Toward Clinical Implementation of Polygenic Scores for Substance Use Disorders: A Multi-Ancestry Study

728. Environmental, psychiatric, and genetic predictors of alcohol use disorder criterion count

Abstract Background Genetic and environmental factors, and psychiatric traits, contribute to risk for alcohol use disorder (AUD) and other substance use disorders (SUDs) and traits. Weighing the importance of the different kinds of contribution to risk is important in understanding risk prediction – which may be important clinically -- and in formulating prevention and treatment strategies. Aims & Objectives We worked to quantify the contribution of environmental, psychiatric, and genetic factors to AUD across different ancestries. Although polygenic risk prediction represents an important future application, its utility may be enhanced when considered in the context of environmental predictors. We used deeply phenotyped African- and European-ancestry (AFR and EUR) samples to examine how genetic, psychiatric, and environmental factors predict AUD criterion count. Method We analyzed data from 11,021 individuals in the Yale-Penn Study sample, 5,843 AFR and 5,178 EUR. Polygenic risk scores (PRSs) were generated from genome-wide association studies (GWAS) of problematic alcohol use (PAU). Generalized linear regression and relative importance analyses determined the independent and interactive effects of environmental and genetic factors on AUD, considering criterion count rather than binary diagnosis to maximize power. Results PRSs for PAU were positively associated with AUD criterion count in both ancestries and predicted 1.9% of variance in AUD criterion count in the EUR sample and 1.3% in the AFR sample. A combination of education, substance use in the household before age 13, annual household income, and male sex explained 73.1% of the variance in AUD criterion count in the AFR sample and 58.9% in EUR. Among examined psychiatric disorders, posttraumatic stress disorder explained the most variance (10.0% in AFR, 9.4% in EUR), followed by anxiety disorders (3.4% in AFR, 6.2% in EUR) and major depressive disorder (1.3% in AFR, 2.1% in EUR). In the EUR sample, education level moderated the relationship between PRS for PAU and AUD criterion count. We completed similar analyses for several other SUDs, including opioid use disorder (OUD), which will also be discussed. Discussion & Conclusions In both AFR and EUR, environmental factors explained most of the variance in AUD criterion count, but polygenic risk was also a statistically significant predictor. The pattern of results for OUD was similar. These findings may help inform clinical, research, and policy efforts to mitigate AUD and OUD risk.

712. Comorbid mental and substance use disorders – the role of genetic susceptibility

Abstract Background Alcohol use disorder (AUD) and alcohol consumption (AC) are highly heritable, globally burdensome, and frequently comorbid with severe psychiatric disorders like schizophrenia (SCZ) and bipolar disorder (BD). While these comorbidities are often linked to greater illness severity, it remains unclear whether they arise solely as complications of substance use or from a shared underlying genetic architecture. Aims & Objectives The overall aim was to leverage massive, diverse datasets and novel statistical frameworks to: i) Identify novel genetic loci associated with a narrow AUD phenotype across multiple ancestries. ii) Characterize the shared genomic loci and polygenic overlap between alcohol traits (AUD/AC) and psychiatric phenotypes (SCZ/BD). iii) Map identified variants to biological pathways and brain regions to uncover potential drug targets. Method A multi-ancestry GWAS was conducted on 1,041,450 individuals (including European, African, Hispanic, and Asian ancestries) using novel statistical tools and cross-ancestry functional analyses. We also used European-ancestry summary statistics (AUD: 34,658 cases; AC: n=200,680; SCZ: 31,013 cases; BD: 20,352 cases), and applied conjunctional False Discovery Rate (conjFDR) analysis to increase the power to detect shared genomic loci. The identified loci were mapped to gene expression data in the brain and examined for enrichment in specific neuronal pathways (GABAergic, dopaminergic, serotonergic) and immune-related gene sets. Results The multi-ancestry analysis identified 37 genome-wide significant loci, including seven novel for AUD. The conjFDR analysis further identified 28 loci shared between SCZ and AUD, and 2 loci shared between BD and AUD, many of which were previously unknown for these phenotypes. Loci were mapped to genes with altered expression in the striatum, hypothalamus, and prefrontal cortex. While European and African samples showed distinct immune-related patterns, shared loci between AUD and psychiatric disorders exhibited a complex mixture of both same and opposite effect directions. Extensive positive genetic correlations and polygenic overlap were found between AUD and both mental and general medical phenotypes, confirming that AUD shares a significant genetic liability with these conditions. Discussion & Conclusions These findings underscore the value of multi-ancestry and cross-disorder genetic studies in SUD. By identifying shared and novel genomic loci, we demonstrates that the relationship between alcohol use and psychiatric disorders is driven by a complex, shared genetic architecture rather than environmental complications alone. This advances our understanding of AUD risk and highlights potential neuronal and immune pathways for future clinical intervention.

Environmental, Genetic, and Neural Correlates of Adolescent Polysubstance Use: Insights from the ABCD Study

Alcohol use disorder and childhood adversity in the association between polygenic risk and suicidality.

OBJECTIVE Suicidal ideation (SI) and suicide attempt (SA) are both influenced by genetic, behavioral, and environmental factors. Alcohol use disorder (AUD) and adverse childhood experiences (ACEs) may mediate or moderate the effects of genetic liability for suicidality. METHODS Using data from 10,275 participants (43.8% female; 47.2% African-like genetic ancestry [AFR], 52.8% European-like genetic ancestry [EUR]), we tested whether polygenic scores (PGS) for SI and SA predicted lifetime suicidality outcomes. We evaluated whether AUD partially accounted for these associations and ACEs moderated the direct and indirect associations. RESULTS The SA PGS was significantly associated with SA (AFR: b = 0.36, SE = 0.01; EUR: b = 0.17, SE = 0.01; both ps < 2e-16), but the SI PGS was not associated with SI (p > 0.55). AUD statistically mediated the association between the SA PGS and SA, accounting for approximately 2% of the total association in AFR individuals and 10% in EUR individuals (both ps < 2e-16). Notably, the proportion of the association that was accounted for by AUD decreased as ACEs exposure increased, from 4.30% to 0.54% in AFR individuals and from 13.31% to 3.44% in EUR individuals. In contrast, there was only very modest mediation and no moderated mediation for SI. CONCLUSIONS Particularly among individuals with lower ACEs exposure, AUD accounted for a meaningful proportion of the association between genetic liability to SA and lifetime SA. These findings highlight different correlates across suicidality phenotypes and suggest potential clinical relevance for AUD in the association between genetic liability and SA.

Genetic liability to addiction underlies comorbid bipolar and substance use disorders.

BACKGROUND Bipolar disorder (BIP) frequently co-occurs with heightened substance use (SU) and substance use disorders (SUDs). Although the strong co-occurrence of these heritable traits points to shared genetic susceptibility, the extent to which there are differences in how SU and SUD overlap with BIP genetic architecture remains unclear. METHODS We quantified the polygenic overlap between BIP and SUDs (alcohol, cannabis, opioid, and tobacco), and BIP and SU traits (drinks per week, lifetime cannabis use, prescription opioid use, and smoking initiation) using GWAS summary statistics and trivariate MiXeR. We then isolated the general and unique genetic contributions of SUD and SU using GWAS-by-subtraction via Genomic SEM. Next, we tested associations between polygenic risk scores derived from these latent factors and diagnostic and behavioral outcomes in the Norwegian Mother, Father and Child Cohort Study. Finally, we applied GSA-MiXeR to explore pleiotropic pathway enrichment shared between the latent factors and BIP. RESULTS We found extensive polygenic overlap between traits, with SUDs being more genetically correlated with BIP than SU traits. The unique SUD factor correlated positively with psychiatric disorders, whereas unique SU correlated negatively. PRS for BIP, shared SUD/SU, and unique SUD were significantly associated with BIP, SUD, and comorbid SUD-BIP; PRS for unique SU was only associated with self-reported lifetime SU. GSA-MiXeR revealed richer gene-set enrichment for SUD/BIP than SU/BIP implicating dopamine signaling and interneuron function. CONCLUSION By dissecting the genetic liability to SUD and SU and investigating their relationship with BIP we find a genetic signature correlated with substance dependence but not substance use more broadly.

Pleiotropic genetic architecture linking schizophrenia and substance use disorders