The current study demonstrates that polygenic liability to cannabis use was nominally associated with cannabis use (ever) and with DSM-5 CUDsx in COGA, a deeply phenotyped family sample enriched for individuals with substance use disorders. In addition, moderation of this polygenic risk for cannabis use was observed with one well-known risk factor, trauma exposure. Weaker evidence of moderation by frequency of religious service attendance was also observed. These findings provide the first evidence that trauma may potentiate polygenic risk for CUDs, while for some groups, religious service attendance may serve to dampen genetic susceptibility.

Our study extends the GxE literature on trauma exposure and cannabis use substantially. Previous studies have shown that different types of trauma exposure (physical assault, sexual assault, etc.) significantly increase risk for CUD^20,46 and that adverse experiences exacerbate genetic influences on alcohol and drug use behaviors⁴⁷. To our knowledge, this is among the first studies to document the role of lifetime trauma in accentuating polygenic risk to cannabis use. Our results indicate that the influence of polygenic risk on cannabis use accounts for ~1–2% of the variance in CUD symptoms among those who are exposed to trauma as compared with 0.1–0.2% among those who are not exposed to trauma. Future genetic studies with larger sample sizes should examine the PRS × trauma exposure effects on substance use behavior considering specific types of trauma, age of trauma exposure, and duration and frequency of trauma exposure to gain further understanding of these findings.

Consistent with previous studies⁴⁸, we observed that individuals who more frequently attended religious services were less likely to use cannabis in their lifetime and endorsed fewer DSM-5 CUD symptoms. Epidemiological research has identified several aspects of religiosity as important protective factors against substance use problems. For example, religious service attendance provides both interpersonal and community social support that may serve to increase resiliency and limit expression of genetic propensity to cannabis use. In addition, protective effects of religion may be mediated by the degree to which specific religions foster restrictive social norms and attitudes regarding substance use⁴⁹. In this study, 12.6% of participants reported that they affiliated with a religion that had rules forbidding alcohol use; these participants were most likely to identify as Christian (broadly), followed by Protestant or Fundamentalist Protestant and Buddhist. We note, however, that, while there may be religious proscriptions regarding alcohol use, these may or may not extend to cannabis use. Further, some twin studies have shown that aspects of religiosity moderate genetic influences on alcohol use behavior^19–22. For example, a Dutch twin study found that, among women without a religious upbringing, genetic influences accounted for 40% of the variance in alcohol use ever compared to 0% among women raised religiously. Conversely, church attendance was not a moderator of genetic influences on adolescent alcohol consumption among adult male twins from Virginia, suggesting that findings may differ as a function of sex and culture. The current study expands this literature by providing evidence that the influence of cannabis use PRS on cannabis use and DSM-5 CUD symptoms is moderated by frequency of religious service attendance in a cohort of males and females between ages 12 and 91 years. We note, however, that none of these findings withstood a multiple test correction. Interestingly, while studies have shown that religious service attendance during adulthood may be a more robust safeguard against heavy substance use and may reflect innate tendencies toward religious affiliations, relative to childhood attendance that bears a strong familial component⁴⁵, our findings did not differ significantly when analyses were stratified by age. In addition, since social support (outside of the religious context) has also been identified as an important protective factor against alcohol and other drug use⁵⁰ and has been shown to diminish genetic risk for other substance use problems¹³, social and community aspects of religiosity, likely captured by frequency of religious service attendance, may be an important moderator of cannabis use.

Keller notes that ignoring two-way interactions between the environmental measure and other covariate terms in GxE analyses can generate spurious findings⁴². Upon addition of these two-way terms, the moderating effect of religious service attendance was diminished by the inclusion of interactions between service attendance frequency and the first ancestral PC and with sex. Interestingly, within the EA analytic sample, PC1 is significantly positively correlated with Jewish religious affiliations (r: 0.39, p < 0.0001) and negatively correlated with Protestant (non-fundamentalist Baptist, Episcopalian, Lutheran, Methodist, Presbyterian) religious affiliations (r: −0.14, p < 0.0001). The influence of ancestral PC1 is likely reflecting both cultural differences regarding cannabis use by ancestral background (i.e., country of origin) within European Americans and differences by religious affiliation in attitudes toward cannabis use demonstrated by previous studies^48,51,52. In addition, religious service attendance was a more prominent buffer from CUD among women relative to men, which is supported by previous studies that have shown the inverse associations of religiosity and substance use behavior are greater among women relative to men^48,51,52.

There are several strengths of this study. We demonstrated polygenic effects of common genetic variation on cannabis use, with weaker associations observed with persistence into DSM-CUD symptoms, in a well-characterized sample enriched for substance use problems. This provides molecular polygenic support for some genetic distinction of cannabis use and CUD demonstrated in several twin studies³. In addition, we used a relatively novel approach by testing GxE using polygenic scores, which allowed a focus on how polygenic influences on cannabis involvement differ as a function of psychosocial context. Further, we responded to critiques of GxE studies, which largely do not account for potential confounding of GxE effects^25,26. Specifically, modeling of cross-term interactions revealed important influences of ancestry and sex on the PRS × frequency of religious service attendance effects observed in the current study. It should be noted that, while this study utilized genetic data to assign ancestry, which in our analytic sample was highly correlated with self-reported “race/ethnicity” (r: 0.95, p < 0.001), these are distinct constructs both shown to influence risk of substance use-related health outcomes, namely, through interactions with the psychosocial environment. In our data, the addition of self-reported “race/ethnicity” does not provide additional explanatory value, over and above genetic ancestry. Future PolyGxE studies should consider the role of other important social and cultural constructs.

Despite its strengths, our results should be interpreted within the context of the following limitations. The present analysis uses retrospective reports of substance use and traumatic life events and relies on measures of past year religiosity. The temporality of associations observed in this study is ambiguous; that is, the timing of traumatic exposures and religious service attendance with regard to cannabis use behaviors was not considered in the present study. While this study has largely focused on interpretations that assume trauma exposure and religious service attendance preceded cannabis use problems, previous studies show that substance use and problems may also precede both trauma exposure and religious service practices. Timing of traumatic exposure, religious service attendance, and cannabis use behaviors should be used to further understanding of the temporality of these associations. In addition, this study focused on participants of EA due to the ancestral composition of the discovery cohorts in the Pasman et al. study⁹. While congruent with what is expected for PRS derived from GWASs with sample sizes and effect sizes similar to those observed in Pasman et al.⁹, predictive power of the PRS observed in this study was poor or non-significant for CUDsx. Given the reliance of PRS on large, well-powered samples, future studies should re-examine the relations examined in this study with larger studies that will soon be available to the research community. In addition, GWAS that specifically examine problematic cannabis use may be needed to achieve predictive utility for CUD. Finally, these findings may not be generalizable to individuals of other ancestral backgrounds as seen in our AA cohort (Supplementary Table 2). While Supplementary Table 2 shows the prediction of cannabis use and CUDsx in COGA’s participants of AA, we note the limitations of applying EA-derived summary statistics to participants of AA. Large discovery GWAS in non-Europeans could be foundational in bridging the disparity in PRS research that is heavily weighted toward European populations even though negative consequences of addictions disproportionately impact those from other ancestral backgrounds⁵³.

Although evidence for GxE on substance use behavior has been well established, translation of this research into useful risk-factor targets for public health and clinical intervention is lacking. Among the reasons is the complex etiology of cannabis use and problems, which involves multiple genetic and psychosocial influences, each having very subtle effects. Despite this challenge, evidence for the influence of GxEs on substance use behaviors is mounting. In this study, we show that polygenic liability to cannabis ever use predicted cannabis use but not progression to DSM-5 CUDsx in COGA. However, this accounts for an extremely limited (∼0.2%) portion of the total variance in cannabis use. Among the trauma exposed, this increased to ~1.4% of the total variance in cannabis use. Given the limited predictive utility of current genetic information for cannabis use and CUD, it is important to note that both of the psychosocial contexts measured in this study explained a significantly greater portion of the variance in CUD as compared with the PRS (trauma exposure R²: 0.026; frequency of service attendance R²: 0.058). Findings from this study suggest that clinicians should pay particular attention to the possible escalation of cannabis use and misuse in those with genetic susceptibility and a history of trauma exposure. Treatment approaches that are tailored toward both prevention of CUD and ameliorating the burden of prior experienced trauma require continued care and monitoring. Encouragingly, regular engagement in religious services, at least within some communities, is likely to dampen the influence of genetic vulnerability. It is likely that other forms of prosocial engagement perform a similar protective function. Therefore, prevention strategies that encourage such pro-social engagement is warranted in vulnerable populations, such as those exposed to trauma. Though we note that alternative explanations for this study’s findings (e.g., confounding by sex and/or ethnicity, the influence of cannabis use, and problems on religiosity) cannot be ruled out.

In conclusion, polygenic liability to cannabis use was nominally associated with cannabis ever use and with progression to DSM-5 CUDsx in an independent sample of individuals enriched for substance use problems. In addition, PRSxE was observed with trauma exposure, with less consistent moderation effects observed with religious service attendance that are driven by important interactions with ancestry and sex. These findings provide the first evidence of PRSxE effects for cannabis use and support previous findings that trauma exacerbates genetic risk for substance use, while religious service attendance may serve as a protective factor. This study also demonstrates that, by not modeling important aspects of the psychosocial environment, we may mask genetic influences on polygenic traits, such as cannabis use.