Potential causal effect of posttraumatic stress disorder on alcohol use disorder and alcohol consumption in individuals of European descent: A Mendelian Randomization Study

Abstract

Background Posttraumatic stress disorder (PTSD) often co‐occurs with alcohol consumption (AC) and alcohol use disorder (AUD). However, it is unknown whether the same etiologic influences that underlie PTSD co‐occurring with AUD are those that underlie PTSD and AC individually. Methods This study used large‐scale genome‐wide association study (GWAS) data to test whether PTSD and drinks per week [DPW]/AUD are causally related to one another, and, if so, whether PTSD precedes DPW/AUD and/or vice versa. We used Mendelian Randomization methods to analyze European ancestry GWAS summary statistics from the Psychiatric Genomics Consortium (PGC; PTSD), GWAS & Sequencing Consortium of Alcohol and Nicotine Use (GSCAN; DPW), and the Million Veteran Program (MVP; AUD). Results PTSD exerted a potentially causal effect on AUD (β = 0.039, SE = 0.014, p = 0.005), but not on DPW (β = 0.002, SE = 0.003, p = 0.414). Additionally, neither DPW (β = 0.019, SE = 0.041, p = 0.637) nor AUD (β = 8.87 × 10−4, SE = 0.001, p = 0.441) exerted a causal effect on PTSD. Conclusions These findings are consistent with the self‐medication model, in which individuals misuse alcohol to cope with aversive trauma‐related symptoms. These findings extend latent analysis and molecular findings of shared and correlated risk between PTSD and alcohol phenotypes. Given the health behaviors associated with these phenotypes, these findings are important in that they suggest groups to prioritize for prevention efforts. Further, they provide a rationale for future preclinical and clinical studies examining the biological mechanisms by which PTSD may impact AUD.

Differences in Genetic Correlations between Posttraumatic Stress Disorder and Alcohol Use Disorder-Related Phenotypes Compared to Alcohol Consumption-Related Phenotypes

“…However, this effect was driven by women, for whom the genetic correlation was moderate and significant, but not for men (Sheerin et al, 2020). Genetic correlation analyses between PTSD and alcohol consumption were also conducted by our group, finding a non-significant association (rG = -.07; Bountress et al, 2021); another group found near zero genetic correlation between PTSD and the Alcohol Use Disorders Identification Test (AUDIT) consumption score subscale (AUDIT-C)(Mallard et al, 2021). Work by our group also found that beyond genetic correlations, using Mendelian Randomization, PTSD exerted a causal effect on AUD, but not alcohol consumption, but that neither alcohol phenotype exerted a causal influence on PTSD (Bountress et al, 2021).…”

“…These results are also consistent with the very small amount of work conducted examining genetic associations between PTSD and alcohol use. Specifically, a paper by our group employing Mendelian Randomization (MR) as the primary method also found in secondary analyses using LDSC a non-significant genetic association between PTSD and DPW among those of EA (Bountress et al, 2021). Additionally, a similar trend has been observed with other psychiatric disorders in terms of the genetic association between alcohol consumption vs. disorder, specifically major depressive disorder, which has substantial genetic overlap with PTSD (Polimanti et al, 2019; Sanchez-Roige et al, 2019; Walters et al, 2018; Zhou et al, 2020).…”

“…Few have investigated the genetic association between PTSD and AUD using genetic techniques such as linkage disequilibrium score regression (Bulik-Sullivan et al, 2015), but work by our group found a significant correlation between PTSD and alcohol dependence (AD; rG = .35, Sheerin et al, 2020) (rG = .28; Bountress et al, 2021) for those of European Ancestry. However, this effect was driven by women, for whom the genetic correlation was moderate and significant, but not for men (Sheerin et al, 2020).…”

Phenome-wide genetic correlation analysis and genetically-informed causal inference of amyotrophic lateral sclerosis

“…The clumping procedure was conducted considering a p value of 10 -5 for the exposure GWAS. Similar to previous MR studies (20)(21)(22)(23), we used this threshold to maximize the statistical power of the analyses performed. The analysis was conducted using five MR methods: inverse variance weighted (IVW), MR-Egger, simple mode, weighted median and weighted mode (24).…”

Understanding the comorbidity between posttraumatic stress severity and coronary artery disease using genome-wide information and electronic health records

“…Genetically-informed causal inference analyses can be used to investigate cause-effect hypotheses that may otherwise not be feasible to test in randomized trials due to practical or ethical considerations. For PTSD, MR has been used to investigate causal hypotheses with respect to psychiatric comorbidities 6,7 , obesity-related traits 8,9 , respiratory outcomes 10 , tobacco smoking 11 , inflammatory biomarkers 12 , sleeping patterns 13 , and socioeconomic factors 14-16 . These MR studies support a complex network of cause-effect relationships involving PTSD.…”