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Objective: This study investigated the genetic and epigenetic mechanisms underlying the comorbidity patterns of five substance dependence diagnoses (SDs; alcohol, AD; cannabis, CaD; cocaine, CoD; opioid, OD; tobacco, TD)., Methods: A latent class analysis (LCA) was performed on 31,197 individuals (average age 42±11 years; 49% females) from six cohorts to identify comorbid DSM-IV SD patterns. In subsets of this sample, we tested SD-latent classes with respect to polygenic burden of psychiatric and behavioral traits and epigenome-wide changes in three population groups., Results: An LCA identified four latent classes related to SD comorbidities: AD+TD, CoD+TD, AD+CoD+OD+TD (i.e., polysubstance use, PSU), and TD. In the epigenome-wide association analysis, SPATA4 cg02833127 was associated with CoD+TD, AD+TD, and PSU latent classes. AD+TD latent class was also associated with CpG sites located on ARID1B , NOTCH1 , SERTAD4, and SIN3B , while additional epigenome-wide significant associations with CoD+TD latent class were observed in ANO6 and MOV10 genes. PSU-latent class was also associated with a differentially methylated region in LDB1 . We also observed shared polygenic score (PGS) associations for PSU, AD+TD, and CoD+TD latent classes (i.e., attention-deficit hyperactivity disorder, anxiety, educational attainment, and schizophrenia PGS). In contrast, TD-latent class was exclusively associated with posttraumatic stress disorder-PGS. Other specific associations were observed for PSU-latent class (subjective wellbeing-PGS and neuroticism-PGS) and AD+TD-latent class (bipolar disorder-PGS)., Conclusions: We identified shared and unique genetic and epigenetic mechanisms underlying SD comorbidity patterns. These findings highlight the importance of modeling the co-occurrence of SD diagnoses when investigating the molecular basis of addiction-related traits.

Cannabis use disorder (CanUD) has increased with the legalization of the use of cannabis. Around 20% of individuals using cannabis develop CanUD, and the number of users has grown with increasing ease of access. CanUD and other substance use disorders (SUDs) are associated phenotypically and genetically. We leveraged new CanUD genomics data to undertake genetically-informed analyses with unprecedented power, to investigate the genetic architecture and causal relationships between CanUD and lifetime cannabis use with risk for developing SUDs and substance use traits. Analyses included calculating local and global genetic correlations, genomic structural equation modeling (genomicSEM), and Mendelian Randomization (MR). Results from the genetic correlation and genomicSEM analyses demonstrated that CanUD and cannabis use differ in their relationships with SUDs and substance use traits. We found significant causal effects of CanUD influencing all the analyzed traits: opioid use disorder (OUD) (Inverse variant weighted, IVW β = 0.925 ± 0.082), problematic alcohol use (PAU) (IVW β = 0.443 ± 0.030), drinks per week (DPW) (IVW β = 0.182 ± 0.025), Fagerström Test for Nicotine Dependence (FTND) (IVW β = 0.183 ± 0.052), cigarettes per day (IVW β = 0.150 ± 0.045), current versus former smokers (IVW β = 0.178 ± 0.052), and smoking initiation (IVW β = 0.405 ± 0.042). We also found evidence of bidirectionality showing that OUD, PAU, smoking initiation, smoking cessation, and DPW all increase risk of developing CanUD. For cannabis use, bidirectional relationships were inferred with PAU, smoking initiation, and DPW; cannabis use was also associated with a higher risk of developing OUD (IVW β = 0.785 ± 0.266). GenomicSEM confirmed that CanUD and cannabis use load onto different genetic factors. We conclude that CanUD and cannabis use can increase the risk of developing other SUDs. This has substantial public health implications; the move towards legalization of cannabis use may be expected to increase other kinds of problematic substance use. These harmful outcomes are in addition to the medical harms associated directly with CanUD., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

There is a high prevalence of antisocial personality disorder (ASPD) in individuals affected by substance use disorders (SUD). However, there is limited information on the specific patterns of association of ASPD with SUD severity and specific SUD diagnostic criteria. We investigated the association of alcohol, cannabis, cocaine, opioid, and tobacco use disorders (AUD, CanUD, CocUD, OUD, and TUD, respectively) in 1660 individuals with ASPD and 6640 controls matched by sex (24% female), age, and racial/ethnic background in a sample ascertained for addiction-related traits. Generalized linear regressions were used to test ASPD with respect to the five DSM-5 SUD diagnoses, their severity (i.e., mild, moderate, severe), and their diagnostic criteria. We found that ASPD is associated with the diagnosis and severity of AUD (Odds Ratio, ORs = 1.89 and 1.25), CanUD (ORs = 2.13 and 1.32), and TUD (ORs = 1.50 and 1.21) (ps < 0.003). Of the specific diagnostic criteria, the "hazardous use" criterion showed the strongest association with ASPD across the five SUDs investigated (from OR TUD  = 1.88 to OR CanUD  = 1.37). However, when criteria of different SUDs were included in the same model, ASPD was independently associated only with TUD "hazardous use" and CocUD "attempts to quit". Attempting to quit cocaine was inversely related to the presence of ASPD and remained significant (OR = 0.57, 95% confidence interval = 0.36-0.89) after controlling for interactive effects with sex. The current work provides novel insights into ASPD-SUD comorbidity, supporting the existence of different SUD patterns among individuals affected by ASPD., (© 2024. The Author(s).)

One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third ( n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations.

Individuals suffering from chronic pain develop substance use disorders (SUDs) more often than others. Understanding the shared genetic influences underlying the comorbidity between chronic pain and SUDs will lead to a greater understanding of their biology. Genome-wide association statistics were obtained from the UK Biobank for multisite chronic pain (MCP, N effective  = 387,649) and from the Million Veteran Program and the Psychiatric Genomics Consortium meta-analyses for alcohol use disorder (AUD, N effective  = 296,974), cannabis use disorder (CanUD, N effective  = 161,053), opioid use disorder (OUD, N effective  = 57,120), and problematic tobacco use (PTU, N effective  = 270,120). SNP-based heritability was estimated for each of the traits and genetic correlation (r g ) analyses were performed to assess MCP-SUD pleiotropy. Bidirectional Mendelian Randomization analyses evaluated possible causal relationships. Finally, to identify and characterize individual loci, we performed a genome-wide pleiotropy analysis and a brain-wide analysis using imaging phenotypes available from the UK Biobank. MCP was positively genetically correlated with AUD (r g  = 0.26, p = 7.55 × 10 -18 ), CanUD (r g  = 0.37, p = 8.21 × 10 -37 ), OUD (r g  = 0.20, p = 1.50 × 10 -3 ), and PTU (r g  = 0.29, p = 8.53 × 10 -12 ). Although the MR analyses supported bi-directional relationships, MCP had larger effects on AUD (pain-exposure: beta = 0.18, p = 8.21 × 10 -4 ; pain-outcome: beta = 0.07, p = 0.018), CanUD (pain-exposure: beta = 0.58, p = 2.70 × 10 -6 ; pain-outcome: beta = 0.05, p = 0.014) and PTU (pain-exposure: beta = 0.43, p = 4.16 × 10 -8 ; pain-outcome: beta = 0.09, p = 3.05 × 10 -6 ) than the reverse. The genome-wide analysis identified two SNPs pleiotropic between MCP and all SUD investigated: IHO1 rs7652746 (p pleiotropy  = 2.69 × 10 -8 ), and CADM2 rs1248857 (p pleiotropy  = 1.98 × 10 -5 ). In the brain-wide analysis, rs7652746 was associated with multiple cerebellum and amygdala imaging phenotypes. When analyzing MCP pleiotropy with each SUD separately, we found 25, 22, and 4 pleiotropic variants for AUD, CanUD, and OUD, respectively. To our knowledge, this is the first large-scale study to provide evidence of potential causal relationships and shared genetic mechanisms underlying MCP-SUD comorbidity., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Elucidation of the interaction of biological and psychosocial/environmental factors on opioid dependence (OD) risk can inform our understanding of the etiology of OD. We examined the role of psychosocial/environmental factors in moderating polygenic risk for opioid use disorder (OUD)., Methods: Data from 1958 European ancestry adults who participated in the Yale-Penn 3 study were analyzed. Polygenic risk scores (PRS) were based on a large-scale multi-trait analysis of genome-wide association studies (MTAG) of OUD., Results: A total of 420 (21.1%) individuals had a lifetime diagnosis of OD. OUD PRS were positively associated with OD (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.21-1.66). Household income and education were the strongest correlates of OD. Among individuals with higher OUD PRS, those with higher education level had lower odds of OD (OR 0.92, 95% CI 0.85-0.98); and those with posttraumatic stress disorder (PTSD) were more likely to have OD relative to those without PTSD (OR 1.56, 95% CI 1.04-2.35)., Conclusions: Results suggest an interplay between genetics and psychosocial environment in contributing to OD risk. While PRS alone do not yet have useful clinical predictive utility, psychosocial factors may help enhance prediction. These findings could inform more targeted clinical and policy interventions to help address this public health crisis.

Background: Opioid use disorder (OUD), a serious health burden worldwide, is associated with lower cognitive function. Recent studies have demonstrated a negative genetic correlation between OUD and general cognitive ability (COG), indicating a shared genetic basis. However, the specific genetic variants involved, and the underlying molecular mechanisms remain poorly understood. Here, we aimed to quantify and identify the genetic basis underlying OUD and COG., Methods: We quantified the extent of genetic overlap between OUD and COG using a bivariate causal mixture model (MiXeR) and identified specific genetic loci applying conditional/conjunctional FDR. Finally, we investigated biological function and expression of implicated genes using available resources., Results: We estimated that ~94% of OUD variants (4.8k out of 5.1k variants) also influence COG. We identified three novel OUD risk loci and one locus shared between OUD and COG. Loci identified implicated biological substrates in the basal ganglia., Conclusion: We provide new insights into the complex genetic risk architecture of OUD and its genetic relationship with COG., Competing Interests: Declaration of Competing Interest OAA has received speaker’s honoraria from Sunovion, Lundbeck and Janssen and is a consultant for Cortechs.ai. AMD is a founder of and holds equity interest in CorTechs Labs and serves on its scientific advisory board. He is also a member of the Scientific Advisory Board of Healthlytix and receives research funding from General Electric Healthcare (GEHC). The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies. JG is a named inventor on PCT patent application #15/878,640 entitled: "Genotype-guided dosing of opioid agonists," filed January 24, 2018 and issued on January 26, 2021 as U.S. Patent No. 10,900,082. JG was paid for editorial work on the journal Complex Psychiatry. Remaining authors have no conflicts of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

We characterized the genetic architecture of the attention-deficit hyperactivity disorder-substance use disorder (ADHD-SUD) relationship by investigating genetic correlation, causality, pleiotropy, and common polygenic risk. Summary statistics from genome-wide association studies (GWAS) were used to investigate ADHD (N eff = 51,568), cannabis use disorder (CanUD, N eff = 161,053), opioid use disorder (OUD, N eff = 57,120), problematic alcohol use (PAU, N eff = 502,272), and problematic tobacco use (PTU, N eff = 97,836). ADHD, CanUD, and OUD GWAS meta-analyses included cohorts with case definitions based on different diagnostic criteria. PAU GWAS combined information related to alcohol use disorder, alcohol dependence, and the items related to alcohol problematic consequences assessed by the alcohol use disorders identification test. PTU GWAS was generated a multi-trait analysis including information regarding Fagerström Test for Nicotine Dependence and cigarettes per day. Linkage disequilibrium score regression analyses indicated positive genetic correlation with CanUD, OUD, PAU, and PTU. Genomic structural equation modeling showed that these genetic correlations were related to two latent factors: one including ADHD, CanUD, and PTU and the other with OUD and PAU. The evidence of a causal effect of PAU and PTU on ADHD was stronger than the reverse in the two-sample Mendelian randomization analysis. Conversely, similar strength of evidence was found between ADHD and CanUD. CADM2 rs62250713 was a pleiotropic SNP between ADHD and all SUDs. We found seven, one, and twenty-eight pleiotropic variants between ADHD and CanUD, PAU, and PTU, respectively. Finally, OUD, CanUD, and PAU PRS were associated with increased odds of ADHD. Our findings demonstrated the contribution of multiple pleiotropic mechanisms to the comorbidity between ADHD and SUDs., Competing Interests: Declaration of competing interest Dr. Polimanti reports a research grant from Alkermes. Drs. Polimanti and Gelernter are paid for their editorial work in the journal Complex Psychiatry. Drs. Gelernter and Kranzler hold US patent 10,900,082 titled: “Genotype-guided dosing of opioid agonists,” issued January 26, 2021. Dr. Kranzler is a member of advisory boards for Clearmind Medicine, Dicerna Pharmaceuticals, Enthion Pharmaceuticals, and Sophrosyne Pharmaceuticals, and Enthion Pharmaceuticals; a consultant to Sobrera Pharmaceuticals; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; and a member of the American Society of Clinical Psychopharmacology's Alcohol Clinical Trials Initiative, which was supported in the past 3 years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, Otsuka, and Pear Therapeutics. Drs. Gelernter and Kranzler hold U.S. patent 10,900,082 titled: "Genotype-guided dosing of opioid agonists," issued 26 January 2021. Dr. Demontis has received speaker fees from Medice Nordic. The other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)