahydrofolate reductase 677C-->T mutation correlate with cognitive performance","volume":"27","author":"Durga","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Smith, D.J., Nicholl, B.I., Cullen, B., Martin, D., Ul-Haq, Z., Evans, J., Gill, J.M., Roberts, B., Gallacher, J., and Mackay, D. (2013). Prevalence and characteristics of probable major depression and bipolar disorder within UK biobank: Cross-sectional study of 172,751 participants. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0075362"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1038\/s41467-018-03242-8","article-title":"Item-level analyses reveal genetic heterogeneity in neuroticism","volume":"9","author":"Nagel","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41586-018-0579-z","article-title":"The UK Biobank resource with deep phenotyping and genomic data","volume":"562","author":"Bycroft","year":"2018","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1038\/s41588-018-0151-7","article-title":"Meta-analysis of genome-wide association studies for neuroticism in 449, 484 individuals identifies novel genetic loci and pathways","volume":"50","author":"Nagel","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9723","DOI":"10.1038\/s41598-019-46001-5","article-title":"The UKB envirome of depression: From interactions to synergistic effects","volume":"9","author":"Hullam","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1998","DOI":"10.1017\/S1368980011000942","article-title":"Development and evaluation of the Oxford WebQ, a low-cost, web-based method for assessment of previous 24 h dietary intakes in large-scale prospective studies","volume":"14","author":"Liu","year":"2011","journal-title":"Public Health Nutr."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1017\/S0007114515004821","article-title":"The acceptability of repeat Internet-based hybrid diet assessment of previous 24-h dietary intake: Administration of the Oxford WebQ in UK Biobank","volume":"115","author":"Galante","year":"2016","journal-title":"Br. J. Nutr."},{"key":"ref_29","unstructured":"John, O.P. (1999). Handbook of Personality: Theory and Research, Guilford Press."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1023\/A:1023910315561","article-title":"Rumination reconsidered: A psychometric analysis","volume":"27","author":"Treynor","year":"2003","journal-title":"Cognit. Ther. Res."},{"key":"ref_31","unstructured":"Derogatis, L.R. (1993). BSI: Brief Symptom Inventory: Administration, Scoring, and Procedures Manual, National Computer Systems Pearson, Inc."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.biopsych.2010.11.019","article-title":"The CREB1-BDNF-NTRK2 pathway in depression: Multiple gene-cognition-environment interactions","volume":"69","author":"Juhasz","year":"2011","journal-title":"Biol. Psychiatry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/ng.3211","article-title":"LD Score regression distinguishes confounding from polygenicity in genome-wide association studies","volume":"47","author":"Loh","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.ajhg.2015.12.022","article-title":"Fast principal-component analysis reveals convergent evolution of ADH1B in Europe and east Asia","volume":"98","author":"Galinsky","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"s13742-015","DOI":"10.1186\/s13742-015-0047-8","article-title":"Second-generation PLINK: Rising to the challenge of larger and richer datasets","volume":"4","author":"Chang","year":"2015","journal-title":"GigaScience"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1038\/s41467-017-01261-5","article-title":"Functional mapping and annotation of genetic associations with FUMA","volume":"8","author":"Watanabe","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"de Leeuw, C.A., Mooij, J.M., Heskes, T., and Posthuma, D. (2015). MAGMA: Generalized Gene-Set Analysis of GWAS Data. PLOS Comput. Biol., 11.","DOI":"10.1371\/journal.pcbi.1004219"},{"key":"ref_38","unstructured":"Human Genomics (2015). The genotype-tissue expression (GTEx) pilot analysis: Multitissue gene regulation in humans. Science, 348, 648\u2013660."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/nature10523","article-title":"Spatio-temporal transcriptome of the human brain","volume":"478","author":"Kang","year":"2011","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"giz082","DOI":"10.1093\/gigascience\/giz082","article-title":"PRSice-2: Polygenic risk score software for biobank-scale data","volume":"8","author":"Choi","year":"2019","journal-title":"Gigascience"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.cpr.2018.06.001","article-title":"Shedding light on the association between repetitive negative thinking and deficits in cognitive control\u2014A meta-analysis","volume":"63","author":"Zetsche","year":"2018","journal-title":"Clin. Psychol. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1176\/appi.ajp.160.4.636","article-title":"The endophenotype concept in psychiatry: Etymology and strategic intentions","volume":"160","author":"Gottesman","year":"2003","journal-title":"Am. J. Psychiatry"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1111\/j.1440-1819.2005.01425.x","article-title":"Serum folate and homocysteine levels in patients with obsessive-compulsive disorder","volume":"59","author":"Atmaca","year":"2005","journal-title":"Psychiatry Clin. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.psychres.2017.04.032","article-title":"Vitamin B12, folic acid, homocysteine and vitamin D levels in children and adolescents with obsessive compulsive disorder","volume":"254","author":"Yaman","year":"2017","journal-title":"Psychiatry Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.clnesp.2019.01.009","article-title":"Association of vitamin B12 mediated hyperhomocysteinemia with depression and anxiety disorder: A cross-sectional study among Bhil indigenous population of India","volume":"30","author":"Saraswathy","year":"2019","journal-title":"Clin. Nutr. ESPEN"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1001\/archpsyc.60.6.618","article-title":"Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: The Hordaland homocysteine study","volume":"60","author":"Bjelland","year":"2003","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1097\/PRA.0000000000000400","article-title":"L-methylfolate calcium supplementation in adolescents and children: A retrospective analysis","volume":"25","author":"Rainka","year":"2019","journal-title":"J. Psychiatr. Pract."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"69","DOI":"10.24869\/psyd.2019.69","article-title":"Double blind controlled study of adding folic acid to fluoxetine in the treatment of OCD","volume":"31","author":"Tural","year":"2019","journal-title":"Psychiatr. Danub."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.jalz.2016.10.003","article-title":"Circadian alterations during early stages of Alzheimer\u2019s disease are associated with aberrant cycles of DNA methylation in BMAL1","volume":"13","author":"Cronin","year":"2017","journal-title":"Alzheimer\u2019s Dement. J. Alzheimer\u2019s Assoc."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1038\/mp.2011.149","article-title":"Adult attention-deficit hyperactivity disorder is associated with alterations in circadian rhythms at the behavioural, endocrine and molecular levels","volume":"17","author":"Baird","year":"2012","journal-title":"Mol. Psychiatry"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/mp.2013.2","article-title":"Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci","volume":"19","author":"Borglum","year":"2014","journal-title":"Mol. Psychiatry"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.jad.2015.07.014","article-title":"Identification of circadian gene variants in bipolar disorder in Latino populations","volume":"186","author":"Gonzalez","year":"2015","journal-title":"J. Affect. Disord."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1080\/07853890701278795","article-title":"Three circadian clock genes Per2, Arntl, and Npas2 contribute to winter depression","volume":"39","author":"Partonen","year":"2007","journal-title":"Ann. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.3109\/07420528.2012.719967","article-title":"CLOCK, PER2 and BMAL1 DNA methylation: Association with obesity and metabolic syndrome characteristics and monounsaturated fat intake","volume":"29","author":"Milagro","year":"2012","journal-title":"Chronobiol. Int."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/npp.2014.173","article-title":"Impaired cognition after stimulation of P2Y1 receptors in the rat medial prefrontal cortex","volume":"40","author":"Koch","year":"2015","journal-title":"Neuropsychopharmacology"},{"key":"ref_56","first-page":"206","article-title":"Integration of neuronal and glial signalling by pyramidal cells of the rat prefrontal cortex; control of cognitive functions and addictive behaviour by purinergic mechanisms","volume":"15","year":"2013","journal-title":"Neuropsychopharmacol. Hung."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1111\/j.1601-183X.2010.00593.x","article-title":"Serotonin transporter gene, childhood emotional abuse and cognitive vulnerability to depression","volume":"9","author":"Antypa","year":"2010","journal-title":"Genes Brain Behav."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1037\/a0016189","article-title":"The BDNF Val66Met polymorphism is associated with rumination in healthy adults","volume":"9","author":"Beevers","year":"2009","journal-title":"Emotion"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1207393","DOI":"10.1155\/2016\/1207393","article-title":"P2Y receptors in synaptic transmission and plasticity: Therapeutic potential in cognitive dysfunction","volume":"2016","author":"Guzman","year":"2016","journal-title":"Neural Plast."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.euroneuro.2010.09.009","article-title":"Epistatic interaction of CREB1 and KCNJ6 on rumination and negative emotionality","volume":"21","author":"Lazary","year":"2011","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e12458","DOI":"10.1111\/gbb.12458","article-title":"P2Y(12) deficiency in mouse impairs noradrenergic system in brain, and alters anxiety-like neurobehavior and memory","volume":"18","author":"Zheng","year":"2019","journal-title":"Genes Brain Behav."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1136\/jnnp.69.2.228","article-title":"Homocysteine, folate, methylation, and monoamine metabolism in depression","volume":"69","author":"Bottiglieri","year":"2000","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"7219","DOI":"10.1523\/JNEUROSCI.0940-08.2008","article-title":"Folate deficiency induces neurodegeneration and brain dysfunction in mice lacking uracil DNA glycosylase","volume":"28","author":"Kronenberg","year":"2008","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.mad.2017.10.001","article-title":"Alzheimer\u2019s disease pathogenesis: Is there a role for folate?","volume":"174","author":"Robinson","year":"2018","journal-title":"Mech. Ageing Dev."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.mrgentox.2018.08.012","article-title":"Folate, genomic stability and colon cancer: The use of single cell gel electrophoresis in assessing the impact of folate in vitro, in vivo and in human biomonitoring","volume":"843","author":"Catala","year":"2019","journal-title":"Mutat. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"300","DOI":"10.3389\/fcell.2019.00300","article-title":"One-carbon metabolism regulates embryonic stem cell fate through epigenetic DNA and histone modifications: Implications for transgenerational metabolic disorders in adults","volume":"7","author":"Ryznar","year":"2019","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1017\/S0007114515002081","article-title":"Prenatal folate, homocysteine and vitamin B(12) levels and child brain volumes, cognitive development and psychological functioning: The generation R study","volume":"122","author":"Ars","year":"2019","journal-title":"Br. J. Nutr."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1002\/bdra.23177","article-title":"Neural tube defects, folate, and immune modulation","volume":"97","author":"Denny","year":"2013","journal-title":"Birth Defects Res. Part A Clin. Mol. Teratol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"S67","DOI":"10.1177\/15648265080292S110","article-title":"The use of blood concentrations of vitamins and their respective functional indicators to define folate and vitamin B12 status","volume":"29","author":"Selhub","year":"2008","journal-title":"Food Nutr. Bull."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.clim.2009.06.008","article-title":"Folate\/homocysteine phenotypes and MTHFR 677C>T genotypes are associated with serum levels of monocyte chemoattractant protein-1","volume":"133","author":"Hammons","year":"2009","journal-title":"Clin. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1586\/ern.09.75","article-title":"Homocysteine, folate and vitamin B12 in neuropsychiatric diseases: Review and treatment recommendations","volume":"9","author":"Stanger","year":"2009","journal-title":"Expert Rev. Neurother."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.clim.2016.09.010","article-title":"An emerging role for eotaxins in neurodegenerative disease","volume":"189","author":"Huber","year":"2018","journal-title":"Clin. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"343","DOI":"10.3389\/fnbeh.2014.00343","article-title":"Homocysteine levels in schizophrenia and affective disorders-focus on cognition","volume":"8","author":"Moustafa","year":"2014","journal-title":"Front. Behav. Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1093\/oxfordjournals.aje.a009439","article-title":"Neurodevelopmental disorders after prenatal famine: The story of the Dutch Famine Study","volume":"147","author":"Susser","year":"1998","journal-title":"Am. J. Epidemiol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Campoy, C., Azaryah, H., Torres-Esp\u00ednola, F.J., Mart\u00ednez-Zald\u00edvar, C., Garc\u00eda-Santos, J.A., Demmelmair, H., Haile, G., Gy\u00f6rei, E., Ram\u00edrez-Tortosa, M.D.C., and Reischl, E. (2020). Long-chain polyunsaturated fatty acids, homocysteine at birth and fatty acid desaturase gene cluster polymorphisms are associated with children\u2019s processing speed up to age 9 years. Nutrients, 13.","DOI":"10.3390\/nu13010131"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1093\/ajcn\/86.3.728","article-title":"Plasma folate concentration and cognitive performance: Rotterdam scan study","volume":"86","author":"Refsum","year":"2007","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"15478","DOI":"10.18632\/aging.103714","article-title":"The impact of folate and vitamin B12 status on cognitive function and brain atrophy in healthy elderly and demented Austrians, a retrospective cohort study","volume":"12","author":"Rabensteiner","year":"2020","journal-title":"Aging"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Smith, A.D., Smith, S.M., de Jager, C.A., Whitbread, P., Johnston, C., Agacinski, G., Oulhaj, A., Bradley, K.M., Jacoby, R., and Refsum, H. (2010). Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: A randomized controlled trial. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012244"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"6874805","DOI":"10.1155\/2019\/6874805","article-title":"Brain hemodynamic intermediate phenotype links vitamin B(12) to cognitive profile of healthy and mild cognitive impaired subjects","volume":"2019","author":"Cecchetti","year":"2019","journal-title":"Neural Plast."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"14637","DOI":"10.1523\/JNEUROSCI.0901-09.2009","article-title":"Disruption of the ether-a-go-go K+ channel gene BEC1\/KCNH3 enhances cognitive function","volume":"29","author":"Miyake","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.1016\/j.cellsig.2006.05.014","article-title":"Interactions between GABA-B1 receptors and Kir 3 inwardly rectifying potassium channels","volume":"18","author":"David","year":"2006","journal-title":"Cell. Signal."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1016\/j.jnutbio.2011.10.006","article-title":"Investigation of the molecular response to folate metabolism inhibition","volume":"23","author":"Carroll","year":"2012","journal-title":"J. Nutr. Biochem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1124\/jpet.116.233239","article-title":"Protective action of anandamide and its COX-2 metabolite against l-homocysteine-induced NLRP3 inflammasome activation and injury in podocytes","volume":"358","author":"Li","year":"2016","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1080\/07315724.2000.10718959","article-title":"The effects of a multivitamin\/mineral supplement on micronutrient status, antioxidant capacity and cytokine production in healthy older adults consuming a fortified diet","volume":"19","author":"McKay","year":"2000","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Nakouzi, G.A., and Nadeau, J.H. (2014). Does dietary folic acid supplementation in mouse NTD models affect neural tube development or gamete preference at fertilization?. BMC Genet., 15.","DOI":"10.1186\/s12863-014-0091-x"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Zhao, M., Yuan, M.M., Yuan, L., Huang, L.L., Liao, J.H., Yu, X.L., Su, C., Chen, Y.H., Yang, Y.Y., and Yu, H. (2018). Chronic folate deficiency induces glucose and lipid metabolism disorders and subsequent cognitive dysfunction in mice. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0202910"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1093\/aje\/kwz165","article-title":"Validation of the Oxford webQ online 24-hour dietary questionnaire using biomarkers","volume":"188","author":"Greenwood","year":"2019","journal-title":"Am. J. Epidemiol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/12\/4396\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:43:41Z","timestamp":1760168621000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/12\/4396"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,8]]},"references-count":87,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["nu13124396"],"URL":"https:\/\/doi.org\/10.3390\/nu13124396","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,8]]}}}