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Coaggregation of SUDs has familial contributions, with twin studies suggesting a strong contribution of additive genetic influences undergirding use disorders for a variety of substances (including alcohol, nicotine, cannabis, and others). GWAS have documented similarly large genetic correlations between alcohol, cannabis, and opioid use disorders. Extending these findings, recent studies have identified multiple genomic loci that contribute to common risk for these SUDs and problematic tobacco use, implicating dopaminergic regulatory and neuronal development mechanisms in the pathophysiology of generalized SUD genetic liability, with certain signals demonstrating cross-species and translational validity. Overlap with genetic signals for other externalizing behaviors, while substantial, does not explain the entirety of the generalized genetic signal for SUD. Polygenic scores (PGS) derived from the generalized genetic liability to SUDs outperform PGS for individual SUDs in prediction of serious mental health and medical comorbidities. Going forward, it will be important to further elucidate the etiology of generalized SUD genetic liability by incorporating additional SUDs, evaluating clinical presentation across the lifespan, and increasing the granularity of investigation (e.g., specific transdiagnostic criteria) to ultimately improve the nosology, prevention, and treatment of SUDs.<\/jats:p>","DOI":"10.1172\/jci172881","type":"journal-article","created":{"date-parts":[[2024,6,2]],"date-time":"2024-06-02T14:00:32Z","timestamp":1717336832000},"source":"Crossref","is-referenced-by-count":19,"title":["Generalized genetic liability to substance use disorders"],"prefix":"10.1172","volume":"134","author":[{"given":"Alex P.","family":"Miller","sequence":"first","affiliation":[{"name":"Department of Psychiatry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Bogdan","sequence":"additional","affiliation":[{"name":"Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arpana","family":"Agrawal","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander S.","family":"Hatoum","sequence":"additional","affiliation":[{"name":"Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2024,6,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(18)30337-7"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31310-2"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(15)00508-8"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.addbeh.2019.106128"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)61611-6"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1017\/S0033291714002888"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/add.16290"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.euroneuro.2017.06.004"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1002\/hup.2625"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2015.2132"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2018.10.010"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.107336"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1186\/s12888-019-2077-8"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/j.1360-0443.2010.02902.x"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2020.107986"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2018.07.025"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-020-00949-3"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.addbeh.2006.03.015"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2008.06.014"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2013.12.011"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2009.07.027"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2014.01.022"},{"key":"B23"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2013.12060782"},{"key":"B25","unstructured":"World Health Organization. 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