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We investigated the associations of multiple SDs with different suicidality outcomes, testing how genetic background moderates these associations. The Yale-Penn cohort (<jats:italic>N<\/jats:italic>\u2009=\u200915,557) was recruited to investigate the genetics of SDs. The Army STARRS (Study to Assess Risk and Resilience in Servicemembers) cohort (<jats:italic>N<\/jats:italic>\u2009=\u200911,236) was recruited to evaluate mental health risk and resilience among Army personnel. We applied multivariate logistic regression to investigate the associations of SDs with suicidality and, in the Yale-Penn cohort, we used the structured linear mixed model (StructLMM) to study multivariate gene\u2013environment interactions. In Yale-Penn, lifetime polysubstance dependence was strongly associated with lifetime suicidality: having five SDs showed an association with suicidality, from odds ratio (OR)\u2009=\u20096.77 (95% confidence interval, CI\u2009=\u20095.74\u20137.99) for suicidal ideation (SI) to OR\u2009=\u20093.61 (95% CI\u2009=\u20092.7\u20134.86) for suicide attempt (SA). In Army STARRS, having multiple substance use disorders for alcohol and\/or drugs was associated with increased suicidality ranging from OR\u2009=\u20092.88 (95% CI\u2009=\u20092.6\u20133.19) for SI to OR\u2009=\u20093.92 (95% CI\u2009=\u20093.19\u20134.81) for SA. In Yale-Penn, we identified multivariate gene\u2013environment interactions (Bayes factors, BF\u2009&gt;\u20090) of SI with respect to a gene cluster on chromosome 16 (<jats:italic>LCAT<\/jats:italic>, <jats:italic>p<\/jats:italic>\u2009=\u20091.82\u2009\u00d7\u200910<jats:sup>\u20137<\/jats:sup>; <jats:italic>TSNAXIP1<\/jats:italic>, <jats:italic>p<\/jats:italic>\u2009=\u20092.13\u2009\u00d7\u200910<jats:sup>\u22127<\/jats:sup>; <jats:italic>CENPT<\/jats:italic>, <jats:italic>p<\/jats:italic>\u2009=\u20092.32\u2009\u00d7\u200910<jats:sup>\u22127<\/jats:sup>; <jats:italic>PARD6A<\/jats:italic>, <jats:italic>p<\/jats:italic>\u2009=\u20095.57\u2009\u00d7\u200910<jats:sup>\u22127<\/jats:sup>) for opioid dependence (BF\u2009=\u200912.2), cocaine dependence (BF\u2009=\u200912.1), nicotine dependence (BF\u2009=\u20099.2), and polysubstance dependence (BF\u2009=\u20092.1). Comorbidity of multiple SDs is a significant associated with suicidality and heritability of suicidality is partially moderated by multivariate gene interactions.<\/jats:p>","DOI":"10.1038\/s41398-020-01153-1","type":"journal-article","created":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T14:27:20Z","timestamp":1610375240000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Multi-environment gene interactions linked to the interplay between polysubstance dependence and suicidality"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0745-6046","authenticated-orcid":false,"given":"Renato","family":"Polimanti","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8431-9569","authenticated-orcid":false,"given":"Daniel F.","family":"Levey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gita A.","family":"Pathak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank R.","family":"Wendt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaira Z.","family":"Nunez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1861-9173","authenticated-orcid":false,"given":"Robert J.","family":"Ursano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4831-2305","authenticated-orcid":false,"given":"Ronald C.","family":"Kessler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1018-0450","authenticated-orcid":false,"given":"Henry R.","family":"Kranzler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9564-2871","authenticated-orcid":false,"given":"Murray B.","family":"Stein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4067-1859","authenticated-orcid":false,"given":"Joel","family":"Gelernter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,1,11]]},"reference":[{"key":"1153_CR1","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1111\/ajad.12185","volume":"24","author":"C Yuodelis-Flores","year":"2015","unstructured":"Yuodelis-Flores, C. & Ries, R. 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Dr. Kranzler is paid for his editorial work on the journal Alcoholism: Clinical and Experimental Research. Drs. Kranzler and Gelernter are named as inventors on PCT patent application #15\/878,640 entitled: \u201cGenotype-guided dosing of opioid agonists,\u201d filed January 24, 2018. In the past 3 years, Dr. Kessler was a consultant for Datastat, Inc, Sage Pharmaceuticals, and Takeda. Dr. Murray Stein is paid for his editorial work on the journals Biological Psychiatry and Depression and Anxiety, and the health professional reference Up-To-Date. Drs. Polimanti and Gelernter are paid for their editorial work on the journal Complex Psychiatry. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"34"}}