Abstract
Substance dependence diagnoses (SDs) are important risk factors for suicidality. We investigated the associations of multiple SDs with different suicidality outcomes, testing how genetic background moderates these associations. The Yale-Penn cohort (N = 15,557) was recruited to investigate the genetics of SDs. The Army STARRS (Study to Assess Risk and Resilience in Servicemembers) cohort (N = 11,236) 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–environment 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) = 6.77 (95% confidence interval, CI = 5.74–7.99) for suicidal ideation (SI) to OR = 3.61 (95% CI = 2.7–4.86) 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 = 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 = 1.82 × 10–7; TSNAXIP1, p = 2.13 × 10−7; CENPT, p = 2.32 × 10−7; PARD6A, p = 5.57 × 10−7) for opioid dependence (BF = 12.2), cocaine dependence (BF = 12.1), nicotine dependence (BF = 9.2), and polysubstance dependence (BF = 2.1). Comorbidity of multiple SDs is a significant associated with suicidality and heritability of suicidality is partially moderated by multivariate gene interactions.
Highlights
Individuals with substance dependence diagnoses (SDs) are a population with high suicide risk
Phenotypic associations To identify effects accounting for the comorbidity among the SDs tested in the Yale-Penn cohort, alcohol dependence (AD), cannabis dependence (CaD), cocaine dependence (CoD), nicotine dependence (ND), and opioid dependence (OD) were entered as terms in the same logistic regression model (Fig. 1, left panel)
Increased odds were observed with respect to CoD for suicidal ideation (SI) (OR = 1.69; 95% CI = 1.52–1.88), suicide planning (SP) (OR = 1.26; 95% CI = 1.08–1.48), and suicide attempt (SA) (OR = 1.51; 95% CI = 1.27–1.79), but not for persistent SI
Summary
Individuals with substance dependence diagnoses (SDs) are a population with high suicide risk. Genome-wide association studies (GWAS) of suicidality have been conducted in large cohorts, identifying several risk loci and strong genetic overlap with depression[4,5,6,7,8]. To our knowledge, no gene-byenvironment genome-wide interaction studies (GEWIS) have yet been conducted to evaluate the genetic interplay between suicidality and SDs. In the context of gene-byenvironment interaction studies, environmental risk factors can include exposures (physical, chemical, biological), behavioral patterns, or life events[9]. Based on the high genetic overlap between suicidality and depression observed across multiple large-scale GWAS4,7,8, we verified whether depression genetic risk interacts with polysubstance dependence in the context of suicidality spectrum.
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