{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T08:22:45Z","timestamp":1776846165154,"version":"3.51.2"},"posted":{"date-parts":[[2026,4,19]]},"group-title":"Addiction Medicine","reference-count":58,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T00:00:00Z","timestamp":1776556800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Substance use disorders run in families, yet the mechanisms underlying intergenerational transmission remain unclear. We investigated indirect genetic effects, pathways through which parental genotypes influence offspring phenotypes via the family environment, for alcohol use disorder (AUD), nicotine dependence (ND), and related quantitative outcomes, and aimed to identify family environmental factors through which such effects may operate. Using transmitted and non-transmitted polygenic scores (PGS) constructed for problematic alcohol use, tobacco use disorder, and general addiction liability, we analyzed 5972 European-ancestry adult offspring with at least one genotyped parent from the population-based Lifelines cohort (Netherlands). Offspring outcomes included lifetime DSM-5 AUD diagnosis, AUD symptom count, maximum drinks in 24 hours, Fagerstr\u00f6m Test for Nicotine Dependence score, and cigarettes per day. AUD findings were meta-analyzed with data from the Brisbane Longitudinal Twin Study (\n                  <jats:italic>N<\/jats:italic>\n                  = 1368; Australia). We also examined parent-of-origin effects and mediation by parental substance use and socioeconomic status using structural equation modeling. Transmitted PGS robustly predicted all AUD and ND outcomes (\n                  <jats:italic>\u03b2<\/jats:italic>\n                  = 0.07-0.16; OR = 1.20 for AUD diagnosis). Non-transmitted PGS, indexing indirect genetic effects, were negligible for all clinical syndrome outcomes. The only significant indirect genetic effect was on cigarettes per day (\n                  <jats:italic>\u03b2<\/jats:italic>\n                  = 0.03,\n                  <jats:italic>p<\/jats:italic>\n                  = 0.01), mediated by parental smoking behavior but not socioeconomic status. These findings indicate that intergenerational transmission of risk for AUD and ND is driven primarily by direct genetic effects, with modest indirect genetic effects on smoking quantity. Larger samples and cross-trait analyses are needed to further elucidate these mechanisms.\n                <\/jats:p>","DOI":"10.64898\/2026.04.17.26351089","type":"posted-content","created":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T20:20:14Z","timestamp":1776630014000},"source":"Crossref","is-referenced-by-count":0,"title":["Indirect Genetic Effects on Alcohol Use Disorder and Nicotine Dependence"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3923-2362","authenticated-orcid":false,"given":"Mannan","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5779-8285","authenticated-orcid":false,"given":"Vict\u00f3ria","family":"Trindade Pons","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3689-4635","authenticated-orcid":false,"given":"Michael","family":"Zakharin","sequence":"additional","affiliation":[{"name":"Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2557-4716","authenticated-orcid":false,"given":"Jean-Baptiste","family":"Pingault","sequence":"additional","affiliation":[{"name":"Department of Clinical, Educational and Health Psychology, Division of Psychology and Language Sciences, University College London, London, United Kingdom"},{"name":"Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8655-2823","authenticated-orcid":false,"given":"Nathan A.","family":"Gillespie","sequence":"additional","affiliation":[{"name":"Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9282-8053","authenticated-orcid":false,"given":"Hanna M.","family":"van Loo","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the 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