Exploring the genetic overlap of suicide-related behaviors and substance use disorders

Abstract

Suicide-related behaviors are heterogeneous and transdiagnostic, and may demonstrate varying levels of genetic overlap with different substance use disorders (SUDs). We used linkage disequilibrium score regression, genomic structural equation models, and Mendelian randomization to examine the genetic relationships between several SUDs and suicide-related behaviors. Our analyses incorporated summary statistics from the largest genome-wide association studies (GWAS) of problematic alcohol use, the Fagerström test for nicotine dependence, cannabis use disorder, and opioid use disorder (Ns ranging from 46,213-435,563) and GWAS of ever self-harmed, suicide attempt, and suicide death (Ns ranging from 18,223-117,733). We also accounted for genetic liability to depression (N = 500,199) and risk tolerance (N = 315,894). Suicide-related behaviors were significantly genetically correlated with each other and each SUD, but there was little evidence of causal relationships between the traits. Simultaneously correlating a common SUD factor with each specific suicide indicator while controlling for depression and risk tolerance revealed significant, positive genetic correlations between the SUD factor and suicide-related behaviors (r_g = 0.26-0.45, SE = 0.08-0.09). In the model, depression's association with suicide death (β = 0.42, SE = 0.06) was weaker compared to ever-self harmed and suicide attempt (β = 0.58, SE = 0.05 and β = 0.50, SE = 0.06, respectively). We identify a general level of genetic overlap between SUDs and suicide-related behaviors, which is independent of depression and risk tolerance. Additionally, our findings suggest that genetic and behavioral contributions to suicide death may somewhat differ from nonlethal suicide-related behaviors.

Keywords: genetic overlap; genome-wide association studies; genomic structural equation models; substance use disorders; suicide.

Figure 1.. Genetic correlations amongst suicide-related behaviors and SUDs.

Error bars represent 95% confidence intervals. All genetic correlation estimates were significant (FDR < 5%). The size of points corresponds to the −log(p-value), with larger points indicating more significant p-values.

Figure 2.. Common SUD and specific suicide-related behaviors model with covariates results.

Parameter estimates are standardized with standard errors in parentheses. Solid black lines are used to indicate significance (p < 0.05) while dotted black lines represent non-significant paths. Model fit was excellent (CFI > 0.99 and SRMR < 0.04): χ²(11) = 9.16, p_chisq = 0.61, AIC = 77.16, CFI = 1.00, SRMR = 0.036.