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Complex multi-environment gene interactions linked to the interplay between polysubstance dependence and suicidal behaviors

By Renato Polimanti, Daniel F Levey, Gita A. Pathak, Frank R Wendt, Yaira Z. Nunez, Robert J Ursano, Ronald C Kessler, Henry R. Kranzler, Murray B Stein, Joel Gelernter

Posted 18 Jan 2020
medRxiv DOI: 10.1101/2020.01.14.20017509

Background and AimsSubstance dependence diagnoses (SDs) are important risk factors for suicidal behaviors. We investigated the associations of multiple SDs with different suicidal behaviors and tested how genetic background moderates these associations. DesignMultivariate logistic regression to investigate the associations of SDs with suicidal behaviors; structured linear mixed model to study multivariate gene- environment interactions. SettingThe Yale-Penn cohort was recruited to investigate the genetics of SDs. The Army STARRS (Study to Assess Risk and Resilience in Servicemembers) cohort was recruited to evaluate mental health risk and resilience for suicidal behaviors among Army personnel. ParticipantsYale-Penn participants (N=15,557) were assessed via the Semi-Structured Assessment for Drug Dependence and Alcoholism. Army STARRS participants (N=11,236) were evaluated using the self-administered Composite International Diagnostic Interview Screening Scales. MeasurementLifetime self-reported suicidal behaviors (ideation, SI; planning; attempt, SA); Lifetime DSM-IV diagnoses and criteria for dependence on alcohol, cannabis, cocaine (CoD), opioid (OD), and nicotine (ND) (Yale-Penn); substance use disorder (SUD) (Army STARRS). FindingsIn Yale-Penn, lifetime polysubstance dependence was strongly associated with lifetime suicidal behaviors: individuals with five SDs showed increased odds ranging from OR=6.77 (95%CI=5.74-7.99) for SI to OR=3.61 (95%CI=2.7-4.86) for SA. In Army STARRS, SUD was associated with increased odds ranging from OR=2.88 (95%CI=2.6-3.19) for SI to OR=3.92 (95%CI=3.19-4.81) for SA. In Yale-Penn, we identified multivariate gene-environment interactions (Bayes factors, BF > 0) of SI with respect to a gene cluster on chromosome 16 (LCAT, p=1.82x10-7; TSNAXIP1, p=2.13x10-7; CENPT, p=2.32x10-7; PARD6A, p=5.57x10-7) for OD (BF=12.2), CoD (BF=12.1), ND (BF=9.2), and polysubstance dependence (BF=2.1). ConclusionsComorbidity of multiple SDs is a significant suicide risk factor and heritability of suicidal behaviors is partially moderated by multivariate gene interactions.

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