{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T10:26:37Z","timestamp":1787567197533,"version":"build-2736575974"},"reference-count":92,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010232","name":"National Institute of Development Administration","doi-asserted-by":"crossref","award":["U01DA053672"],"award-info":[{"award-number":["U01DA053672"]}],"id":[{"id":"10.13039\/501100010232","id-type":"DOI","asserted-by":"crossref"}]},{"award":["U01DA053672"],"award-info":[{"award-number":["U01DA053672"]}],"id":[{"id":"https:\/\/ror.org\/010g30191","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    We generated time-series data for 105 morphine- and naloxone-related traits across ~700 BXD mice (64 diverse strains for both sexes) for 3 hr after a single morphine injection. Variations in responses were mapped using genome sequencing-based genotypes. The locomotor responses to morphine mapped to the \u00b5 opioid receptor gene (\n                    <jats:italic>Oprm1<\/jats:italic>\n                    ) on chromosome (Chr) 10 with a peak linkage of 12.4 (\u2013logp). The\n                    <jats:italic>B<\/jats:italic>\n                    allele inherited from C57BL\/6J was associated with up to 60% higher activity. This effect climaxed at 75 min but was exhausted by 160 min. A second major modulator of locomotion emerged after approximately 100 min. This locus was located on Chr 16 with peak linkage of 10.6 in females and included one compelling candidate, fibroblast growth factor 12 (\n                    <jats:italic>Fgf12<\/jats:italic>\n                    ). A strong and transient epistatic interaction existed between the\n                    <jats:italic>Oprm1<\/jats:italic>\n                    and\n                    <jats:italic>Fgf12<\/jats:italic>\n                    loci during a short time window (45\u201375 min). In heterogeneous stock rats, we demonstrated that\n                    <jats:italic>Oprm1<\/jats:italic>\n                    and\n                    <jats:italic>Fgf12<\/jats:italic>\n                    were co-expressed in one subtype of Drd1\n                    <jats:sup>+<\/jats:sup>\n                    medium spiny neuron. A Bayesian network analysis supported an\n                    <jats:italic>Oprm1<\/jats:italic>\n                    -to-\n                    <jats:italic>Fgf12<\/jats:italic>\n                    network that involves a MAP kinase cascade that modulates\n                    <jats:italic>FGF12<\/jats:italic>\n                    phosphorylation and locomotor activation.\n                    <jats:italic>OPRM1<\/jats:italic>\n                    and\n                    <jats:italic>FGF12<\/jats:italic>\n                    networks in human genome-wide association study (GWAS) data highlight enrichment of signals associated with substance use disorder. This study represents the first demonstration of a time-dependent epistatic interaction modulating drug response in mammals and the first linkage of\n                    <jats:italic>Fgf12<\/jats:italic>\n                    to opioid-induced behavior.\n                  <\/jats:p>","DOI":"10.7554\/elife.108845","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T14:30:19Z","timestamp":1763044219000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.108845","source":"Crossref","is-referenced-by-count":1,"title":["Acute opioid responses are modulated by dynamic interactions of Oprm1 and Fgf12"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1774-0385","authenticated-orcid":true,"given":"Paige M","family":"Lemen","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0011qv509","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Tennessee Health Science Center","place":["Memphis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Yanning","family":"Zuo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0168r3w48","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, San Diego","place":["San Diego, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8002-7267","authenticated-orcid":true,"given":"Alexander S","family":"Hatoum","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Washington University School of Medicine","place":["St. Louis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Price E","family":"Dickson","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02erqft81","id-type":"ROR","asserted-by":"publisher"}],"name":"Marshall University","place":["Huntington, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Guy","family":"Mittleman","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00k6tx165","id-type":"ROR","asserted-by":"publisher"}],"name":"Ball State University","place":["Muncie, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Arpana","family":"Agrawal","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Washington University School of Medicine","place":["St. Louis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Benjamin C","family":"Reiner","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00b30xv10","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Pennsylvania","place":["Philadelphia, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Wade","family":"Berrettini","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00b30xv10","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Pennsylvania","place":["Philadelphia, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7397-8910","authenticated-orcid":true,"given":"David George","family":"Ashbrook","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0011qv509","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Tennessee Health Science Center","place":["Memphis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Mustafa Hakan","family":"Gunturkun","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0011qv509","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Tennessee Health Science Center","place":["Memphis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Xusheng","family":"Wang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0011qv509","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Tennessee Health Science Center","place":["Memphis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Megan K","family":"Mulligan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0011qv509","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Tennessee Health Science Center","place":["Memphis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Caleb J","family":"Brown","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04a9tmd77","id-type":"ROR","asserted-by":"publisher"}],"name":"Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai","place":["New York, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7905-2000","authenticated-orcid":true,"given":"Eric J","family":"Nestler","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04a9tmd77","id-type":"ROR","asserted-by":"publisher"}],"name":"Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai","place":["New York, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Francesca","family":"Telese","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0168r3w48","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, San Diego","place":["San Diego, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8924-4447","authenticated-orcid":true,"given":"Robert W","family":"Williams","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0011qv509","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Tennessee Health Science Center","place":["Memphis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2680-6921","authenticated-orcid":true,"given":"Hao","family":"Chen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0011qv509","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Tennessee Health Science Center","place":["Memphis, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"4374","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","DOI":"10.1101\/2023.10.16.562623","type":"preprint","article-title":"Chst9 Marks a spatially and transcriptionally unique population of oprm1 -expressing neurons in the nucleus accumbens","volume-title":"bioRxiv","author":"Andraka","year":"2023"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.cels.2020.12.002","type":"journal-article","article-title":"A platform for experimental precision medicine: The extended BXD mouse family","volume":"12","author":"Ashbrook","year":"2021","journal-title":"Cell Systems"},{"key":"bib3","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-021-01775-z","type":"journal-article","article-title":"Risk for opioid misuse in chronic pain patients is associated with endogenous opioid system dysregulation","volume":"12","author":"Ballester","year":"2022","journal-title":"Translational Psychiatry"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/nature24277","type":"journal-article","article-title":"Genetic effects on gene expression across human tissues","volume":"550","author":"Battle","year":"2017","journal-title":"Nature"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1007\/BF01067426","type":"journal-article","article-title":"Quantitative trait loci (QTL) applications to substances of abuse: physical dependence studies with nitrous oxide and ethanol in BXD mice","volume":"23","author":"Belknap","year":"1993","journal-title":"Behavior Genetics"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"L117","DOI":"10.1016\/0024-3205(95)02040-p","type":"journal-article","article-title":"Localization to chromosome 10 of a locus influencing morphine analgesia in crosses derived from C57BL\/6 and DBA\/2 strains","volume":"57","author":"Belknap","year":"1995","journal-title":"Life Sciences"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1007\/s003350020022","type":"journal-article","article-title":"Quantitative trait loci influencing morphine antinociception in four mapping populations","volume":"12","author":"Bergeson","year":"2001","journal-title":"Mammalian Genome"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"229","DOI":"10.31887\/DCNS.2017.19.3\/wberrettini","type":"journal-article","article-title":"A brief review of the genetics and pharmacogenetics of opioid use disorders","volume":"19","author":"Berrettini","year":"2017","journal-title":"Dialogues in Clinical Neuroscience"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1089\/omi.2017.0116","type":"journal-article","article-title":"Identification and validation of fibroblast growth factor 12 gene as a novel potential biomarker in esophageal cancer using cancer genomic datasets","volume":"21","author":"Bhushan","year":"2017","journal-title":"OMICS"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/j.neuroscience.2019.07.030","type":"journal-article","article-title":"Escalated oxycodone self-administration causes differential striatal mrna expression of fgfs and iegs following abstinence-associated incubation of oxycodone craving","volume":"415","author":"Blackwood","year":"2019","journal-title":"Neuroscience"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"4073","DOI":"10.1128\/MCB.22.12.4073-4085.2002","type":"journal-article","article-title":"Interaction of Rac exchange factors Tiam1 and Ras-GRF1 with a scaffold for the p38 mitogen-activated protein kinase cascade","volume":"22","author":"Buchsbaum","year":"2002","journal-title":"Molecular and Cellular Biology"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1002\/ajmg.b.32168","type":"journal-article","article-title":"A genome\u2010wide association study of sleep habits and insomnia","volume":"162","author":"Byrne","year":"2013","journal-title":"American Journal of Medical Genetics Part B"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1016\/j.tig.2018.08.002","type":"journal-article","article-title":"Analysis of epistasis in natural traits using model organisms","volume":"34","author":"Campbell","year":"2018","journal-title":"Trends in Genetics"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1038\/nrg1407","type":"journal-article","article-title":"Epistasis: too often neglected in complex trait studies?","volume":"5","author":"Carlborg","year":"2004","journal-title":"Nature Reviews Genetics"},{"key":"bib15","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0033-21.2021","type":"journal-article","article-title":"The cocaine and oxycodone biobanks","volume":"8","author":"Carrette","year":"2021","journal-title":"eNeuro"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1016\/j.biopsych.2017.12.016","type":"journal-article","article-title":"Genome-wide association study identifies a regulatory variant of RGMA associated with opioid dependence in european americans","volume":"84","author":"Cheng","year":"2018","journal-title":"Biological Psychiatry"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1007\/978-1-0716-0947-7_11","type":"journal-article","article-title":"Brief survey on machine learning in epistasis","volume":"2212","author":"Chicco","year":"2021","journal-title":"Methods in Molecular Biology"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1016\/j.conb.2004.05.005","type":"journal-article","article-title":"Mu opioid receptor: a gateway to drug addiction","volume":"14","author":"Contet","year":"2004","journal-title":"Current Opinion in Neurobiology"},{"key":"bib19","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9010180","type":"journal-article","article-title":"Genome-wide association study of opioid cessation","volume":"9","author":"Cox","year":"2020","journal-title":"Journal of Clinical Medicine"},{"key":"bib20","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/S0022-3565(24)37583-4","type":"journal-article","article-title":"Provisional mapping of quantitative trait loci for chronic ethanol withdrawal severity in BXD recombinant inbred mice","volume":"286","author":"Crabbe","year":"1998","journal-title":"The Journal of Pharmacology and Experimental Therapeutics"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.copsyc.2018.07.014","type":"journal-article","article-title":"A review of opioid addiction genetics","volume":"27","author":"Crist","year":"2019","journal-title":"Current Opinion in Psychology"},{"key":"bib22","doi-asserted-by":"publisher","DOI":"10.1186\/s12920-024-01935-2","type":"journal-article","article-title":"Evidence for a relationship between genetic polymorphisms of the L-DOPA transporter LAT2\/4F2hc and risk of hypertension in the context of chronic kidney disease","volume":"17","author":"Crocco","year":"2024","journal-title":"BMC Medical Genomics"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1038\/nn.3622","type":"journal-article","article-title":"Targeted expression of \u03bc-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward","volume":"17","author":"Cui","year":"2014","journal-title":"Nature Neuroscience"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"3970","DOI":"10.1038\/s41380-022-01709-1","type":"journal-article","article-title":"Genome-wide association study in individuals of European and African ancestry and multi-trait analysis of opioid use disorder identifies 19 independent genome-wide significant risk loci","volume":"27","author":"Deak","year":"2022","journal-title":"Molecular Psychiatry"},{"key":"bib25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1004219","type":"journal-article","article-title":"MAGMA: generalized gene-set analysis of GWAS data","volume":"11","author":"de Leeuw","year":"2015","journal-title":"PLOS Computational Biology"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"3321","DOI":"10.1523\/JNEUROSCI.22-09-03321.2002","type":"journal-article","article-title":"Neural systems underlying opiate addiction","volume":"22","author":"De Vries","year":"2002","journal-title":"The Journal of Neuroscience"},{"key":"bib27","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-11270-0","type":"journal-article","article-title":"Concurrent outcomes from multiple approaches of epistasis analysis for human body mass index associated loci provide insights into obesity biology","volume":"12","author":"D\u2019Silva","year":"2022","journal-title":"Scientific Reports"},{"key":"bib28","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-55554-7","type":"journal-article","article-title":"Enhanced motivated behavior mediated by pharmacological targeting of the FGF14\/Nav1.6\u2009complex in nucleus accumbens neurons","volume":"16","author":"Dvorak","year":"2025","journal-title":"Nature Communications"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"15506","DOI":"10.1073\/pnas.0406788101","type":"journal-article","article-title":"Dysregulation of the fibroblast growth factor system in major depression","volume":"101","author":"Evans","year":"2004","journal-title":"PNAS"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"8742","DOI":"10.1523\/JNEUROSCI.0890-17.2017","type":"journal-article","article-title":"Fibroblast growth factor 2 in the Dorsomedial striatum is a novel positive regulator of alcohol consumption","volume":"37","author":"Even-Chen","year":"2017","journal-title":"The Journal of Neuroscience"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"2552","DOI":"10.1111\/ejn.14133","type":"journal-article","article-title":"The role of fibroblast growth factor 2 in drug addiction","volume":"50","author":"Even-Chen","year":"2019","journal-title":"The European Journal of Neuroscience"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"7947","DOI":"10.1523\/JNEUROSCI.0805-19.2019","type":"journal-article","article-title":"Inhibition of FGF receptor-1 suppresses alcohol consumption: role of PI3 kinase signaling in dorsomedial striatum","volume":"39","author":"Even-Chen","year":"2019","journal-title":"The Journal of Neuroscience"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.cmet.2021.12.024","type":"journal-article","article-title":"FGF21 suppresses alcohol consumption through an amygdalo-striatal circuit","volume":"34","author":"Flippo","year":"2022","journal-title":"Cell Metabolism"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/j.neuroscience.2009.10.009","type":"journal-article","article-title":"Fibroblast growth factor-1 within the ventral tegmental area participates in motor sensitizing effects of morphine","volume":"165","author":"Flores","year":"2010","journal-title":"Neuroscience"},{"key":"bib35","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-21003-y","type":"journal-article","article-title":"Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond","volume":"12","author":"Gaddis","year":"2022","journal-title":"Scientific Reports"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.biopsych.2013.08.034","type":"journal-article","article-title":"Genome-wide association study of opioid dependence: multiple associations mapped to calcium and potassium pathways","volume":"76","author":"Gelernter","year":"2014","journal-title":"Biological Psychiatry"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1016\/j.neuron.2007.07.006","type":"journal-article","article-title":"Fibroblast growth factor homologous factors control neuronal excitability through modulation of voltage-gated sodium channels","volume":"55","author":"Goldfarb","year":"2007","journal-title":"Neuron"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1038\/ng.2653","type":"journal-article","article-title":"The genotype-tissue expression (GTEx) project","volume":"45","author":"GTEx Consortium","year":"2013","journal-title":"Nature Genetics"},{"key":"bib39","doi-asserted-by":"publisher","DOI":"10.1093\/g3journal\/jkac059","type":"journal-article","article-title":"GeneCup: mining PubMed and GWAS catalog for gene-keyword relationships","volume":"12","author":"Gunturkun","year":"2022","journal-title":"G3"},{"key":"bib40","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-019-1874-1","type":"journal-article","article-title":"Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression","volume":"20","author":"Hafemeister","year":"2019","journal-title":"Genome Biology"},{"key":"bib41","doi-asserted-by":"publisher","DOI":"10.1101\/2022.01.06.22268753","type":"preprint","article-title":"Substance use disorder working group of the psychiatric genomics consortium","volume-title":"bioRxiv","author":"Hatoum","year":"2022"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1038\/s41386-021-01209-w","type":"journal-article","article-title":"The addiction risk factor: A unitary genetic vulnerability characterizes substance use disorders and their associations with common correlates","volume":"47","author":"Hatoum","year":"2022","journal-title":"Neuropsychopharmacology"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.ajps.2019.09.002","type":"journal-article","article-title":"The solute carrier transporters and the brain: Physiological and pharmacological implications","volume":"15","author":"Hu","year":"2020","journal-title":"Asian Journal of Pharmaceutical Sciences"},{"key":"bib44","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.1042989","type":"journal-article","article-title":"SLC7A8 coding for LAT2 is associated with early disease progression in osteosarcoma and transports doxorubicin","volume":"13","author":"Hurkmans","year":"2022","journal-title":"Frontiers in Pharmacology"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1007\/s00213-008-1165-0","type":"journal-article","article-title":"Comparison of dopamine D1 and D5 receptor knockout mice for cocaine locomotor sensitization","volume":"200","author":"Karlsson","year":"2008","journal-title":"Psychopharmacology"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1038\/nrd4626","type":"journal-article","article-title":"SLC transporters as therapeutic targets: emerging opportunities","volume":"14","author":"Lin","year":"2015","journal-title":"Nature Reviews Drug Discovery"},{"key":"bib47","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1074\/jbc.M207074200","type":"journal-article","article-title":"Modulation of the cardiac sodium channel Nav1.5 by fibroblast growth factor homologous factor 1B","volume":"278","author":"Liu","year":"2003","journal-title":"The Journal of Biological Chemistry"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/nrg3627","type":"journal-article","article-title":"Epistasis and quantitative traits: using model organisms to study gene-gene interactions","volume":"15","author":"Mackay","year":"2014","journal-title":"Nature Reviews. Genetics"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"10847","DOI":"10.1073\/pnas.0901800106","type":"journal-article","article-title":"Mouse model of OPRM1 (A118G) polymorphism has sex-specific effects on drug-mediated behavior","volume":"106","author":"Mague","year":"2009","journal-title":"PNAS"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.neuroscience.2016.05.046","type":"journal-article","article-title":"Altered brain morphology and functional connectivity reflect a vulnerable affective state after cumulative multigenerational stress in rats","volume":"330","author":"McCreary","year":"2016","journal-title":"Neuroscience"},{"key":"bib51","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/j.cels.2019.03.003","type":"journal-article","article-title":"Doubletfinder: Doublet detection in single-cell rna sequencing data using artificial nearest neighbors","volume":"8","author":"McGinnis","year":"2019","journal-title":"Cell Systems"},{"key":"bib52","doi-asserted-by":"publisher","first-page":"22457","DOI":"10.18632\/aging.104198","type":"journal-article","article-title":"Generalized correlation coefficient for genome-wide association analysis of cognitive ability in twins","volume":"12","author":"Mohammadnejad","year":"2020","journal-title":"Aging"},{"key":"bib53","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1254\/jphs.fpj04039x","type":"journal-article","article-title":"Combined effects of psychostimulants and morphine on locomotor activity in mice","volume":"96","author":"Mori","year":"2004","journal-title":"Journal of Pharmacological Sciences"},{"key":"bib54","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1007\/978-1-4939-6427-7","type":"book-chapter","article-title":"GeneNetwork: a toolbox for systems genetics in","volume-title":"Systems Genetics: Methods and Protocols","author":"Mulligan","year":"2017"},{"key":"bib55","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1046\/j.1471-4159.2001.00599.x","type":"journal-article","article-title":"A comparison of morphine-induced locomotor activity and mesolimbic dopamine release in C57BL6, 129Sv and DBA2 mice","volume":"79","author":"Murphy","year":"2001","journal-title":"Journal of Neurochemistry"},{"key":"bib56","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1038\/mp.2015.102","type":"journal-article","article-title":"Evidence of CNIH3 involvement in opioid dependence","volume":"21","author":"Nelson","year":"2016","journal-title":"Molecular Psychiatry"},{"key":"bib57","doi-asserted-by":"publisher","first-page":"D733","DOI":"10.1093\/nar\/gkv1189","type":"journal-article","article-title":"Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation","volume":"44","author":"O\u2019Leary","year":"2016","journal-title":"Nucleic Acids Research"},{"key":"bib58","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.659012","type":"journal-article","article-title":"Genetic modulation of initial sensitivity to \u03949-tetrahydrocannabinol (THC) among the BXD family of mice","volume":"12","author":"Parks","year":"2021","journal-title":"Frontiers in Genetics"},{"key":"bib59","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1111\/j.1601-183X.2009.00540.x","type":"journal-article","article-title":"High-throughput behavioral phenotyping in the expanded panel of BXD recombinant inbred strains","volume":"9","author":"Philip","year":"2010","journal-title":"Genes, Brain, and Behavior"},{"key":"bib60","doi-asserted-by":"publisher","first-page":"5685","DOI":"10.1523\/JNEUROSCI.2317-18.2019","type":"journal-article","article-title":"Synaptic regulation by OPRM1 variants in reward neurocircuitry","volume":"39","author":"Popova","year":"2019","journal-title":"The Journal of Neuroscience"},{"key":"bib61","type":"software","article-title":"GEMMA","volume-title":"GitHub","author":"Prins","year":"2021","unstructured":"Prins P, Carbonetto P, Zhou X. 2021. GEMMA. GitHub. 0.98.5. https:\/\/github.com\/genetics-statistics\/GEMMA."},{"key":"bib62","doi-asserted-by":"publisher","first-page":"6209","DOI":"10.1038\/s41380-021-01335-3","type":"journal-article","article-title":"Genome-wide association study of problematic opioid prescription use in 132,113 23andMe research participants of European ancestry","volume":"26","author":"Sanchez-Roige","year":"2021","journal-title":"Molecular Psychiatry"},{"key":"bib63","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aba4221","type":"journal-article","article-title":"A dopamine-induced gene expression signature regulates neuronal function and cocaine response","volume":"6","author":"Savell","year":"2020","journal-title":"Science Advances"},{"key":"bib64","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1016\/s0960-9822(01)00232-9","type":"journal-article","article-title":"Fibroblast growth factor homologous factors are intracellular signaling proteins","volume":"11","author":"Schoorlemmer","year":"2001","journal-title":"Current Biology"},{"key":"bib65","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104234","type":"journal-article","article-title":"Modulating effects of FGF12 variants on NaV1.2 and NaV1.6 being associated with developmental and epileptic encephalopathy and Autism spectrum disorder: a case series","volume":"83","author":"Seiffert","year":"2022","journal-title":"EBioMedicine"},{"key":"bib66","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0146-20.2020","type":"journal-article","article-title":"\u03bc-opioid receptors on distinct neuronal populations mediate different aspects of opioid reward-related behaviors","volume":"7","author":"Severino","year":"2020","journal-title":"eNeuro"},{"key":"bib67","doi-asserted-by":"publisher","DOI":"10.1172\/JCI183749","type":"journal-article","article-title":"Sensory neuron-expressed FGF13 controls nociceptive signaling in diabetic neuropathy models","volume":"135","author":"Singh","year":"2025","journal-title":"The Journal of Clinical Investigation"},{"key":"bib68","doi-asserted-by":"publisher","DOI":"10.21105\/joss.00025","type":"journal-article","article-title":"GeneNetwork: framework for web-based genetics","volume":"1","author":"Sloan","year":"2016","journal-title":"The Journal of Open Source Software"},{"key":"bib69","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1124\/jpet.108.150011","type":"journal-article","article-title":"The effects of repeated opioid administration on locomotor activity: I","volume":"330","author":"Smith","year":"2009","journal-title":"Opposing Actions of Mu and Kappa Receptors. J Pharmacol Exp Ther"},{"key":"bib70","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-020-00573-2","type":"journal-article","article-title":"FHF1 is a bona fide fibroblast growth factor that activates cellular signaling in FGFR-dependent manner","volume":"18","author":"Sochacka","year":"2020","journal-title":"Cell Communication and Signaling"},{"key":"bib71","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1038\/s41386-020-00924-0","type":"journal-article","article-title":"Convergent genomic and pharmacological evidence of PI3K\/GSK3 signaling alterations in neurons from schizophrenia patients","volume":"46","author":"Stertz","year":"2021","journal-title":"Neuropsychopharmacology"},{"key":"bib72","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","type":"journal-article","article-title":"Comprehensive integration of single-cell data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"bib73","doi-asserted-by":"publisher","first-page":"629","DOI":"10.3181\/00379727-143-37380","type":"journal-article","article-title":"Genetic analysis of resistance to cadmium-induced testicular damage in mice","volume":"143","author":"Taylor","year":"1973","journal-title":"Proceedings of the Society for Experimental Biology and Medicine"},{"key":"bib74","volume-title":"Opioid AntagonistsStatPearls","author":"Theriot","year":"2022","type":"book"},{"key":"bib75","doi-asserted-by":"publisher","first-page":"32437","DOI":"10.1074\/jbc.273.49.32437","type":"journal-article","article-title":"Identification and characterization of a membrane protein (y+L amino acid transporter-1) that associates with 4F2hc to encode the amino acid transport activity y+L. A candidate gene for lysinuric protein intolerance","volume":"273","author":"Torrents","year":"1998","journal-title":"The Journal of Biological Chemistry"},{"key":"bib76","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/6809","type":"journal-article","article-title":"Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene","volume":"21","author":"Torrents","year":"1999","journal-title":"Nature Genetics"},{"key":"bib77","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s43586-021-00056-9","type":"journal-article","article-title":"Genome-wide association studies","volume":"1","author":"Uffelmann","year":"2021","journal-title":"Nature Reviews Methods Primers"},{"key":"bib78","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1176\/appi.ajp.2012.12020237","type":"journal-article","article-title":"Common genetic variation and antidepressant efficacy in major depressive disorder: a meta-analysis of three genome-wide pharmacogenetic studies","volume":"170","author":"Uher","year":"2013","journal-title":"American Journal of Psychiatry"},{"key":"bib79","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00295","type":"journal-article","article-title":"Programming of dopaminergic neurons by early exposure to sex hormones: Effects on morphine-induced accumbens dopamine release, reward, and locomotor behavior in male and female rats","volume":"10","author":"Vel\u00e1squez","year":"2019","journal-title":"Frontiers in Pharmacology"},{"key":"bib80","doi-asserted-by":"publisher","first-page":"180","DOI":"10.4238\/2015.January.16.1","type":"journal-article","article-title":"Dopamine receptor D1 but not D3 essential for morphine-induced conditioned responses","volume":"14","author":"Wang","year":"2015","journal-title":"Genetics and Molecular Research"},{"key":"bib81","doi-asserted-by":"publisher","DOI":"10.1101\/2020.12.23.424047","type":"preprint","article-title":"Genenetwork: a continuously updated tool for systems genetics analyses","volume-title":"bioRxiv","author":"Watson","year":"2020"},{"key":"bib82","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1038\/nrg3747","type":"journal-article","article-title":"Detecting epistasis in human complex traits","volume":"15","author":"Wei","year":"2014","journal-title":"Nature Reviews. Genetics"},{"key":"bib83","doi-asserted-by":"publisher","first-page":"1288","DOI":"10.1074\/mcp.M114.040055","type":"journal-article","article-title":"Quantitative proteomics reveals protein\u2013protein interactions with fibroblast growth factor 12 as a component of the voltage-gated sodium channel 1.2 (Nav1.2) macromolecular complex in mammalian brain","volume":"14","author":"Wildburger","year":"2015","journal-title":"Molecular & Cellular Proteomics"},{"key":"bib84","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2001-2-11-research0046","type":"journal-article","article-title":"The genetic structure of recombinant inbred mice: high-resolution consensus maps for complex trait analysis","volume":"2","author":"Williams","year":"2001","journal-title":"Genome Biology"},{"key":"bib85","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1016\/0092-8674(94)90026-4","type":"journal-article","article-title":"Elimination of cocaine-induced hyperactivity and dopamine-mediated neurophysiological effects in dopamine D1 receptor mutant mice","volume":"79","author":"Xu","year":"1994","journal-title":"Cell"},{"key":"bib86","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19082164","type":"journal-article","article-title":"General pathways of pain sensation and the major neurotransmitters involved in pain regulation","volume":"19","author":"Yam","year":"2018","journal-title":"International Journal of Molecular Sciences"},{"key":"bib87","doi-asserted-by":"publisher","first-page":"W741","DOI":"10.1093\/nar\/gki475","type":"journal-article","article-title":"WebGestalt: an integrated system for exploring gene sets in various biological contexts","volume":"33","author":"Zhang","year":"2005","journal-title":"Nucleic Acids Research"},{"key":"bib88","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.01078","type":"journal-article","article-title":"Mu opioid receptor heterodimers emerge as novel therapeutic targets: recent progress and future perspective","volume":"11","author":"Zhang","year":"2020","journal-title":"Frontiers in Pharmacology"},{"key":"bib89","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1038\/ng.2310","type":"journal-article","article-title":"Genome-wide efficient mixed-model analysis for association studies","volume":"44","author":"Zhou","year":"2012","journal-title":"Nature Genetics"},{"key":"bib90","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1001\/jamapsychiatry.2020.1206","type":"journal-article","article-title":"Association of OPRM1 functional coding variant with opioid use disorder: a genome-wide association study","volume":"77","author":"Zhou","year":"2020","journal-title":"JAMA Psychiatry"},{"key":"bib91","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1007\/978-1-4939-6427-7_15","type":"journal-article","article-title":"precise network modeling of systems genetics data using the bayesian network webserver","volume":"1488","author":"Ziebarth","year":"2017","journal-title":"Methods in Molecular Biology"},{"key":"dataset1","type":"dataset","article-title":"Opiate responses are controlled by interactions of Oprm1 and Fgf12 loci in the murine BXD family: Correspondence to human GWAS findings","volume-title":"NCBI Gene Expression Omnibus","author":"Zuo","year":"2023","unstructured":"Zuo Y, Telese F, Chen H. 2023. Opiate responses are controlled by interactions of Oprm1 and Fgf12 loci in the murine BXD family: Correspondence to human GWAS findings. NCBI Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE214388. GSE214388."}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/108845\/elife-108845-v1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/108845\/elife-108845-v1.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/108845","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T08:53:49Z","timestamp":1787561629000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/108845"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,29]]},"references-count":92,"alternative-id":["10.7554\/eLife.108845"],"URL":"https:\/\/doi.org\/10.7554\/elife.108845","archive":["CLOCKSS"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.03.11.483993","asserted-by":"subject"}],"is-same-as":[{"id-type":"doi","id":"10.7554\/eLife.108845.3","asserted-by":"subject"}],"is-version-of":[{"id-type":"doi","id":"10.7554\/eLife.108845.1","asserted-by":"subject"},{"id-type":"doi","id":"10.7554\/eLife.108845.2","asserted-by":"subject"}],"is-supplemented-by":[{"id-type":"accession","id":"GSE214388","asserted-by":"subject"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,29]]},"assertion":[{"value":"single anonymised","name":"peer_review_transparency","label":"Peer review transparency","group":{"name":"peer_review_taxonomy"}},{"value":"other reviewer(s), editor","name":"peer_review_interaction","label":"Peer review interaction","group":{"name":"peer_review_taxonomy"}},{"value":"review summaries, review reports, author\/editor communication, reviewer identities reviewer opt in, editor identities","name":"peer_review_published","label":"Peer review published","group":{"name":"peer_review_taxonomy"}},{"value":"open (sign in with ORCID iD required)","name":"post_publication_commenting","label":"Post publication commenting","group":{"name":"post_publication_commenting"}}],"article-number":"RP108845"}}