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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.)

Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights-together with neuroscience, biology and data science-closer., (© 2023. The Author(s).)

As recreational use of cannabis is being decriminalized in many places and medical use widely sanctioned, there are growing concerns about increases in cannabis use disorder (CanUD), which is associated with numerous medical comorbidities. Here we performed a genome-wide association study of CanUD in the Million Veteran Program (MVP), followed by meta-analysis in 1,054,365 individuals (n cases  = 64,314) from four broad ancestries designated by the reference panel used for assignment (European n = 886,025, African n = 123,208, admixed American n = 38,289 and East Asian n = 6,843). Population-specific methods were applied to calculate single nucleotide polymorphism-based heritability within each ancestry. Statistically significant single nucleotide polymorphism-based heritability for CanUD was observed in all but the smallest population (East Asian). We discovered genome-wide significant loci unique to each ancestry: 22 in European, 2 each in African and East Asian, and 1 in admixed American ancestries. A genetically informed causal relationship analysis indicated a possible effect of genetic liability for CanUD on lung cancer risk, suggesting potential unanticipated future medical and psychiatric public health consequences that require further study to disentangle from other known risk factors such as cigarette smoking., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background and Aims: Genome-wide association studies (GWAS) of opioid use disorder (OUD) and cannabis use disorder (CUD) have lagged behind those of alcohol use disorder (AUD) and smoking, where many more loci have been identified. We sought to identify novel loci for substance use traits (SUTs) in both African- (AFR) and European- (EUR) ancestry individuals to enhance our understanding of the traits' genetic architecture., Design: We used multi-trait analysis of GWAS (MTAG) to analyze four SUTs in EUR subjects (OUD, CUD, AUD and smoking initiation [SMKinitiation]), and three SUTs in AFR subjects (OUD, AUD and smoking trajectory [SMKtrajectory]). We conducted gene-set and protein-protein interaction analyses and calculated polygenic risk scores (PRS) in two independent samples., Setting: This study was conducted in the United States., Participants: A total of 5692 EUR and 4918 AFR individuals in the Yale-Penn sample and 29 054 EUR and 10 265 AFR individuals in the Penn Medicine BioBank sample., Findings: MTAG identified genome-wide significant (GWS) single nucleotide polymorphisms (SNPs) for all four traits in EUR: 41 SNPs in 36 loci for OUD; 74 SNPs in 60 loci for CUD; 63 SNPs in 52 loci for AUD; and 183 SNPs in 144 loci for SMKinitiation. MTAG also identified GWS SNPs in AFR: 2 SNPs in 2 loci for OUD; 3 SNPs in 3 loci for AUD; and 1 SNP in 1 locus for SMKtrajectory. In the Yale-Penn sample, the MTAG-derived PRS consistently yielded more significant associations with both the corresponding substance use disorder diagnosis and multiple related phenotypes than the GWAS-derived PRS., Conclusions: Multi-trait analysis of genome-wide association studies boosted the number of loci found for substance use traits, identifying genes not previously linked to any substance, and increased the power of polygenic risk scores. Multi-trait analysis of genome-wide association studies can be used to identify novel associations for substance use, especially those for which the samples are smaller than those for historically legal substances., (© 2023 Society for the Study of Addiction.)

Sleep duration has been linked to a wide range of negative health outcomes and to reduced life expectancy. We present genome-wide association studies of short ( ≤ 5 h) and long ( ≥ 10 h) sleep duration in adults of European (N = 445,966), African (N = 27,785), East Asian (N = 3141), and admixed-American (N = 16,250) ancestry from UK Biobank and the Million Veteran Programme. In a cross-population meta-analysis, we identify 84 independent loci for short sleep and 1 for long sleep. We estimate SNP-based heritability for both sleep traits in each ancestry based on population derived linkage disequilibrium (LD) scores using cov-LDSC. We identify positive genetic correlation between short and long sleep traits (r g = 0.16 ± 0.04; p = 0.0002), as well as similar patterns of genetic correlation with other psychiatric and cardiometabolic phenotypes. Mendelian randomisation reveals a directional causal relationship between short sleep and depression, and a bidirectional causal relationship between long sleep and depression., (© 2023. Springer Nature Limited.)

Background: Recent well-powered genome-wide association studies have enhanced prediction of substance use outcomes via polygenic scores (PGSs). Here, we test (1) whether these scores contribute to prediction over-and-above family history, (2) the extent to which PGS prediction reflects inherited genetic variation v. demography (population stratification and assortative mating) and indirect genetic effects of parents (genetic nurture), and (3) whether PGS prediction is mediated by behavioral disinhibition prior to substance use onset., Methods: PGSs for alcohol, cannabis, and nicotine use/use disorder were calculated for Minnesota Twin Family Study participants ( N = 2483, 1565 monozygotic/918 dizygotic). Twins' parents were assessed for histories of substance use disorder. Twins were assessed for behavioral disinhibition at age 11 and substance use from ages 14 to 24. PGS prediction of substance use was examined using linear mixed-effects, within-twin pair, and structural equation models., Results: Nearly all PGS measures were associated with multiple types of substance use independently of family history. However, most within-pair PGS prediction estimates were substantially smaller than the corresponding between-pair estimates, suggesting that prediction is driven in part by demography and indirect genetic effects of parents. Path analyses indicated the effects of both PGSs and family history on substance use were mediated via disinhibition in preadolescence., Conclusions: PGSs capturing risk of substance use and use disorder can be combined with family history measures to augment prediction of substance use outcomes. Results highlight indirect sources of genetic associations and preadolescent elevations in behavioral disinhibition as two routes through which these scores may relate to substance use.

Genetic liability to substance use disorders can be parsed into loci that confer general or substance-specific addiction risk. We report a multivariate genome-wide association meta-analysis that disaggregates general and substance-specific loci for published summary statistics of problematic alcohol use, problematic tobacco use, cannabis use disorder, and opioid use disorder in a sample of 1,025,550 individuals of European descent and 92,630 individuals of African descent. Nineteen independent SNPs were genome-wide significant ( P < 5e-8) for the general addiction risk factor ( addiction-rf ), which showed high polygenicity. Across ancestries, PDE4B was significant (among other genes), suggesting dopamine regulation as a cross-substance vulnerability. An addiction-rf polygenic risk score was associated with substance use disorders, psychopathologies, somatic conditions, and environments associated with the onset of addictions. Substance-specific loci (9 for alcohol, 32 for tobacco, 5 for cannabis, 1 for opioids) included metabolic and receptor genes. These findings provide insight into genetic risk loci for substance use disorders that could be leveraged as treatment targets., Competing Interests: Disclosure: Dr. Kranzler is a member of advisory boards for Dicerna Pharmaceuticals and Sophrosyne Pharmaceuticals, and Enthion Pharmaceuticals; a consultant to Sobrera Pharmaceuticals; and a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the last three years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, and Otsuka. Drs. Kranzler and Gelernter hold U..S. Patent 10900,082: “Genotype-guided dosing of opioid agonists,” issued 26 January 2021. The remaining authors declare not conflicts of interest.

Importance: Alcohol genome-wide association studies (GWASs) have generally focused on alcohol consumption and alcohol use disorder (AUD); few have examined habitual drinking behaviors like maximum habitual alcohol intake (MaxAlc)., Objectives: To identify genetic loci associated with MaxAlc and to elucidate the genetic architecture across alcohol traits., Design, Setting, and Participants: This MaxAlc genetic association study was performed among Million Veteran Program participants enrolled from January 10, 2011, to September 30, 2020. Ancestry-specific GWASs were conducted in participants with European (n = 218 623) and African (n = 29 132) ancestry, then meta-analyzed (N = 247 755). Linkage-disequilibrium score regression was used to estimate single nucleotide variant (SNV)-heritability and genetic correlations (rg) with other alcohol and psychiatric traits. Genomic structural equation modeling (gSEM) was used to evaluate genetic associations between MaxAlc and other alcohol traits. Mendelian randomization was used to examine potential causal relationships between MaxAlc and liver enzyme levels. MTAG (multitrait analysis of GWAS) was used to analyze MaxAlc and problematic alcohol use (PAU) jointly., Exposures: Genetic associations., Main Outcomes and Measures: MaxAlc was defined from the following survey item: "in a typical month, what is/was the largest number of drinks of alcohol you may have had in one day?" with ordinal responses from 0 to 15 or more drinks., Results: GWASs were conducted on sample sizes of as many as 247 455 US veterans. Participants were 92.68% male and had mean (SD) age of 65.92 (11.70) years. The MaxAlc GWAS resulted in 15 genome-wide significant loci. Top associations in European-ancestry and African-ancestry participants were with known functional variants in the ADH1B gene, namely rs1229984 (P = 3.12 × 10-101) and rs2066702 (P = 6.30 × 10-17), respectively. Novel associations were also found. SNV-heritability was 6.65% (SE, 0.41) in European-ancestry participants and 3.42% (SE, 1.46) in African-ancestry participants. MaxAlc was positively correlated with PAU (rg = 0.79; P = 3.95 × 10-149) and AUD (rg = 0.76; P = 1.26 × 10-127) and had negative rg with the UK Biobank "alcohol usually taken with meals" (rg = -0.53; P = 1.40 × 10-50). For psychiatric traits, MaxAlc had the strongest genetic correlation with suicide attempt (rg = 0.40; P = 3.02 × 10-21). gSEM supported a 2-factor model with MaxAlc loading on a factor with PAU and AUD and other alcohol consumption measures loading on a separate factor. Mendelian randomization supported an association between MaxAlc and the liver enzyme gamma-glutamyltransferase (β = 0.012; P = 2.66 × 10-10). MaxAlc MTAG resulted in 31 genome-wide significant loci., Conclusions and Relevance: The findings suggest that MaxAlc closely aligns genetically with PAU traits. This study improves understanding of the mechanisms associated with normative alcohol consumption vs problematic habitual use and AUD as well as how MaxAlc relates to psychiatric and medical conditions genetically and biologically.

Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. We performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs). Meta-analysis included seven cohorts: the Million Veteran Program, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N = 639,063 (N cases  = 20,686;N effective  = 77,026) across ancestries. OUD cases were defined as having a lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h 2 SNP ) and genetic correlations (r g ). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD). A leave-one-out polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD case status in Yale-Penn 3. The EUR meta-analysis identified three genome-wide significant (GWS; p ≤ 5 × 10 - 8 ) lead SNPs-one at FURIN (rs11372849; p = 9.54 × 10 - 10 ) and two OPRM1 variants (rs1799971, p = 4.92 × 10 - 09 ; rs79704991, p = 1.11 × 10 - 08 ; r 2  = 0.02). Rs1799971 (p = 4.91 × 10 - 08 ) and another OPRM1 variant (rs9478500; p = 1.95 × 10 - 08 ; r 2  = 0.03) were identified in the cross-ancestry meta-analysis. Estimated h 2 SNP was 12.75%, with strong r g with CanUD (r g  = 0.82; p = 1.14 × 10 - 47 ) and AUD (r g  = 0.77; p = 6.36 × 10 - 78 ). The OUD-MTAG resulted in a GWAS N equivalent  = 128,748 and 18 independent GWS loci, some mapping to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes. The OUD-MTAG PRS accounted for 3.81% of OUD variance (beta = 0.61;s.e. = 0.066; p = 2.00 × 10 - 16 ) compared to 2.41% (beta = 0.45; s.e. = 0.058; p = 2.90 × 10 - 13 ) explained by the OUD PRS. The current study identified OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. The genetic architecture of OUD is likely influenced by both OUD-specific loci and loci shared across SUDs., (© 2022. The Author(s).)

UK Biobank (UKB) is a key contributor in mental health genome-wide association studies (GWAS) but only ~31% of participants completed the Mental Health Questionnaire ("MHQ responders"). We predicted generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), and major depression symptoms using elastic net regression in the ~69% of UKB participants lacking MHQ data ("MHQ non-responders"; N Training  = 50%; N Test  = 50%), maximizing the informative sample for these traits. MHQ responders were more likely to be female, from higher socioeconomic positions, and less anxious than non-responders. Genetic correlation of GAD and PTSD between MHQ responders and non-responders ranged from 0.636 to 1.08; both were predicted by polygenic scores generated from independent cohorts. In meta-analyses of GAD (N = 489,579) and PTSD (N = 497,803), we discovered many novel genomic risk loci (13 for GAD and 40 for PTSD). Transcriptomic analyses converged on altered regulation of prenatal dorsolateral prefrontal cortex in these disorders. Our results provide one roadmap by which sample size and statistical power may be improved for gene discovery of incompletely ascertained traits in the UKB and other biobanks with limited mental health assessment., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Aims: Molecular genetic studies of alcohol and nicotine use have identified many genome-wide association study (GWAS) loci. We measured associations between drinking and smoking polygenic scores (PGS) and trajectories of alcohol and nicotine use outcomes from late childhood to early adulthood, substance-specific versus broader-liability PGS effects, and if PGS performance varied for consumption versus problematic substance use., Design, Setting, Participants and Measurements: We fitted latent growth curve models with structured residuals to scores on measures of alcohol and nicotine use and problems from ages 14 to 34 years. We then estimated associations between the intercept (initial status) and slope (rate of change) parameters and PGSs for drinks per week (DPW), problematic alcohol use (PAU), cigarettes per day (CPD) and ever being a regular smoker (SMK), controlling for sex and genetic principal components. All data were analyzed in the United States. PGSs were calculated for participants of the Minnesota Twin Family Study (n = 3225) using results from the largest GWAS of alcohol and nicotine consumption and problematic use to date., Findings: Each PGS was associated with trajectories of use for their respective substances [i.e. DPW (β mean  = 0.08; β range  = 0.02-0.12) and PAU (β mean  = 0.12; β range  = -0.02 to 0.31) for alcohol; CPD (β mean  = 0.08; β range  = 0.04-0.14) and SMK (β mean  = 0.18; β range  = 0.05-0.36) for nicotine]. The PAU and SMK PGSs also exhibited cross-substance associations (i.e. PAU for nicotine-specific intercepts and SMK for alcohol intercepts and slope). All identified SMK PGS effects remained as significant predictors of nicotine and alcohol trajectories (β mean  = 0.15; β range  = 0.02-0.33), even after adjusting for the respective effects of all other PGSs., Conclusions: Substance use-related polygenic scores (PGSs) vary in the strength and generality versus specificity of their associations with substance use and problems over time. The regular smoking PGS appears to be a robust predictor of substance use trajectories and seems to measure both nicotine-specific and non-specific genetic liability for substance use, and potentially externalizing problems in general., (© 2021 Society for the Study of Addiction.)

Background: Prior studies have established the importance of genetic contributions to the etiology of alcohol dependence (AD), and suggested an early onset of alcohol use represents an initial marker of this genetic risk, which is associated with a more rapid progression to AD and increased risk for AD itself. Building on prior work, the current study examined whether the additive effects of AD risk variants predicted the rate of progression to AD from the onset of regular drinking, a drinking milestone with high clinical relevance to AD prevention., Methods: Data from 1501 European-ancestry adults from the University of California - San Francisco Family Alcoholism Study were used to examine whether polygenic risk scores for AD (PRS AD ) and age-at-onset of regular drinking contributed uniquely to the likelihood of having a lifetime AD diagnosis and the rate of progression from regular drinking to AD. Mixed effects logistic regression and Cox proportional hazards regression analyses were employed., Results: Increases in PRS AD were associated with a faster progression from regular drinking to AD independent of age-at-onset of regular drinking. An independent effect of age-at-onset of regular drinking was also observed indicating that a one-year delay in regular drinking was associated with a 7% decrease in the hazard of progression to AD among drinkers with an early onset (≤ 18), but a 3% increase among drinkers with a late onset (> 18) of regular drinking., Conclusions: These results broaden our understanding of the contributions of measured genotypes underlying AD-risk on the etiology and clinical course of AD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

We examined whether a polygenic score (PGS) for smoking measured genetic risk for general behavioral disinhibition by estimating its associations with externalizing and internalizing psychopathology and related personality traits at multiple time points in adolescence (ages 11, 14, and 17 years; N = 3225). The smoking PGS had strong associations with the stable variance across time for all the externalizing measures (mean standardized β = .27), agreeableness ( β = -.22, 95% CI: -.28, -.16), and conscientiousness ( β = -.19, 95% CI: -.24, -.13), but was not significantly associated with internalizing measures (mean β = .06) or extraversion ( β = .01, 95% CI: -.05, .07). After controlling for smoking at age 17, the associations with externalizing, low agreeableness, and low conscientiousness remained statistically significant. The smoking PGS measures genetic influences that contribute to a spectrum of phenotypes related to behavioral disinhibition including externalizing psychopathology and normal-range personality traits related to behavioral control, but not internalizing psychopathology., Competing Interests: Conflict of Interest: The authors have no conflict of interest to report.

Background and Aims: While epidemiological studies support a role for heavy, high-potency cannabis use on first-episode psychosis, genetic models of causation suggest reverse causal effects of schizophrenia on cannabis use liability. We estimated the genetic relationship between cannabis use disorder (CUD) and schizophrenia (SCZ) and tested whether liability for CUD is causally associated with increased liability to SCZ while adjusting for tobacco smoking., Design: This study used summary statistics from published genome-wide association studies (GWAS). We used genomic structural equation modeling, latent causal variable analysis, and multivariable Mendelian randomization to examine genetic relationships between CUD, cannabis ever-use, ever-smoked tobacco regularly, nicotine dependence and SCZ, and to test for a causal relationship between liability to CUD and liability to SCZ., Setting: Genome-wide association studies were published previously as part of international consortia., Participants: Sample sizes of the GWAS summary statistics used in this study ranged from 161 405 to 357 806 individuals of European ancestry., Measurements: Genome-wide summary statistics for CUD and SCZ were the primary measurements, while summary statistics for cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence were included as additional variables in the genomic structural equation models and the multivariable Mendelian randomization analyses., Findings: Genetic liability to CUD was significantly associated with SCZ [β = 0.29, 95% confidence interval (CI) = 0.11, 0.46, P = 0.001], even when accounting for cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence as simultaneous predictors. We found mixed evidence of a causal relationship, with the latent causal variable analysis finding no evidence of causality (genetic causality proportion = -0.08, 95% CI = -0.40, 0.23, P = 0.87) but the multivariable Mendelian randomization analyses suggesting a significant, risk-increasing effect of CUD on liability to SCZ (β = 0.10, 95% CI = 0.02, 0.18, P = 0.02), accounting for the additional risk factors (cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence)., Conclusions: Genetic liability for cannabis use disorder appears to be robustly associated with schizophrenia, above and beyond tobacco smoking and cannabis ever-use, with mixed evidence to support a causal relationship between cannabis use disorder and schizophrenia., (© 2021 Society for the Study of Addiction.)

Substance use disorders (SUDs) are prevalent and result in an array of negative consequences. They are influenced by genetic factors (h2 = ~50%). Recent years have brought substantial progress in our understanding of the genetic etiology of SUDs and related traits. The present review covers the current state of the field for SUD genetics, including the epidemiology and genetic epidemiology of SUDs, findings from the first-generation of SUD genome-wide association studies (GWAS), cautions about translating GWAS findings to clinical settings, and suggested prioritizations for the next wave of SUD genetics efforts. Recent advances in SUD genetics have been facilitated by the assembly of large GWAS samples, and the development of state-of-the-art methods modeling the aggregate effect of genome-wide variation. These advances have confirmed that SUDs are highly polygenic with many variants across the genome conferring risk, the vast majority of which are of small effect. Downstream analyses have enabled finer resolution of the genetic architecture of SUDs and revealed insights into their genetic relationship with other psychiatric disorders. Recent efforts have also prioritized a closer examination of GWAS findings that have suggested non-uniform genetic influences across measures of substance use (e.g. consumption) and problematic use (e.g. SUD). Additional highlights from recent SUD GWAS include the robust confirmation of loci in alcohol metabolizing genes (e.g. ADH1B and ALDH2) affecting alcohol-related traits, and loci within the CHRNA5-CHRNA3-CHRNB4 gene cluster influencing nicotine-related traits. Similar successes are expected for cannabis, opioid, and cocaine use disorders as sample sizes approach those assembled for alcohol and nicotine.

Educational success is associated with greater quality of life and depends, in part, on heritable cognitive and non-cognitive traits. We used polygenic scores (PGS) for smoking and educational attainment to examine different genetic influences on facets of academic adjustment in adolescence and educational attainment in adulthood. PGSs were calculated for participants of the Minnesota Twin Family Study (N = 3225) and included as predictors of grades, academic motivation, and discipline problems at ages 11, 14, and 17 years-old, cigarettes per day from ages 14 to 24 years old, and educational attainment in adulthood (mean age 29.4 years). Smoking and educational attainment PGSs had significant incremental associations with each academic variable and cigarettes per day. About half of the adjusted effects of the smoking and education PGSs on educational attainment in adulthood were mediated by the academic variables in adolescence. Cigarettes per day from ages 14 to 24 years old did not account for the effect of the smoking PGS on educational attainment, suggesting the smoking PGS indexes genetic influences related to general behavioral disinhibition. In sum, distinct genetic influences measured by the smoking and educational attainment PGSs contribute to academic adjustment in adolescence and educational attainment in adulthood., Competing Interests: The authors have declared that no competing interests exist.

Objective: Epidemiological estimates suggest that nearly half of individuals diagnosed with alcohol use disorder will be diagnosed with another mental health disorder, with strong associations involving other externalizing disorders. Molecular genetic studies investigating the relation between alcohol use disorder and externalizing behaviors (e.g., antisocial behavior) have focused on a cluster of chromosome 4 γ-aminobutyric acid (GABA) receptor genes (GABRG1-A2-A4-B1) but have generated varying results., Method: The current study examined associations between common and rare variation in this region with alcohol use disorder and antisocial behavior using genetic sequencing data. Specifically, the University of California at San Francisco Family Alcoholism Sample (n = 1,610; 62% female) was used to conduct common and rare variant association tests in the GABRG1-A2-A4-B1 cluster with DSM-5 alcohol use disorder symptom counts, antisocial behavior, and a product term representing their interaction., Results: Gene-based analyses of rare variation resulted in a significant association between rare GABRA2 variation and the interaction term. Single-variant analysis yielded only nominally significant associations. The strongest association for alcohol use disorder (rs3756007) was located in GABRA2, the strongest association for antisocial behavior (rs11941860) was located in GABRG1, and the interaction term yielded top associations in GABRA2 (rs2119183) and the intergenic region between GABRA2 and GABRG1 (rs536599). Common and rare variant associations for the interaction remained similar when covarying for the effects of the other type of variation, suggesting that the significant rare variant signal is independent of common variant contributions., Conclusions: The present study suggests that both rare and common variant associations in GABRA2 confer risk for alcohol use disorder and antisocial behaviors, indicating a potential liability toward externalizing behavior more broadly., Competing Interests: The authors have no competing interests to disclose.

Individuals with schizophrenia have higher lifetime rates of substance use disorders than the general population, and research suggests high comorbidity rates may be partially explained by shared genetic influences related to common underlying etiology. Moreover, deficits in executive functions are thought to be central to the diagnosis of schizophrenia and are likewise associated with alcohol and tobacco use. The current study examined the associations between schizophrenia polygenic risk scores and tobacco and alcohol use and the mediation of these associations by executive function sub-domains. Results from the Psychiatric Genomics Consortium's meta-analysis of genome-wide association studies of schizophrenia were used to calculate polygenic risk scores in a sample of moderate drinkers. Schizophrenia risk scores were significantly associated with shifting-specific executive function deficits and tobacco use phenotypes. However, risk scores were not significantly associated with alcohol use and executive functions were not significantly associated with either tobacco or alcohol use. These findings extend previous research by suggesting that genetic risk for schizophrenia may be associated with specific sub-domains of executive function as well as smoking. The lack of a relation with alcohol use suggests genetic factors related to schizophrenia and executive functioning may not influence drinking in a non-disordered, social-drinking sample., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Alcohol use disorder (AUD) represents a significant and ongoing public health concern with 12-month prevalence estimates of ∼5.6%. Quantitative genetic studies suggest a heritability of approximately 50% for AUD, and as a result, significant efforts have been made to identify specific variation within the genome related to the etiology of AUD. Given the limited number of replicable findings that have emerged from genome-wide linkage and candidate gene association studies, more recent efforts have focused on the use of genome-wide association studies (GWAS). These studies have suggested that hundreds of variants across the genome, most of small effect (R 2  < 0.002), contribute to the genetic etiology of AUD. The present review describes the initial, though limited, successes of GWAS to identify loci related to risk for AUD as well as other etiologically relevant traits (e.g. alcohol consumption). In addition, 'Post-GWAS' approaches that rely on GWAS data to estimate the heritability and co-heritability of traits, test causal relations between traits, and aid in gene discovery are described. Together, the described research findings illustrate the importance of molecular genetic research on AUD as we seek to better understand the mechanisms through which genetic variation leads to increased risk for AUD., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Previous studies indicate that low initial sensitivity to alcohol may be a risk factor for later alcohol misuse. Evidence suggests that initial sensitivity is influenced by genetic factors, but few molecular genetic studies have been reported., Methods: We conducted a meta-analysis of 2 population-based genome-wide association studies of the Self-Rating of the Effects of Alcohol scale. Our final sample consisted of 7,339 individuals (82.3% of European descent; 59.2% female) who reported having used alcohol at least 5 times. In addition, we estimated single nucleotide polymorphism (SNP)-based heritability and conducted a series of secondary aggregate genetic analyses., Results: No individual locus reached genome-wide significance. Gene and set based analyses, both overall and using tissue-specific expression data, yielded largely null results, and genes previously implicated in alcohol problems and consumption were overall not associated with initial sensitivity. Only 1 gene set, related to hormone signaling and including core clock genes, survived correction for multiple testing. A meta-analysis of SNP-based heritability resulted in a modest estimate of h SNP 2  = 0.19 (SE = 0.10), though this was driven by 1 sample (N = 3,683, h SNP 2  = 0.36, SE = 0.14, p = 0.04). No significant genetic correlations with other relevant outcomes were observed., Conclusions: Findings yielded only modest support for a genetic component underlying initial alcohol sensitivity. Results suggest that its biological underpinnings may diverge somewhat from that of other alcohol outcomes and may be related to core clock genes or other aspects of hormone signaling. Larger samples, ideally of prospectively assessed samples, are likely necessary to improve gene identification efforts and confirm the current findings., (© 2018 by the Research Society on Alcoholism.)

Background: A functional polymorphism within the μ-opioid receptor (OPRM1) gene, rs1799971 (A118G), previously has been associated with measures of alcohol use and sensitivity to its effects, but findings have been inconclusive. A recent study suggested that a second nearby variant within OPRM1, rs3778150, is robustly associated with heroin dependence and fully explained a smaller observed association with rs1799971. Given evidence that the rs3778150-C allele is associated with decreased OPRM1 expression levels in the human brain, the current study sought to test the hypothesis that rs3778150 represents a causal variant within OPRM1 that increases risk for a variety of alcohol use phenotypes., Methods: Participants with genotype and phenotype data from a larger experimental study (N = 152) were assessed on measures of subjective response to alcohol and alcohol use. Measures included (i) the Self-Rating of the Effects of Alcohol and the Alcohol Sensitivity Questionnaire, (ii) the Biphasic Alcohol Effects Scale (BAES) and ratings of subjective intoxication, and (iii) average number of drinks per week in the past month., Results: Compared to rs3778150-T homozygous individuals, carriers of the rs3778150-C allele exhibited significantly lower retrospective self-report levels of alcohol sensitivity. Carriers of the rs3778150-C allele also exhibited lower levels of BAES alcohol-related stimulation during an alcohol challenge and reported higher levels of drinking in the last 30 days. With the exception of lower levels of BAES alcohol-related sedation, the rs1799971 variant did not show consistent significant association with any of the alcohol phenotypes in the presence of rs3778150., Conclusions: Results suggest that rs3778150 may be causally related to alcohol use phenotypes, and could potentially account for previously observed associations of rs1799971 with substance use phenotypes. Future studies may investigate potential causal relations among genetic variants in OPRM1, subjective response to alcohol, and drinking phenotypes to further delineate the effects of rs3778150., (Copyright © 2017 by the Research Society on Alcoholism.)

The chief aim of this study was to investigate how different species of solitary trees in temperate urban areas vary in their branch structure during winter by assessing branch area indices (BAIs). The BAI data showed significant differences ( < 0.0001) between species and genotypes. The lowest mean BAI in the dataset was for L., which had a BAI of 0.27. L. 'Fastigiata' represented the largest mean BAI of 2.09. The results from the BAI analysis further indicate that within the same species group differences occur between genotypes. For example, the five genotypes of L. range from a mean BAI of 1.77 for 'Globosum' to a mean BAI of 0.50 for 'Fassen Black'. A further aim was to apply the compiled BAI data in the computational modeling program of ENVI-met 3.1, which simulates the surface-air interaction and microclimates in complex urban settings. The simulations focused on mean radiant temperature and wind speed. Results illustrate how wind speed on the leeward side of the trees gradually decrease with an increasing BAI. With an increasing BAI, the Tmrt decreases to the leeward of the row of trees. The results are further discussed in the perspective of sustainable urban development (i.e., where, why, and how the species studied could be integrated in the urban fabric). This is of particular interest for the design of urban green space in densely built-up urban environments where space may be restricted., (Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.)