{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T13:09:34Z","timestamp":1778332174979,"version":"3.51.4"},"posted":{"date-parts":[[2025,3,24]]},"group-title":"Addiction Medicine","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T00:00:00Z","timestamp":1742774400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Polysubstance use (PSU) initiation often occurs during adolescence and is associated with increased risk of psychiatric comorbidity and substance use disorders (SUDs), yet factors associated with PSU initiation remain poorly understood. Using the Adolescent Brain Cognitive Development Study (N=9,174; 6-year follow-up), we examined associations of PSU initiation with shared genetic liability, multidimensional environmental exposures, and functional brain connectivity. We found that polygenic risk for shared genetic vulnerability across multiple SUDs, derived from independent adult GWAS, was associated with increased likelihood of PSU initiation. Environmental risk factors for PSU included peer victimization and adverse life events, particularly among adolescents with high genetic susceptibility, whereas parental monitoring and family cohesion were protective. Adolescents who later initiated PSU showed altered subcortical\u2013cortical functional connectivity across development. These findings suggest that adolescent PSU initiation may mark a broader pattern of developmental vulnerability associated with shared genetic liability, environmental adversity, and altered brain network development.<\/jats:p>","DOI":"10.1101\/2025.03.21.25324407","type":"posted-content","created":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T03:58:31Z","timestamp":1742875111000},"source":"Crossref","is-referenced-by-count":0,"title":["Genetic liability, environmental adversity, and brain development predict adolescent polysubstance use initiation"],"prefix":"10.64898","author":[{"given":"Dongmei","family":"Zhi","sequence":"first","affiliation":[{"name":"Center for Addiction Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Psychiatry, Mass General Brigham and Harvard Medical School, Boston, MA 02114, USA"},{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brandon T.","family":"Sanzo","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel H.","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Psychology and Behavioral Neuroscience, Cornell University, Ithaca, NY 14853, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judit","family":"Cabana-Dom\u00ednguez","sequence":"additional","affiliation":[{"name":"Department of Genetics, Microbiology and Statistics, Faculty of Biology, Universitat de Barcelona, Barcelona, Catalunya 08028, Spain"},{"name":"Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d\u2019Hebron Research Institute (VHIR), Universitat Aut\u00f2noma de Barcelona, Barcelona 08035, Spain"},{"name":"Department of Mental Health, Hospital Universitari Vall d\u2019Hebron, Barcelona 08035, Spain"},{"name":"Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid 28029, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noelia","family":"Fern\u00e0ndez-Castillo","sequence":"additional","affiliation":[{"name":"Department of Genetics, Microbiology and Statistics, Faculty of Biology, Universitat de Barcelona, Barcelona, Catalunya 08028, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades raras (CIBERER), Instituto de Salud Carlos III, Madrid 28029, Spain"},{"name":"Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Catalonia 08028, Spain"},{"name":"Institut de Recerca Sant Joan de D\u00e9u, Esplugues de Llobregat, Catalonia 08950, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5318-4382","authenticated-orcid":false,"given":"Bru","family":"Cormand","sequence":"additional","affiliation":[{"name":"Department of Genetics, Microbiology and Statistics, Faculty of Biology, Universitat de Barcelona, Barcelona, Catalunya 08028, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades raras (CIBERER), Instituto de Salud Carlos III, Madrid 28029, Spain"},{"name":"Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Catalonia 08028, Spain"},{"name":"Institut de Recerca Sant Joan de D\u00e9u, Esplugues de Llobregat, Catalonia 08950, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Sui","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing 100875, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rongtao","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT 06510, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"23andMe Research Team","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harrison T.","family":"Reeder","sequence":"additional","affiliation":[{"name":"Biostatistics, Massachusetts General Hospital, Boston, MA 02115, USA"},{"name":"Department of Medicine, Harvard Medical School, 02155, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah A.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Alpert Medical School of Brown University, Providence, Rhode Island, 02903, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. Eden","family":"Evins","sequence":"additional","affiliation":[{"name":"Center for Addiction Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Psychiatry, Mass General Brigham and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3189-6199","authenticated-orcid":false,"given":"Scott E.","family":"Hadland","sequence":"additional","affiliation":[{"name":"Division of Adolescent and Young Adult Medicine, Mass General Brigham for Children, Boston, MA 02114, USA"},{"name":"Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua L.","family":"Roffman","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Mass General Brigham and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard T.","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Mass General Brigham and Harvard Medical School, Boston, MA 02114, USA"},{"name":"Stanly Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jodi M.","family":"Gilman","sequence":"additional","affiliation":[{"name":"Center for Addiction Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Psychiatry, Mass General Brigham and Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1770-3100","authenticated-orcid":false,"given":"Phil H.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Mass General Brigham and Harvard Medical School, Boston, MA 02114, USA"},{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Stanly Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026050905200590000_2025.03.21.25324407v3.1","unstructured":"Organization, W. H. in Lexicon of alcohol and drug terms (1994)."},{"key":"2026050905200590000_2025.03.21.25324407v3.2","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1111\/add.14547","article-title":"Patterns and correlates of polysubstance use among US youth aged 15\u201317 years: wave 1 of the Population Assessment of Tobacco and Health (PATH) Study","volume":"114","year":"2019","journal-title":"Addiction"},{"key":"2026050905200590000_2025.03.21.25324407v3.3","doi-asserted-by":"publisher","DOI":"10.1080\/17523281.2013.786750"},{"key":"2026050905200590000_2025.03.21.25324407v3.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpsychires.2023.09.020"},{"key":"2026050905200590000_2025.03.21.25324407v3.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-026-03618-z"},{"key":"2026050905200590000_2025.03.21.25324407v3.6","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.00569"},{"key":"2026050905200590000_2025.03.21.25324407v3.7","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.15314"},{"key":"2026050905200590000_2025.03.21.25324407v3.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05477-4"},{"key":"2026050905200590000_2025.03.21.25324407v3.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-023-02409-2"},{"key":"2026050905200590000_2025.03.21.25324407v3.10","doi-asserted-by":"crossref","unstructured":"Poore, H. E. et al. Multivariate genetic analyses of 2.2 million individuals reveal broad and substance-specific pathways of addiction risk. Nature Mental Health, 1\u201312 (2026).","DOI":"10.1038\/s44220-026-00608-6"},{"key":"2026050905200590000_2025.03.21.25324407v3.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-021-01209-w"},{"key":"2026050905200590000_2025.03.21.25324407v3.12","doi-asserted-by":"publisher","DOI":"10.1038\/s44220-023-00034-y"},{"key":"2026050905200590000_2025.03.21.25324407v3.13","doi-asserted-by":"publisher","DOI":"10.1101\/2023.04.04.23287779"},{"key":"2026050905200590000_2025.03.21.25324407v3.14","doi-asserted-by":"publisher","DOI":"10.1186\/s12889-021-11906-2"},{"key":"2026050905200590000_2025.03.21.25324407v3.15","doi-asserted-by":"publisher","DOI":"10.1080\/10826084.2025.2505142"},{"key":"2026050905200590000_2025.03.21.25324407v3.16","doi-asserted-by":"publisher","DOI":"10.1080\/10826084.2022.2161319"},{"key":"2026050905200590000_2025.03.21.25324407v3.17","doi-asserted-by":"crossref","first-page":"3866","DOI":"10.1007\/s12144-023-04944-z","article-title":"A meta-analysis study on peer influence and adolescent substance use","volume":"43","year":"2024","journal-title":"Current psychology"},{"key":"2026050905200590000_2025.03.21.25324407v3.18","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-clinpsy-032210-104518"},{"key":"2026050905200590000_2025.03.21.25324407v3.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-025-03396-2"},{"key":"2026050905200590000_2025.03.21.25324407v3.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.pscychresns.2022.111461"},{"key":"2026050905200590000_2025.03.21.25324407v3.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpsc.2024.10.002"},{"key":"2026050905200590000_2025.03.21.25324407v3.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.dcn.2021.101031"},{"key":"2026050905200590000_2025.03.21.25324407v3.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.dcn.2018.02.007"},{"key":"2026050905200590000_2025.03.21.25324407v3.24","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2022.29158"},{"key":"2026050905200590000_2025.03.21.25324407v3.25","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2024.13708"},{"key":"2026050905200590000_2025.03.21.25324407v3.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2019.116091"},{"key":"2026050905200590000_2025.03.21.25324407v3.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2021.06.016"},{"key":"2026050905200590000_2025.03.21.25324407v3.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2013.04.030"},{"key":"2026050905200590000_2025.03.21.25324407v3.29","doi-asserted-by":"publisher","DOI":"10.1037\/0893-164X.19.4.339"},{"key":"2026050905200590000_2025.03.21.25324407v3.30","doi-asserted-by":"publisher","DOI":"10.1037\/0012-1649.43.6.1531"},{"key":"2026050905200590000_2025.03.21.25324407v3.31","doi-asserted-by":"publisher","DOI":"10.1037\/fam0000350"},{"key":"2026050905200590000_2025.03.21.25324407v3.32","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/s40894-019-00130-0","article-title":"Peer influence and adolescent substance use: A systematic review of dynamic social network research","volume":"6","year":"2021","journal-title":"Adolescent research review"},{"key":"2026050905200590000_2025.03.21.25324407v3.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2020.172969"},{"key":"2026050905200590000_2025.03.21.25324407v3.34","doi-asserted-by":"publisher","DOI":"10.1159\/000441777"},{"key":"2026050905200590000_2025.03.21.25324407v3.35","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2017.0028"},{"key":"2026050905200590000_2025.03.21.25324407v3.36","doi-asserted-by":"publisher","DOI":"10.1111\/jcpp.12783"},{"key":"2026050905200590000_2025.03.21.25324407v3.37","unstructured":"Achenbach, T. M. & Rescorla, L. A. Manual for the ASEBA preschool forms and profiles. Vol. 30 (Burlington, VT: University of Vermont, Research center for children, youth \u2026, 2000)."},{"key":"2026050905200590000_2025.03.21.25324407v3.38","doi-asserted-by":"publisher","DOI":"10.1007\/s10519-023-10143-0"},{"key":"2026050905200590000_2025.03.21.25324407v3.39","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/s41562-019-0566-x","article-title":"Genomic SEM provides insights into the multivariate genetic architecture of complex traits","volume":"3","year":"2019","journal-title":"Nat Hum Behav"},{"key":"2026050905200590000_2025.03.21.25324407v3.40","doi-asserted-by":"publisher","DOI":"10.1038\/s41562-019-0566-x"},{"key":"2026050905200590000_2025.03.21.25324407v3.41","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2018.18040369"},{"key":"2026050905200590000_2025.03.21.25324407v3.42","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(20)30339-4"},{"key":"2026050905200590000_2025.03.21.25324407v3.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2019.109667"},{"key":"2026050905200590000_2025.03.21.25324407v3.44","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01335-3"},{"key":"2026050905200590000_2025.03.21.25324407v3.45","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-020-0677-9"},{"key":"2026050905200590000_2025.03.21.25324407v3.46","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0481-0"},{"key":"2026050905200590000_2025.03.21.25324407v3.47","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09718-5"},{"key":"2026050905200590000_2025.03.21.25324407v3.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2023.12.019"},{"key":"2026050905200590000_2025.03.21.25324407v3.49","doi-asserted-by":"publisher","DOI":"10.1101\/2025.07.23.25331227"},{"key":"2026050905200590000_2025.03.21.25324407v3.50","doi-asserted-by":"publisher","DOI":"10.4236\/ojs.2015.57075"},{"key":"2026050905200590000_2025.03.21.25324407v3.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2013.09.006"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.03.21.25324407","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T12:20:17Z","timestamp":1778329217000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.03.21.25324407"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,24]]},"references-count":51,"URL":"https:\/\/doi.org\/10.1101\/2025.03.21.25324407","relation":{},"subject":[],"published":{"date-parts":[[2025,3,24]]},"subtype":"preprint"}}