{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T06:45:30Z","timestamp":1762325130283,"version":"build-2065373602"},"reference-count":33,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T00:00:00Z","timestamp":1634601600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002261","name":"Russian Foundation for Basic Research","doi-asserted-by":"publisher","award":["19-315-90032"],"award-info":[{"award-number":["19-315-90032"]}],"id":[{"id":"10.13039\/501100002261","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Alcohol use disorder (AUD) not only influences individuals and families but also has a lasting social impact on communities at the national level. Dopaminergic neurotransmission is involved in excessive alcohol consumption. Phosphatidylinositol-5-phosphate-4-kinase type 2 \u03b1 (PIP4K2A) plays an important role in the regulation of ascending dopamine pathways. In this study; we determined possible associations between nine polymorphisms in PIP4K2A and AUD in Russian men. Methods: 279 Russian men with AUD were investigated. The control group consisted of 222 healthy men from the general Russian population. Genotyping of DNA samples for nine polymorphic variants of PIP4K2A was carried out by the Applied Biosystems\u2122 QuantStudio\u2122 5 Real-Time PCR System with use of the TaqMan1 Validated SNP Genotyping Assay (Applied Biosystems; CIIIA). Results: Carriage of the PIP4K2A rs2230469*TT\/T genotype\/allele was a relative risk factor for developing AUD in men (p = 0.026 and p = 0.0084 accordingly). Moreover; men with AUD had a higher frequency of PIP4K2A rs746203*T allele (p = 0.023) compared to healthy men. Conclusions: For the first time; we demonstrated different PIP4K2A polymorphisms to be associated with AUD presumably due to dopamine system modulation resulting from regulation of the lateral habenula.<\/jats:p>","DOI":"10.3390\/genes12101642","type":"journal-article","created":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T03:01:13Z","timestamp":1634698873000},"page":"1642","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Association of PIP4K2A Polymorphisms with Alcohol Use Disorder"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9565-6314","authenticated-orcid":false,"given":"Olga Yu.","family":"Fedorenko","sequence":"first","affiliation":[{"name":"Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 634014 Tomsk, Russia"},{"name":"Division for Control and Diagnostics, School of Non-Destructive Testing and Security, National Research Tomsk Polytechnic University, 634050 Tomsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7085-2741","authenticated-orcid":false,"given":"Ekaterina V.","family":"Mikhalitskaya","sequence":"additional","affiliation":[{"name":"Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 634014 Tomsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina A.","family":"Toshchakova","sequence":"additional","affiliation":[{"name":"Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 634014 Tomsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4942-6195","authenticated-orcid":false,"given":"Anton J. M.","family":"Loonen","sequence":"additional","affiliation":[{"name":"PharmacoTherapy, Epidemiology and Economics, Groningen Research Institute of Pharmacy, University of Groningen, 9713AV Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1052-855X","authenticated-orcid":false,"given":"Nikolay A.","family":"Bokhan","sequence":"additional","affiliation":[{"name":"Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 634014 Tomsk, Russia"},{"name":"Department of Psychotherapy and Psychological Counseling, National Research Tomsk State University, 634050 Tomsk, Russia"},{"name":"Department of Psychiatry, Addictology and Psychotherapy, Siberian State Medical University, 634050 Tomsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7078-323X","authenticated-orcid":false,"given":"Svetlana A.","family":"Ivanova","sequence":"additional","affiliation":[{"name":"Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 634014 Tomsk, Russia"},{"name":"Division for Control and Diagnostics, School of Non-Destructive Testing and Security, National Research Tomsk Polytechnic University, 634050 Tomsk, Russia"},{"name":"Department of Psychiatry, Addictology and Psychotherapy, Siberian State Medical University, 634050 Tomsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,19]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2018). Global Status Report on Alcohol and Health 2018, WHO. Available online: https:\/\/apps.who.int\/iris\/bitstream\/handle\/10665\/274603\/9789241565639-eng.pdf."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1017\/S0033291714002165","article-title":"The heritability of alcohol use disorders: A meta-analysis of twin and adoption studies","volume":"45","author":"Verhulst","year":"2015","journal-title":"Psychol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.neuropharm.2017.01.017","article-title":"Genetic studies of alcohol dependence in the context of the addiction cycle","volume":"122","author":"Reilly","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1111\/acer.12792","article-title":"Alcohol Dependence Genetics: Lessons Learned From Genome-Wide Association Studies (GWAS) and Post-GWAS Analyses","volume":"39","author":"Hart","year":"2015","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1017\/neu.2013.27","article-title":"Polymorphisms in genes encoding dopamine signalling pathway and risk of alcohol dependence: A systematic review","volume":"26","author":"Bhaskar","year":"2013","journal-title":"Acta Neuropsychiatr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.drugalcdep.2015.01.017","article-title":"Meta-analysis of six genes (BDNF, DRD1, DRD3, DRD4, GRIN2B and MAOA) involved in neuroplasticity and the risk for alcohol dependence","volume":"149","author":"Forero","year":"2015","journal-title":"Drug Alcohol Depend."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1038\/s41467-019-09480-8","article-title":"Genome-wide association study of alcohol consumption and use disorder in 274,424 individuals from multiple populations","volume":"10","author":"Kranzler","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"eaay5034","DOI":"10.1126\/sciadv.aay5034","article-title":"Functional validity, role, and implications of heavy alcohol consumption genetic loci","volume":"6","author":"Thompson","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1111\/acer.13104","article-title":"Meta-Analysis Reveals Significant Association of the 3\u2032-UTR VNTR in SLC6A3 with Alcohol Dependence","volume":"40","author":"Ma","year":"2016","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1126\/science.278.5335.52","article-title":"Drug Abuse: Hedonic Homeostatic Dysregulation","volume":"278","author":"Koob","year":"1997","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.neubiorev.2017.03.019","article-title":"The role of the habenula in the transition from reward to misery in substance use and mood disorders","volume":"80","author":"Batalla","year":"2017","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1017\/neu.2017.8","article-title":"Circuits regulating pleasure and happiness: Evolution and role in mental disorders","volume":"30","author":"Loonen","year":"2018","journal-title":"Acta Neuropsychiatr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1017\/S1092852917000748","article-title":"Evolution of circuits regulating pleasure and happiness with the habenula in control","volume":"24","author":"Loonen","year":"2019","journal-title":"CNS Spectrums"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s00213-013-3299-y","article-title":"Enzyme activity of the PIP4K2A gene product polymorphism that is implicated in schizophrenia","volume":"230","author":"Clarke","year":"2013","journal-title":"Psychopharmacology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1002\/ajmg.b.30982","article-title":"Association analysis of the PIP4K2A gene on chromosome 10p12 and schizophrenia in the Irish study of high density schizophrenia families (ISHDSF) and the Irish case-control study of schizophrenia (ICCSS)","volume":"153","author":"Thiselton","year":"2010","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref_16","first-page":"58","article-title":"Association of (N251S)-PIP5K2A with schizophrenic disorders: A study of the Russian population of Siberia","volume":"113","author":"Fedorenko","year":"2013","journal-title":"Zhurnal Nevrol. Psikhiatrii Im. SS Korsakova"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"pyu098","DOI":"10.1093\/ijnp\/pyu098","article-title":"Association Study Indicates a Protective Role of Phosphatidylinositol-4-Phosphate-5-Kinase against Tardive Dyskinesia","volume":"18","author":"Fedorenko","year":"2015","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00213-008-1095-x","article-title":"A schizophrenia-linked mutation in PIP5K2A fails to activate neuronal M channels","volume":"199","author":"Fedorenko","year":"2008","journal-title":"Psychopharmacology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1007\/s00213-009-1621-5","article-title":"PIP5K2A-dependent regulation of excitatory amino acid transporter EAAT3","volume":"206","author":"Fedorenko","year":"2009","journal-title":"Psychopharmacology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1007\/s00424-013-1424-8","article-title":"Structural basis of PI(4,5)P2-dependent regulation of GluA1 by phosphatidylinositol-5-phosphate 4-kinase, type II, alpha (PIP5K2A)","volume":"466","author":"Seebohm","year":"2014","journal-title":"Pfl\u00fcgers Archiv-Eur. J. Physiol."},{"key":"ref_21","unstructured":"World Health Organization (2010). International Statistical Classification of Diseases and Health Related Problems ICD-10, World Health Organization. Available online: https:\/\/www.who.int\/classifications\/icd\/ICD10Volume2_en_2010.pdf."},{"key":"ref_22","first-page":"591","article-title":"Enhanced Striatal Dopamine Release to Expectation of Alcohol: A Potential Risk Factor for Alcohol Use Disorder","volume":"3","author":"Kegeles","year":"2018","journal-title":"Biol. Psychiatry Cogn. Neurosci. Neuroimaging"},{"key":"ref_23","first-page":"E3670","article-title":"Independent circuits in the basal ganglia for the evaluation and selection of actions","volume":"110","author":"Kardamakis","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","first-page":"289","article-title":"A basal ganglia circuit for evaluating action outcomes","volume":"539","author":"Yu","year":"2016","journal-title":"Nat. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1016\/j.neuron.2019.12.006","article-title":"Opposing Contributions of GABAergic and Glutamatergic Ventral Pallidal Neurons to Motivational Behaviors","volume":"105","author":"Ahrens","year":"2020","journal-title":"Neuron"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.pbb.2017.06.005","article-title":"The lateral habenula and alcohol: Role of glutamate and M-type potassium channels","volume":"162","author":"Shah","year":"2017","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Nieuwenhuys, R. (1985). The Chemoarchitecture of the Brain, Springer.","DOI":"10.1007\/978-3-642-70426-0"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.2217\/pgs-2019-0100","article-title":"Putative role of pharmacogenetics to elucidate the mechanism of tardive dyskinesia in schizophrenia","volume":"20","author":"Loonen","year":"2019","journal-title":"Pharmacogenomics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1016\/j.cell.2015.04.049","article-title":"A Corticostriatal Path Targeting Striosomes Controls Decision-Making under Conflict","volume":"161","author":"Friedman","year":"2015","journal-title":"Cell"},{"key":"ref_30","first-page":"227","article-title":"Decision making, risky behavior, and alcoholism","volume":"125","author":"Camchong","year":"2014","journal-title":"Frontal Lobes"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.drugalcdep.2017.09.023","article-title":"Decision making measured by the Iowa Gambling Task in alcohol use disorder and gambling disorder: A systematic review and meta-analysis","volume":"181","author":"Richman","year":"2017","journal-title":"Drug Alcohol Depend."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3139","DOI":"10.1007\/s00213-020-05599-5","article-title":"The catechol-O-methyltransferase inhibitor tolcapone modulates alcohol consumption and impulsive choice in alcohol use disorder","volume":"237","author":"Coker","year":"2020","journal-title":"Psychopharmacology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/bs.vh.2014.12.009","article-title":"The Structure and Function of the Dopamine Transporter and its Role in CNS Diseases","volume":"98","author":"McHugh","year":"2015","journal-title":"Vitam. Horm."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/10\/1642\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:18:05Z","timestamp":1760167085000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/10\/1642"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,19]]},"references-count":33,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["genes12101642"],"URL":"https:\/\/doi.org\/10.3390\/genes12101642","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2021,10,19]]}}}