{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T05:57:44Z","timestamp":1785823064861,"version":"3.56.0"},"reference-count":108,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T00:00:00Z","timestamp":1734652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Division of Natural Sciences and Mathematics at Colgate University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background\/Objectives: The circadian clockwork is implicated in the etiology of addiction, with circadian rhythm disruptions bidirectionally linked to substance abuse, but the molecular mechanisms that underlie this connection are not well known. Methods: Here, we use machine learning to reveal sex- and substance-specific associations with addiction in variants from 51 circadian-related genes (156,702 SNPs) in 98,800 participants from a UK Biobank cohort. We further analyze SNP associations in a subset of the cohort for substance-specific addictions (alcohol, illicit drugs (narcotics), and prescription drugs (opioids)). Results: We find robust (OR &gt; 10) and novel sex-specific and substance-specific associations with variants in synaptic transcription factors (ZBTB20, CHRNB3) and hormone receptors (RORA), particularly in individuals addicted to narcotics and opioids. Circadian-related gene variants associated with male and female addiction were non-overlapping; variants in males primarily involve dopaminergic pathways, while variants in females factor in metabolic and inflammation pathways, with a novel gene association of female addiction with DELEC1, a gene of unknown function. Conclusions: Our findings underscore the complexity of genetic pathways associated with addiction, involving core clock genes and circadian-regulated pathways, and reveal novel circadian-related gene associations that will aid the development of targeted, sex-specific therapeutic interventions for substance abuse.<\/jats:p>","DOI":"10.3390\/brainsci14121282","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T02:39:56Z","timestamp":1734921596000},"page":"1282","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Sex- and Substance-Specific Associations of Circadian-Related Genes with Addiction in the UK Biobank Cohort Implicate Neuroplasticity Pathways"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-7964-9441","authenticated-orcid":false,"given":"Ayub","family":"Khan","sequence":"first","affiliation":[{"name":"Department of Biology, Colgate University, Hamilton, NY 13346, USA"},{"name":"Department of Computer Science, Colgate University, Hamilton, NY 13346, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8492-2032","authenticated-orcid":false,"given":"Mete","family":"Minbay","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Colgate University, Hamilton, NY 13346, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziad","family":"Attia","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Colgate University, Hamilton, NY 13346, USA"},{"name":"Department of Mathematics, Colgate University, Hamilton, NY 13346, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmet Ali","family":"Ay","sequence":"additional","affiliation":[{"name":"Department of Biology, Colgate University, Hamilton, NY 13346, USA"},{"name":"Department of Mathematics, Colgate University, Hamilton, NY 13346, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4512-1549","authenticated-orcid":false,"given":"Krista K.","family":"Ingram","sequence":"additional","affiliation":[{"name":"Department of Biology, Colgate University, Hamilton, NY 13346, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1037\/0021-843X.97.2.118","article-title":"The Neurobiology of Craving: Implications for the Understanding and Treatment of Addiction","volume":"97","author":"Wise","year":"1988","journal-title":"J. Abnorm. Psychol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1002\/jnr.23963","article-title":"Sex Differences, Gender and Addiction","volume":"95","author":"Becker","year":"2017","journal-title":"J. Neurosci. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1177\/02698811221089040","article-title":"Regulation of Clock and Clock-Controlled Genes during Morphine Reward and Reinforcement: Involvement of the Period 2 Circadian Clock","volume":"36","author":"Custodio","year":"2022","journal-title":"J. Psychopharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Lin, Y., Wang, S., Zhou, Z., Guo, L., Yu, F., and Wu, B. (2019). Bmal1 Regulates Circadian Expression of Cytochrome P450 3a11 and Drug Metabolism in Mice. Commun. Biol., 2.","DOI":"10.1038\/s42003-019-0607-z"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"van den Oord, E.J.C.G., Xie, L.Y., Zhao, M., Aberg, K.A., and Clark, S.L. (2023). A Single-Nucleus Transcriptomics Study of Alcohol Use Disorder in the Nucleus Accumbens. Addict. Biol., 28.","DOI":"10.1111\/adb.13250"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Saad, L., Zwiller, J., Kalsbeek, A., and Anglard, P. (2021). Epigenetic Regulation of Circadian Clocks and Its Involvement in Drug Addiction. Genes, 12.","DOI":"10.3390\/genes12081263"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.alcohol.2014.09.034","article-title":"Circadian Clock Genes: Effects on Dopamine, Reward and Addiction","volume":"49","author":"Parekh","year":"2015","journal-title":"Alcohol"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/j.cub.2008.04.012","article-title":"Regulation of Monoamine Oxidase A by Circadian-Clock Components Implies Clock Influence on Mood","volume":"18","author":"Hampp","year":"2008","journal-title":"Curr. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1002\/syn.20552","article-title":"Time-of-Day Differences in Dopamine Clearance in the Rat Medial Prefrontal Cortex and Nucleus Accumbens","volume":"62","author":"Sleipness","year":"2008","journal-title":"Synapse"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/nm1163","article-title":"The Clock Gene Per2 Influences the Glutamatergic System and Modulates Alcohol Consumption","volume":"11","author":"Spanagel","year":"2005","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Tamura, E.K., Oliveira-Silva, K.S., Ferreira-Moraes, F.A., Marinho, E.A.V., and Guerrero-Vargas, N.N. (2021). Circadian Rhythms and Substance Use Disorders: A Bidirectional Relationship. Pharmacol. Biochem. Behav., 201.","DOI":"10.1016\/j.pbb.2021.173105"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Challet, E., and Kalsbeek, A. (2017). Editorial: Circadian Rhythms and Metabolism. Front. Endocrinol., 8.","DOI":"10.3389\/fendo.2017.00201"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Croce, P., Quercia, A., Costa, S., and Zappasodi, F. (2018). Circadian Rhythms in Fractal Features of EEG Signals. Front. Physiol., 9.","DOI":"10.3389\/fphys.2018.01567"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1038\/nrendo.2014.78","article-title":"Circadian Clock Control of Endocrine Factors","volume":"10","author":"Gamble","year":"2014","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1152\/physrev.00009.2009","article-title":"Physiology of Circadian Entrainment","volume":"90","author":"Golombek","year":"2010","journal-title":"Physiol. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1126\/science.add0846","article-title":"Sex-Dimorphic and Age-Dependent Organization of 24-Hour Gene Expression Rhythms in Humans","volume":"379","author":"Talamanca","year":"2023","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1080\/07420528.2023.2267677","article-title":"Chronotype Is Associated with Addiction-like Eating Behavior, Mindful Eating and Ultra-Processed Food Intake among Undergraduate Students","volume":"40","year":"2023","journal-title":"Chronobiol. Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"248","DOI":"10.3109\/07420528.2011.553018","article-title":"Influence of Circadian Typology on Drug Consumption, Hazardous Alcohol Use, and Hangover Symptoms","volume":"28","author":"Prat","year":"2011","journal-title":"Chronobiol. Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1080\/07420528.2020.1800028","article-title":"Evening Chronotype, Alcohol Use Disorder Severity, and Emotion Regulation in College Students","volume":"37","author":"Taylor","year":"2020","journal-title":"Chronobiol. Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.bbr.2017.02.024","article-title":"Eveningness among Late Adolescent Males Predicts Neural Reactivity to Reward and Alcohol Dependence 2 Years Later","volume":"327","author":"Hasler","year":"2017","journal-title":"Behav. Brain Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.3109\/07420528.2015.1085062","article-title":"Perceived Morningness\u2013Eveningness Predicts Academic Adjustment and Substance Use across University, but Social Jetlag Is Not to Blame","volume":"32","author":"Tavernier","year":"2015","journal-title":"Chronobiol. Int."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Adane, A., Getnet, M., Belete, M., Yeshaw, Y., and Dagnew, B. (2022). Shift-Work Sleep Disorder among Health Care Workers at Public Hospitals, the Case of Sidama National Regional State, Ethiopia: A Multicenter Cross-Sectional Study. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0270480"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Cousin, L., Roucoux, G., Petit, A.S., Baumann-Coblentz, L., Torrente, O.R., Cannafarina, A., Chassany, O., Duracinsky, M., and Carrieri, P. (2022). Perceived Stigma, Substance Use and Self-Medication in Night-Shift Healthcare Workers: A Qualitative Study. BMC Health Serv. Res., 22.","DOI":"10.1186\/s12913-022-08018-x"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/S0376-8716(01)00126-0","article-title":"Comorbidity between Patterns of Substance Use Dependence and Psychiatric Syndromes","volume":"64","author":"Kandel","year":"2001","journal-title":"Drug Alcohol Depend."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"571","DOI":"10.5665\/sleep.1748","article-title":"PER3 Polymorphism and Insomnia Severity in Alcohol Dependence","volume":"35","author":"Brower","year":"2012","journal-title":"Sleep"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e5720842","DOI":"10.1155\/2017\/5720842","article-title":"Neural Mechanisms of Circadian Regulation of Natural and Drug Reward","volume":"2017","author":"DePoy","year":"2017","journal-title":"Neural Plast."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.cophys.2018.08.004","article-title":"The Intertwined Roles of Circadian Rhythmsand Neuronal Metabolism Fueling Drug Reward and Addiction","volume":"5","author":"Freyberg","year":"2018","journal-title":"Curr. Opin. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.jad.2018.07.080","article-title":"Clock Genes Polymorphisms in Male Bipolar Patients with Comorbid Alcohol Abuse","volume":"241","author":"Banach","year":"2018","journal-title":"J. Affect. Disord."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"645","DOI":"10.15288\/jsad.2017.78.645","article-title":"Addiction and the Role of Circadian Genes","volume":"78","author":"Forde","year":"2017","journal-title":"J. Stud. Alcohol Drugs"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.bbrc.2021.04.053","article-title":"Increase of Cry 1 Expression Is a Common Phenomenon of the Disturbed Circadian Clock in Ischemic Stroke and Opioid Addiction","volume":"558","author":"Roy","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1080\/07420528.2018.1523797","article-title":"Several Clock Genes Polymorphisms Are Meaningful Risk Factors in the Development and Severity of Cannabis Addiction","volume":"36","author":"Saffroy","year":"2019","journal-title":"Chronobiol. Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1740-3391-8-1","article-title":"CLOCK Is Suggested to Associate with Comorbid Alcohol Use and Depressive Disorders","volume":"8","author":"Kovanen","year":"2010","journal-title":"J. Circadian Rhythm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"9377","DOI":"10.1073\/pnas.0503584102","article-title":"Regulation of Dopaminergic Transmission and Cocaine Reward by the Clock Gene","volume":"102","author":"McClung","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1038\/mp.2017.153","article-title":"Genome-Wide Association Study of Alcohol Consumption and Genetic Overlap with Other Health-Related Traits in UK Biobank (N = 112 117)","volume":"22","author":"Clarke","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"109128","DOI":"10.1016\/j.drugalcdep.2021.109128","article-title":"Prevalence of Insomnia Symptoms and Associated Risk Factors in UK Biobank Participants with Hazardous Alcohol Use and Major Depression","volume":"229","author":"Kolla","year":"2021","journal-title":"Drug Alcohol Depend."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"115948","DOI":"10.1016\/j.psychres.2024.115948","article-title":"Sex-Specific Associations between Circadian-Related Genes and Depression in UK Biobank Participants Highlight Links to Glucose Metabolism, Inflammation and Neuroplasticity Pathways","volume":"337","author":"Minbay","year":"2024","journal-title":"Psychiatry Res."},{"key":"ref_37","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_38","doi-asserted-by":"crossref","first-page":"1.30.1","DOI":"10.1002\/cpbi.5","article-title":"The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses","volume":"54","author":"Stelzer","year":"2016","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1111\/adb.12660","article-title":"Cannabidiol Affects Circadian Clock Core Complex and Its Regulation in Microglia Cells","volume":"24","author":"Lafaye","year":"2019","journal-title":"Addict. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e17171","DOI":"10.7554\/eLife.17171","article-title":"Loss of ZBTB20 Impairs Circadian Output and Leads to Unimodal Behavioral Rhythms","volume":"5","author":"Qu","year":"2016","journal-title":"eLife"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/s41398-023-02409-2","article-title":"Multi-Trait Genome-Wide Association Analyses Leveraging Alcohol Use Disorder Findings Identify Novel Loci for Smoking Behaviors in the Million Veteran Program","volume":"13","author":"Cheng","year":"2023","journal-title":"Transl. Psychiatry"},{"key":"ref_42","first-page":"9","article-title":"The UK Biobank Data Parser: A Tool with Built in and Customizable Filters for Brain Studies","volume":"6","author":"Zhu","year":"2019","journal-title":"Organ. Hum. Brain Mapp. Rome Italy"},{"key":"ref_43","unstructured":"Cram\u00e9r, H. (1991). Mathematical Methods of Statistics, Princeton University Press."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1080\/01621459.1992.10475190","article-title":"Generalized Collinearity Diagnostics","volume":"87","author":"Fox","year":"1992","journal-title":"J. Am. Stat. Assoc."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Bastian, M., Heymann, S., and Jacomy, M. (2009, January 17\u201320). Gephi: An Open Source Software for Exploring and Manipulating Networks. Proceedings of the International AAAI Conference on Web and Social Media, San Jose, CA, USA.","DOI":"10.1609\/icwsm.v3i1.13937"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v059.i05","article-title":"Mediation: R Package for Causal Mediation Analysis","volume":"59","author":"Tingley","year":"2014","journal-title":"J. Stat. Softw."},{"key":"ref_47","first-page":"2021","article-title":"The Arules R-Package Ecosystem: Analyzing Interesting Patterns from Large Transaction Data Sets","volume":"12","author":"Hahsler","year":"2011","journal-title":"J. Mach. Learn. Res."},{"key":"ref_48","unstructured":"Cs\u00e1rdi, G., Nepusz, T., Traag, V., Horv\u00e1t, S., Zanini, F., Noom, D., and M\u00fcller, K. (2024, November 10). Igraph: Network Analysis and Visualization in R; R Package Version 2.1.2. Available online: https:\/\/CRAN.R-project.org\/package=igraph."},{"key":"ref_49","unstructured":"Smith, A.B. (2024, November 10). Adamlilith\/Legendary 2023. Available online: https:\/\/github.com\/adamlilith\/enmSdm."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Cheng, Z., Peng, Y., Wen, J., Chen, W., Pan, W., Xu, X., Lu, X., Cai, Q., Ge, F., and Fan, Y. (2023). Sex-Specific Metabolic Signatures in Methamphetamine Addicts. Addict. Biol., 28.","DOI":"10.1111\/adb.13255"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1523\/JNEUROSCI.1830-20.2020","article-title":"Circadian-Dependent and Sex-Dependent Increases in Intravenous Cocaine Self-Administration in Npas2 Mutant Mice","volume":"41","author":"DePoy","year":"2021","journal-title":"J. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s00213-022-06247-w","article-title":"Sexually Dimorphic Role of Circadian Clock Genes in Alcohol Drinking Behavior","volume":"240","author":"Ferraro","year":"2023","journal-title":"Psychopharmacology"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Foo, J.C., Skorodumov, I., Spanagel, R., and Meinhardt, M.W. (2023). Sex- and Age-Specific Effects on the Development of Addiction and Compulsive-like Drinking in Rats. Biol. Sex. Differ., 14.","DOI":"10.1186\/s13293-023-00529-4"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3117","DOI":"10.1038\/s41380-024-02569-7","article-title":"Cell-Type and Sex-Specific Rhythmic Gene Expression in the Nucleus Accumbens","volume":"29","author":"DePoy","year":"2024","journal-title":"Mol. Psychiatry"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Falcon, E., Ozburn, A., Mukherjee, S., Roybal, K., and McClung, C.A. (2013). Differential Regulation of the Period Genes in Striatal Regions Following Cocaine Exposure. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0066438"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2001","DOI":"10.2217\/pgs.14.145","article-title":"Dopaminergic Pathway Polymorphisms and Heroin Addiction: Further Support for Association of CSNK1E Variants","volume":"15","author":"Levran","year":"2014","journal-title":"Pharmacogenomics"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Levran, O., Randesi, M., Rotrosen, J., Ott, J., Adelson, M., and Kreek, M.J. (2019). A 3\u2019 UTR SNP Rs885863, a Cis-eQTL for the Circadian Gene VIPR2 and lincRNA 689, Is Associated with Opioid Addiction. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0224399"},{"key":"ref_58","first-page":"517","article-title":"The Effect of Chronic Morphine or Methadone Exposure and Withdrawal on Clock Gene Expression in the Rat Suprachiasmatic Nucleus and AA-NAT Activity in the Pineal Gland","volume":"65","year":"2016","journal-title":"Physiol. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"7929","DOI":"10.1007\/s12035-019-01650-5","article-title":"Opioid-Induced Hyperalgesia Is Associated with Dysregulation of Circadian Rhythm and Adaptive Immune Pathways in the Mouse Trigeminal Ganglia and Nucleus Accumbens","volume":"56","author":"Zhang","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e73","DOI":"10.1038\/tp.2011.71","article-title":"A Promoter Polymorphism in the Per3 Gene Is Associated with Alcohol and Stress Response","volume":"2","author":"Wang","year":"2012","journal-title":"Transl. Psychiatry"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1111\/j.1601-183X.2007.00314.x","article-title":"Association of the 54-Nucleotide Repeat Polymorphism of hPer3 with Heroin Dependence in Han Chinese Population","volume":"7","author":"Zou","year":"2008","journal-title":"Genes. Brain Behav."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1007\/s00439-013-1388-y","article-title":"Association of the HTR2A Gene with Alcohol and Heroin Abuse","volume":"133","author":"Cao","year":"2014","journal-title":"Hum. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.brainres.2010.08.064","article-title":"Association Study of Polymorphisms in the Promoter Region of DRD4 with Schizophrenia, Depression, and Heroin Addiction","volume":"1359","author":"Lai","year":"2010","journal-title":"Brain Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.alcohol.2013.08.004","article-title":"Gene Expression within the Extended Amygdala of 5 Pairs of Rat Lines Selectively Bred for High or Low Ethanol Consumption","volume":"47","author":"McBride","year":"2013","journal-title":"Alcohol"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Takahashi, M., Tahara, Y., Tsubosaka, M., Fukazawa, M., Ozaki, M., Iwakami, T., Nakaoka, T., and Shibata, S. (2018). Chronotype and Social Jetlag Influence Human Circadian Clock Gene Expression. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-28616-2"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Ingram, K.K., Ay, A., Kwon, S.B., Woods, K., Escobar, S., Gordon, M., Smith, I.H., Bearden, N., Filipowicz, A., and Jain, K. (2016). Molecular Insights into Chronotype and Time-of-Day Effects on Decision-Making. Sci. Rep., 6.","DOI":"10.1038\/srep29392"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1177\/0748730420935328","article-title":"Genetic Associations of Chronotype in the Finnish General Population","volume":"35","author":"Maukonen","year":"2020","journal-title":"J. Biol. Rhythm."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"807","DOI":"10.3109\/07420528.2014.906445","article-title":"Association between Circadian Genes, Bipolar Disorders and Chronotypes","volume":"31","author":"Etain","year":"2014","journal-title":"Chronobiol. Int."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1080\/15592294.2020.1827719","article-title":"Adolescent Sleep Timing and Dietary Patterns in Relation to DNA Methylation of Core Circadian Genes: A Pilot Study of Mexican Youth","volume":"16","author":"Jansen","year":"2021","journal-title":"Epigenetics"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.30773\/pi.2020.0358","article-title":"Association of the Serotonin 2A Receptor Rs6311 Polymorphism with Diurnal Preference in Koreans","volume":"17","author":"Yeom","year":"2020","journal-title":"Psychiatry Investig."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Jones, K.A., Luo, Y., Dukes-Rimsky, L., Srivastava, D.P., Koul-Tewari, R., Russell, T.A., Shapiro, L.P., Srivastava, A.K., and Penzes, P. (2018). Neurodevelopmental Disorder-Associated ZBTB20 Gene Variants Affect Dendritic and Synaptic Structure. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0203760"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"5302","DOI":"10.1038\/s41467-020-18489-3","article-title":"Genome-Wide Association Study of Smoking Trajectory and Meta-Analysis of Smoking Status in 842,000 Individuals","volume":"11","author":"Xu","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/s41398-018-0246-z","article-title":"Genome-Wide Association Study of Seasonal Affective Disorder","volume":"8","author":"Ho","year":"2018","journal-title":"Transl. Psychiatry"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Dang, T., Russel, W.A., Saad, T., Dhawka, L., Ay, A., and Ingram, K.K. (2023). Risk for Seasonal Affective Disorder (SAD) Linked to Circadian Clock Gene Variants. Biology, 12.","DOI":"10.3390\/biology12121532"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"agad093","DOI":"10.1093\/alcalc\/agad093","article-title":"A High-Resolution PheWAS Approach to Alcohol-Related Polygenic Risk Scores Reveals Mechanistic Influences of Alcohol Reinforcing Value and Drinking Motives","volume":"59","author":"Deng","year":"2024","journal-title":"Alcohol Alcohol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s11920-018-0873-3","article-title":"Human Genetics of Addiction: New Insights and Future Directions","volume":"20","author":"Hancock","year":"2018","journal-title":"Curr. Psychiatry Rep."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Sadler, B., Haller, G., Agrawal, A., Culverhouse, R., Bucholz, K., Brooks, A., Tischfield, J., Johnson, E.O., Edenberg, H., and Schuckit, M. (2014). Variants near CHRNB3-CHRNA6 Are Associated with DSM-5 Cocaine Use Disorder: Evidence for Pleiotropy. Sci. Rep., 4.","DOI":"10.1038\/srep04497"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Wen, L., Han, H., Liu, Q., Su, K., Yang, Z., Cui, W., Yuan, W., Ma, Y., Fan, R., and Chen, J. (2017). Significant Association of the CHRNB3-CHRNA6 Gene Cluster with Nicotine Dependence in the Chinese Han Population. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-09492-8"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e843","DOI":"10.1038\/tp.2016.103","article-title":"Crucial Roles of the CHRNB3\u2013CHRNA6 Gene Cluster on Chromosome 8 in Nicotine Dependence: Update and Subjects for Future Research","volume":"6","author":"Wen","year":"2016","journal-title":"Transl. Psychiatry"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1097\/WNR.0000000000002033","article-title":"Inhibition of SIRT1 in the Nucleus Accumbens Attenuates Heroin Addiction-Related Behavior by Decreasing D1 Neuronal Autophagy","volume":"35","author":"Huang","year":"2024","journal-title":"Neuroreport"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3789","DOI":"10.12659\/MSM.910550","article-title":"Effect of Sirtuin-1 on Synaptic Plasticity in Nucleus Accumbens in a Rat Model of Heroin Addiction","volume":"24","author":"Xia","year":"2018","journal-title":"Med. Sci. Monit."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1038\/s41386-018-0125-6","article-title":"Sex Differences in Neural Mechanisms Mediating Reward and Addiction","volume":"44","author":"Becker","year":"2019","journal-title":"Neuropsychopharmacology"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"108491","DOI":"10.1016\/j.neuropharm.2021.108491","article-title":"Sex Differences in Vulnerability to Addiction","volume":"187","author":"Quigley","year":"2021","journal-title":"Neuropharmacology"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.drugalcdep.2013.09.009","article-title":"Sex Differences in the Effects of Estradiol in the Nucleus Accumbens and Striatum on the Response to Cocaine: Neurochemistry and Behavior","volume":"135","author":"Cummings","year":"2014","journal-title":"Drug Alcohol. Depend."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.biopsycho.2016.05.002","article-title":"Prediction of Alcohol Drinking in Adolescents: Personality-Traits, Behavior, Brain Responses, and Genetic Variations in the Context of Reward Sensitivity","volume":"118","author":"Heinrich","year":"2016","journal-title":"Biol. Psychol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1038\/npp.2011.122","article-title":"A Genomewide Linkage Scan of Cocaine Dependence and Major Depressive Episode in Two Populations","volume":"36","author":"Yang","year":"2011","journal-title":"Neuropsychopharmacology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1176\/appi.ajp.2011.10111579","article-title":"Effects of the Circadian Rhythm Gene Period 1 (Per1) on Psychosocial Stress-Induced Alcohol Drinking","volume":"168","author":"Dong","year":"2011","journal-title":"AJP"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1111\/j.1369-1600.2011.00342.x","article-title":"Ethanol Consumption and Pineal Melatonin Daily Profile in Rats","volume":"16","author":"Peres","year":"2011","journal-title":"Addict. Biol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1177\/07487304221141464","article-title":"Chronic Alcohol Consumption Disrupts the Skeletal Muscle Circadian Clock in Female Mice","volume":"38","author":"Tice","year":"2023","journal-title":"J. Biol. Rhythm."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/s41398-023-02605-0","article-title":"Brain Proteomic Atlas of Alcohol Use Disorder in Adult Males","volume":"13","author":"Teng","year":"2023","journal-title":"Transl. Psychiatry"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/s41398-022-01894-1","article-title":"Molecular Rhythm Alterations in Prefrontal Cortex and Nucleus Accumbens Associated with Opioid Use Disorder","volume":"12","author":"Xue","year":"2022","journal-title":"Transl. Psychiatry"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1002\/syn.21822","article-title":"The Effect of Dopamine D4 Receptor Density on Novelty Seeking, Activity, Social Interaction, and Alcohol Binge Drinking in Adult Mice","volume":"69","author":"Thanos","year":"2015","journal-title":"Synapse"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1111\/j.1465-3362.2008.00023.x","article-title":"Hormones and Drinking Behaviour: New Findings on Ghrelin, Insulin, Leptin and Volume-Regulating Hormones. An ESBRA Symposium Report","volume":"28","author":"Addolorato","year":"2009","journal-title":"Drug Alcohol Rev."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1093\/alcalc\/agaa044","article-title":"The Impact of Appetite-Regulating Neuropeptide Leptin on Alcohol Use, Alcohol Craving and Addictive Behavior: A Systematic Review of Preclinical and Clinical Data","volume":"56","author":"Bach","year":"2021","journal-title":"Alcohol Alcohol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"342","DOI":"10.2337\/diab.46.3.342","article-title":"Depot- and Sex-Specific Differences in Human Leptin mRNA Expression: Implications for the Control of Regional Fat Distribution","volume":"46","author":"Montague","year":"1997","journal-title":"Diabetes"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1111\/j.1601-183X.2008.00410.x","article-title":"Genetic Susceptibility to Heroin Addiction; a Candidate-Gene Association Study","volume":"7","author":"Levran","year":"2008","journal-title":"Genes Brain Behav."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1038\/npp.2011.287","article-title":"Csnk1e Is a Genetic Regulator of Sensitivity to Psychostimulants and Opioids","volume":"37","author":"Bryant","year":"2012","journal-title":"Neuropsychopharmacology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/S2215-0366(18)30139-1","article-title":"Association of Disrupted Circadian Rhythmicity with Mood Disorders, Subjective Wellbeing, and Cognitive Function: A Cross-Sectional Study of 91\u2013105 Participants from the UK Biobank","volume":"5","author":"Lyall","year":"2018","journal-title":"Lancet Psychiatry"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"5172","DOI":"10.1038\/s41467-023-40977-5","article-title":"Diurnal Rhythms of Wrist Temperature Are Associated with Future Disease Risk in the UK Biobank","volume":"14","author":"Brooks","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Wainberg, M., Jones, S.E., Beaupre, L.M., Hill, S.L., Felsky, D., Rivas, M.A., Lim, A.S.P., Ollila, H.M., and Tripathy, S.J. (2021). Association of Accelerometer-Derived Sleep Measures with Lifetime Psychiatric Diagnoses: A Cross-Sectional Study of 89,205 Participants from the UK Biobank. PLoS Med., 18.","DOI":"10.1371\/journal.pmed.1003782"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"R93","DOI":"10.1530\/JME-19-0153","article-title":"Circadian Clock Genes and the Transcriptional Architecture of the Clock Mechanism","volume":"63","author":"Cox","year":"2019","journal-title":"J. Mol. Endocrinol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1093\/aje\/kwx246","article-title":"Comparison of Sociodemographic and Health-Related Characteristics of UK Biobank Participants with Those of the General Population","volume":"186","author":"Fry","year":"2017","journal-title":"Am. J. Epidemiol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1093\/bioinformatics\/btm025","article-title":"SNPassoc: An R package to perform whole genome association studies","volume":"23","author":"Armengol","year":"2007","journal-title":"Bioinformatics"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Koren\u010di\u010d, A., Ko\u0161ir, R., Bordyugov, G., Lehmann, R., Rozman, D., and Herzel, H. (2014). Timing of circadian genes in mammalian tissues. Sci. Rep., 4.","DOI":"10.1038\/srep05782"},{"key":"ref_105","first-page":"2825","article-title":"Scikit-learn: Machine learning in Python","volume":"12","author":"Pedregosa","year":"2011","journal-title":"J. Mach. Learn. Res."},{"key":"ref_106","unstructured":"R Core Team (2024, November 09). R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing. Available online: https:\/\/www.R-project.org\/."},{"key":"ref_107","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 (Methodol.)"},{"key":"ref_108","first-page":"3","article-title":"SciPy 1.0: Fundamental algorithms for scientific computing in Python","volume":"17","author":"Virtanen","year":"2020","journal-title":"Nat. Methods"}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/14\/12\/1282\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:57:11Z","timestamp":1760115431000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/14\/12\/1282"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,20]]},"references-count":108,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["brainsci14121282"],"URL":"https:\/\/doi.org\/10.3390\/brainsci14121282","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,20]]}}}