Integrated Single-Cell Multiomic Profiling of Caudate Nucleus Suggests Key Mechanisms in Alcohol Use Disorder.

Alcohol use disorder (AUD) is likely associated with complex transcriptional alterations in addiction-relevant brain regions. We characterize AUD-associated differences in cell type-specific gene expression and chromatin accessibility in the caudate nucleus by conducting a single-nucleus RNA-seq assay and a single-nucleus RNA-seq + ATAC-seq (multiome) assay on caudate tissue from 143 human postmortem brains (74 with AUD). We identified 17 cell types. AUD was associated with a higher proportion of microglia in an activated state and more astrocytes in a reactive state. There was widespread evidence for differentially expressed genes across cell types with the most identified in oligodendrocytes and astrocytes, including genes involved in immune response and synaptic regulation, many of which appeared to be regulated in part by JUND and OLIG2 . Microglia-astrocyte communication via interleukin-1 beta, and microglia-astrocyte-oligodendrocyte interaction via transforming growth factor beta 1 were increased in individuals with AUD. Expression quantitative trait loci analysis revealed potential driver genes of AUD, including ADAL, that may protect against AUD in medium spiny neurons and interneurons. This work provides a thorough profile of the effects of AUD in the human brain and identifies several promising genes for further study.

Genome-wide meta-analyses of cross substance use disorders in European, African, and Latino ancestry populations.

Genetic risks for substance use disorders (SUDs) are due to both SUD-specific and SUD-shared genes. We performed the largest multivariate analyses to date to search for SUD-shared genes using samples of European (EA), African (AA), and Latino (LA) ancestries. By focusing on variants having cross-SUD and cross-ancestry concordant effects, we identified 45 loci. Through gene-based analyses, gene mapping, and gene prioritization, we identified 250 SUD-shared genes. These genes are highly expressed in amygdala, cortex, hippocampus, hypothalamus, and thalamus, primarily in neuronal cells. Cross-SUD concordant variants explained ~ 50% of the heritability of each SUD in EA. The top 5% individuals having the highest polygenic scores were approximately twice as likely to have SUDs as others in EA and LA. Polygenic scores had higher predictability in females than in males in EA. Using real-world data, we identified five drugs targeting identified SUD-shared genes that may be repurposed to treat SUDs.

Cross-ancestry genetic investigation of schizophrenia, cannabis use disorder, and tobacco smoking.

Individuals with schizophrenia frequently experience co-occurring substance use, including tobacco smoking and heavy cannabis use, and substance use disorders. There is interest in understanding the extent to which these relationships are causal, and to what extent shared genetic factors play a role. We explored the relationships between schizophrenia (Scz; European ancestry N = 161,405; African ancestry N = 15,846), cannabis use disorder (CanUD; European ancestry N = 886,025; African ancestry N = 120,208), and ever-regular tobacco smoking (Smk; European ancestry N = 805,431; African ancestry N = 24,278) using the largest available genome-wide studies of these phenotypes in individuals of African and European ancestries. All three phenotypes were positively genetically correlated (rgs = 0.17-0.62). Genetic instrumental variable analyses suggested the presence of shared heritable factors, but evidence for bidirectional causal relationships was also found between all three phenotypes even after correcting for these shared genetic factors. We identified 327 pleiotropic loci with 439 lead SNPs in the European ancestry data, 150 of which were novel (i.e., not genome-wide significant in the original studies). Of these pleiotropic loci, 202 had lead variants which showed convergent effects (i.e., same direction of effect) on Scz, CanUD, and Smk. Genetic variants convergent across all three phenotypes showed strong genetic correlations with risk-taking, executive function, and several mental health conditions. Our results suggest that both shared genetic factors and causal mechanisms may play a role in the relationship between CanUD, Smk, and Scz, but longitudinal, prospective studies are needed to confirm a causal relationship.

Candidate Genes from an FDA-Approved Algorithm Fail to Predict Opioid Use Disorder Risk in Over 450,000 Veterans.

Importance: Recently, the Food and Drug Administration gave pre-marketing approval to algorithm based on its purported ability to identify genetic risk for opioid use disorder. However, the clinical utility of the candidate genes comprising the algorithm has not been independently demonstrated. Objective: To assess the utility of 15 variants in candidate genes from an algorithm intended to predict opioid use disorder risk. Design: This case-control study examined the association of 15 candidate genetic variants with risk of opioid use disorder using available electronic health record data from December 20, 1992 to September 30, 2022. Setting: Electronic health record data, including pharmacy records, from Million Veteran Program participants across the United States. Participants: Participants were opioid-exposed individuals enrolled in the Million Veteran Program (n = 452,664). Opioid use disorder cases were identified using International Classification of Disease diagnostic codes, and controls were individuals with no opioid use disorder diagnosis. Exposures: Number of risk alleles present across 15 candidate genetic variants. Main Outcome and Measures: Predictive performance of 15 genetic variants for opioid use disorder risk assessed via logistic regression and machine learning models. Results: Opioid exposed individuals (n=33,669 cases) were on average 61.15 (SD = 13.37) years old, 90.46% male, and had varied genetic similarity to global reference panels. Collectively, the 15 candidate genetic variants accounted for 0.4% of variation in opioid use disorder risk. The accuracy of the ensemble machine learning model using the 15 genes as predictors was 52.8% (95% CI = 52.1 - 53.6%) in an independent testing sample. Conclusions and Relevance: Candidate genes that comprise the approved algorithm do not meet reasonable standards of efficacy in predicting opioid use disorder risk. Given the algorithm's limited predictive accuracy, its use in clinical care would lead to high rates of false positive and negative findings. More clinically useful models are needed to identify individuals at risk of developing opioid use disorder.

Alcohol milestones and internalizing, externalizing, and executive function: longitudinal and polygenic score associations.

BACKGROUND: Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk. METHODS: Data came from the Collaborative Study on the Genetics of Alcoholism (n = 3681; ages 11-36). Alcohol transitions (first: drink, intoxication, alcohol use disorder [AUD] symptom, AUD diagnosis), internalizing, and externalizing phenotypes came from the Semi-Structured Assessment for the Genetics of Alcoholism. EF was measured with the Tower of London and Visual Span Tasks. Polygenic scores (PGS) were computed for alcohol-related and behavioral phenotypes. Cox models estimated associations among PGS, behavior, and alcohol milestones. RESULTS: Externalizing phenotypes (e.g. conduct disorder symptoms) were associated with future initiation and drinking problems (hazard ratio (HR)⩾1.16). Internalizing (e.g. social anxiety) was associated with hazards for progression from first drink to severe AUD (HR⩾1.55). Initiation and AUD were associated with increased hazards for later depressive symptoms and suicidal ideation (HR⩾1.38), and initiation was associated with increased hazards for future conduct symptoms (HR = 1.60). EF was not associated with alcohol transitions. Drinks per week PGS was linked with increased hazards for alcohol transitions (HR⩾1.06). Problematic alcohol use PGS increased hazards for suicidal ideation (HR = 1.20). CONCLUSIONS: Behavioral markers of addiction vulnerability precede and follow alcohol transitions, highlighting dynamic, bidirectional relationships between behavior and emerging addiction.

A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals.

BACKGROUND: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes. METHODS: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.g., substance-use, mental health, sleep, immune, cardiovascular, metabolic) from a diverse 23andMe cohort, including European (N ≤ 2,619,939), Latin American (N ≤ 446,646) and African American (N ≤ 146,776) populations to uncover new and perhaps unexpected associations. These SNPs have been consistently implicated by both candidate gene studies and genome-wide association studies of alcohol-related behaviours but have not been investigated in detail for other relevant phenotypes in a hypothesis-free approach in such a large cohort of multiple ancestries. To provide insight into potential causal effects of alcohol consumption on the outcomes significant in the PheWAS, we performed univariable two-sample and one-sample Mendelian randomisation (MR) analyses. FINDINGS: The minor allele rs1229984-T, which is protective against alcohol behaviours, showed the highest number of PheWAS associations across the three cohorts (N = 232, European; N = 29, Latin American; N = 7, African American). rs1229984-T influenced multiple domains of health. We replicated associations with alcohol-related behaviours, mental and sleep conditions, and cardio-metabolic health. We also found associations with understudied traits related to neurological (migraines, epilepsy), immune (allergies), musculoskeletal (fibromyalgia), and reproductive health (preeclampsia). MR analyses identified evidence of causal effects of alcohol consumption on liability for 35 of these outcomes in the European cohort. INTERPRETATION: Our work demonstrates that polymorphisms in genes encoding alcohol metabolising enzymes affect multiple domains of health beyond alcohol-related behaviours. Understanding the underlying mechanisms of these effects could have implications for treatments and preventative medicine. FUNDING: MVJ, NCK, SBB, SSR and AAP were supported by T32IR5226 and 28IR-0070. SSR was also supported by NIDA DP1DA054394. NCK and RBC were also supported by R25MH081482. ASH was supported by funds from NIAAA K01AA030083. JLMO was supported by VA 1IK2CX002095. JLMO and JJMM were also supported by NIDA R21DA050160. JJMM was also supported by the Kavli Postdoctoral Award for Academic Diversity. EGA was supported by K01MH121659 from the NIMH/NIH, the Caroline Wiess Law Fund for Research in Molecular Medicine and the ARCO Foundation Young Teacher-Investigator Fund at Baylor College of Medicine. MSA was supported by the Instituto de Salud Carlos III and co-funded by the European Union Found: Fondo Social Europeo Plus (FSE+) (P19/01224, PI22/00464 and CP22/00128).

Functional 3'-UTR Variants Identify Regulatory Mechanisms Impacting Alcohol Use Disorder and Related Traits.

Although genome-wide association studies (GWAS) have identified loci associated with alcohol consumption and alcohol use disorder (AUD), they do not identify which variants are functional. To approach this, we evaluated the impact of variants in 3' untranslated regions (3'-UTRs) of genes in loci associated with substance use and neurological disorders using a massively parallel reporter assay (MPRA) in neuroblastoma and microglia cells. Functionally impactful variants explained a higher proportion of heritability of alcohol traits than non-functional variants. We identified genes whose 3'UTR activities are associated with AUD and alcohol consumption by combining variant effects from MPRA with GWAS results. We examined their effects by evaluating gene expression after CRISPR inhibition of neuronal cells and stratifying brain tissue samples by MPRA-derived 3'-UTR activity. A pathway analysis of differentially expressed genes identified inflammation response pathways. These analyses suggest that variation in response to inflammation contributes to the propensity to increase alcohol consumption.

Upregulated GIRK2 Counteracts Ethanol-Induced Changes in Excitability and Respiration in Human Neurons.

Genome-wide association studies (GWAS) of electroencephalographic endophenotypes for alcohol use disorder (AUD) has identified noncoding polymorphisms within the KCNJ6 gene. KCNJ6 encodes GIRK2, a subunit of a G-protein-coupled inwardly rectifying potassium channel that regulates neuronal excitability. We studied the effect of upregulating KCNJ6 using an isogenic approach with human glutamatergic neurons derived from induced pluripotent stem cells (male and female donors). Using multielectrode arrays, population calcium imaging, single-cell patch-clamp electrophysiology, and mitochondrial stress tests, we find that elevated GIRK2 acts in concert with 7-21 d of ethanol exposure to inhibit neuronal activity, to counteract ethanol-induced increases in glutamate response, and to promote an increase intrinsic excitability. Furthermore, elevated GIRK2 prevented ethanol-induced changes in basal and activity-dependent mitochondrial respiration. These data support a role for GIRK2 in mitigating the effects of ethanol and a previously unknown connection to mitochondrial function in human glutamatergic neurons.

Clinical, genomic, and neurophysiological correlates of lifetime suicide attempts among individuals with alcohol dependence.

Research has identified clinical, genomic, and neurophysiological markers associated with suicide attempts (SA) among individuals with psychiatric illness. However, there is limited research among those with an alcohol use disorder (AUD), despite their disproportionately higher rates of SA. We examined lifetime SA in 4,068 individuals with DSM-IV alcohol dependence from the Collaborative Study on the Genetics of Alcoholism (23% lifetime suicide attempt; 53% female; 17% Admixed African American ancestries; mean age: 38). We 1) conducted a genome-wide association study (GWAS) of SA and performed downstream analyses to determine whether we could identify specific biological pathways of risk, and 2) explored risk in aggregate across other clinical conditions, polygenic scores (PGS) for comorbid psychiatric problems, and neurocognitive functioning between those with AD who have and have not reported a lifetime suicide attempt. The GWAS and downstream analyses did not produce any significant associations. Participants with an AUD who had attempted suicide had greater rates of trauma exposure, major depressive disorder, post-traumatic stress disorder, and other substance use disorders compared to those who had not attempted suicide. Polygenic scores for suicide attempt, depression, and PTSD were associated with reporting a suicide attempt (ORs = 1.22-1.44). Participants who reported a SA also had decreased right hemispheric frontal-parietal theta and decreased interhemispheric temporal-parietal alpha electroencephalogram resting-state coherences relative to those who did not, but differences were small. Overall, individuals with alcohol dependence who report SA appear to experience a variety of severe comorbidities and elevated polygenic risk for SA. Our results demonstrate the need to further investigate suicide attempts in the presence of substance use disorders.

Cross-ancestry genetic investigation of schizophrenia, cannabis use disorder, and tobacco smoking.

Individuals with schizophrenia frequently experience co-occurring substance use, including tobacco smoking and heavy cannabis use, and substance use disorders. There is interest in understanding the extent to which these relationships are causal, and to what extent shared genetic factors play a role. We explored the relationships between schizophrenia (Scz), cannabis use disorder (CanUD), and ever-regular tobacco smoking (Smk) using the largest available genome-wide studies of these phenotypes in individuals of African and European ancestries. All three phenotypes were positively genetically correlated (rgs = 0.17 - 0.62). Causal inference analyses suggested the presence of horizontal pleiotropy, but evidence for bidirectional causal relationships was also found between all three phenotypes even after correcting for horizontal pleiotropy. We identified 439 pleiotropic loci in the European ancestry data, 150 of which were novel (i.e., not genome-wide significant in the original studies). Of these pleiotropic loci, 202 had lead variants which showed convergent effects (i.e., same direction of effect) on Scz, CanUD, and Smk. Genetic variants convergent across all three phenotypes showed strong genetic correlations with risk-taking, executive function, and several mental health conditions. Our results suggest that both horizontal pleiotropy and causal mechanisms may play a role in the relationship between CanUD, Smk, and Scz, but longitudinal, prospective studies are needed to confirm a causal relationship.

Associations between alcohol use disorder polygenic score and remission in participants from high-risk families and the Indiana Biobank.

BACKGROUND: In the United States, ~50% of individuals who meet criteria for alcohol use disorder (AUD) during their lifetimes do not remit. We previously reported that a polygenic score for AUD (PGSAUD ) was positively associated with AUD severity as measured by DSM-5 lifetime criterion count, and AUD severity was negatively associated with remission. Thus, we hypothesized that PGSAUD would be negatively associated with remission. METHODS: Individuals of European (EA) and African ancestry (AA) from the Collaborative Study on the Genetics of Alcoholism (COGA) who met lifetime criteria for AUD, and two EA cohorts ascertained for studies of liver diseases and substance use disorders from the Indiana Biobank were included. In COGA, 12-month remission was defined as any period of ≥12 consecutive months without meeting AUD criteria except craving and was further categorized as abstinent and non-abstinent. In the Indiana Biobank, remission was defined based on ICD codes and could not be further distinguished as abstinent or non-abstinent. Sex and age were included as covariates. COGA analyses included additional adjustment for AUD severity, family history of remission, and AUD treatment history. RESULTS: In COGA EA, PGSAUD was negatively associated with 12-month and non-abstinent remission (p ≤ 0.013, ßs between -0.15 and -0.10) after adjusting for all covariates. In contrast to the COGA findings, PGSAUD was positively associated with remission (p = 0.004, ß = 0.28) in the Indiana Biobank liver diseases cohort but not in the Indiana Biobank substance use disorder cohort (p = 0.17, ß = 0.15). CONCLUSIONS: PGSAUD was negatively associated with 12-month and non-abstinent remission in COGA EA, independent of behavioral measures of AUD severity and family history of remission. The discrepant results in COGA and the Indiana Biobank could reflect different ascertainment strategies: the Indiana Biobank participants were older and had higher rates of liver disease, suggesting that these individuals remitted due to alcohol-related health conditions that manifested in later life.

A polygenic resilience score moderates the genetic risk for schizophrenia: Replication in 18,090 cases and 28,114 controls from the Psychiatric Genomics Consortium.

Identifying heritable factors that moderate the genetic risk for schizophrenia (SCZ) could help clarify why some individuals remain unaffected despite having relatively high genetic liability. Previously, we developed a framework to mine genome-wide association (GWAS) data for common genetic variants that protect high-risk unaffected individuals from SCZ, leading to derivation of the first-ever "polygenic resilience score" for SCZ (resilient controls n = 3786; polygenic risk score-matched SCZ cases n = 18,619). Here, we performed a replication study to verify the moderating effect of our polygenic resilience score on SCZ risk (OR = 1.09, p = 4.03 × 10-5 ) using newly released GWAS data from 23 independent case-control studies collated by the Psychiatric Genomics Consortium (PGC) (resilient controls n = 2821; polygenic risk score-matched SCZ cases n = 5150). Additionally, we sought to optimize our polygenic resilience-scoring formula to improve subsequent modeling of resilience to SCZ and other complex disorders. We found significant replication of the polygenic resilience score, and found that strict pruning of SNPs based on linkage disequilibrium to known risk SNPs and their linked loci optimizes the performance of the polygenic resilience score.

Upregulated GIRK2 counteracts ethanol-induced changes in excitability & respiration in human neurons.

Genome-wide association analysis (GWAS) of electroencephalographic endophenotypes for alcohol use disorder (AUD) has identified non-coding polymorphisms within the KCNJ6 gene. KCNJ6 encodes GIRK2, a subunit of a G protein-coupled inwardly-rectifying potassium channel that regulates neuronal excitability. How changes in GIRK2 affect human neuronal excitability and the response to repeated ethanol exposure is poorly understood. Here, we studied the effect of upregulating KCNJ6 using an isogenic approach with human glutamatergic neurons derived from induced pluripotent stem cells (male and female donors). Using multi-electrode-arrays, population calcium imaging, single-cell patch-clamp electrophysiology, and mitochondrial stress tests, we find that elevated GIRK2 acts in concert with 7-21 days of ethanol exposure to inhibit neuronal activity, to counteract ethanol-induced increases in glutamate response, and to promote an increase intrinsic excitability. Furthermore, elevated GIRK2 prevented ethanol-dependent changes in basal and activity-dependent mitochondrial respiration. These data support a role for GIRK2 in mitigating the effects of ethanol and a previously unknown connection to mitochondrial function in human glutamatergic neurons. SIGNIFICANCE STATEMENT: Alcohol use disorder (AUD) is a major health problem that has worsened since COVID, affecting over 100 million people worldwide. While it is known that heritability contributes to AUD, specific genes and their role in neuronal function remain poorly understood, especially in humans. In the current manuscript, we focused on the inwardly-rectifying potassium channel GIRK2, which has been identified in an AUD-endophenotype genome-wide association study. We used human excitatory neurons derived from healthy donors to study the impact of GIRK2 expression. Our results reveal that elevated GIRK2 counteracts ethanol-induced increases in glutamate response and intracellular calcium, as well as deficits in activity-dependent mitochondrial respiration. The role of GIRK2 in mitigating ethanol-induced hyper-glutamatergic and mitochondrial offers therapeutic promise for treating AUD.

Examining associations between genetic and neural risk for externalizing behaviors in adolescence and early adulthood.

BACKGROUND: Researchers have identified genetic and neural risk factors for externalizing behaviors. However, it has not yet been determined if genetic liability is conferred in part through associations with more proximal neurophysiological risk markers. METHODS: Participants from the Collaborative Study on the Genetics of Alcoholism, a large, family-based study of alcohol use disorders were genotyped and polygenic scores for externalizing (EXT PGS) were calculated. Associations with target P3 amplitude from a visual oddball task (P3) and broad endorsement of externalizing behaviors (indexed via self-report of alcohol and cannabis use, and antisocial behavior) were assessed in participants of European (EA; N = 2851) and African ancestry (AA; N = 1402). Analyses were also stratified by age (adolescents, age 12-17 and young adults, age 18-32). RESULTS: The EXT PGS was significantly associated with higher levels of externalizing behaviors among EA adolescents and young adults as well as AA young adults. P3 was inversely associated with externalizing behaviors among EA young adults. EXT PGS was not significantly associated with P3 amplitude and therefore, there was no evidence that P3 amplitude indirectly accounted for the association between EXT PGS and externalizing behaviors. CONCLUSIONS: Both the EXT PGS and P3 amplitude were significantly associated with externalizing behaviors among EA young adults. However, these associations with externalizing behaviors appear to be independent of each other, suggesting that they may index different facets of externalizing.

A Developmentally-Informative Genome-wide Association Study of Alcohol Use Frequency.

Contemporary genome-wide association study (GWAS) methods typically do not account for variability in genetic effects throughout development. We applied genomic structural equation modeling to combine developmentally-informative phenotype data and GWAS to create polygenic scores (PGS) for alcohol use frequency that are specific to developmental stage. Longitudinal cohort studies targeted for gene-identification analyses include the Collaborative Study on the Genetics of Alcoholism (adolescence n = 1,118, early adulthood n = 2,762, adulthood n = 5,255), the National Longitudinal Study of Adolescent to Adult Health (adolescence n = 3,089, early adulthood n = 3,993, adulthood n = 5,149), and the Avon Longitudinal Study of Parents and Children (ALSPAC; adolescence n = 5,382, early adulthood n = 3,613). PGS validation analyses were conducted in the COGA sample using an alternate version of the discovery analysis with COGA removed. Results suggest that genetic liability for alcohol use frequency in adolescence may be distinct from genetic liability for alcohol use frequency later in developmental periods. The age-specific PGS predicts an increase of 4 drinking days per year per PGS standard deviation when modeled separately from the common factor PGS in adulthood. The current work was underpowered at all steps of the analysis plan. Though small sample sizes and low statistical power limit the substantive conclusions that can be drawn regarding these research questions, this work provides a foundation for future genetic studies of developmental variability in the genetic underpinnings of alcohol use behaviors and genetically-informed, age-matched phenotype prediction.

Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals.

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.

Polygenic Contributions to Suicidal Thoughts and Behaviors in a Sample Ascertained for Alcohol Use Disorders.

Introduction: Suicidal thoughts and behaviors have partially distinct genetic etiologies. Methods: We used PRS-CS to create polygenic risk scores (PRSs) from GWAS of non-suicidal self-injury, broad-sense self-harm ideation, nonfatal suicide attempt, death by suicide, and depression. Using mixed-effect models, we estimated whether these PRSs were associated with a range of suicidal thoughts and behaviors in the Collaborative Study on the Genetics of Alcoholism (N = 7,526). Results: All PRSs were significantly associated with suicidal ideation and suicide attempt (betas = 0.08-0.44, false discovery rate [FDR] <0.023). All PRSs except non-suicidal self-injury PRS were associated with active suicidal ideation (betas = 0.14-0.22, FDR <0.003). Several associations remained significant in models where all significant PRSs were included as simultaneous predictors, and when all PRSs predicted suicide attempt, the PRS together explained 6.2% of the variance in suicide attempt. Significant associations were also observed between some PRSs and persistent suicidal ideation, non-suicidal self-injury, compounded suicide attempt, and desire to die. Conclusion: Our findings suggest that PRS for depression does not explain the entirety of the variance in suicidal thoughts and behaviors, with PRS specifically for suicidal thoughts and behaviors making additional and sometimes unique contributions.

Multi-ancestry genome-wide association study of cannabis use disorder yields insight into disease biology and public health implications.

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 (ncases = 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.