INTRODUCTION:Opioid use disorder (OUD) may adversely affect brain health, but its role in dementia risk remains poorly understood. METHODS:We investigated associations between OUD and dementia using observational data from 222,518 participants (European and African ancestry) in the Million Veteran Program and Mendelian randomization (MR) using genome-wide association study summary statistics from 6,066,918 individuals. Polygenic risk score (PRS) analyses were conducted in 229 opioid-naïve Lifebrain consortium participants with longitudinal magnetic resonance imaging data. RESULTS:OUD was associated with increased risk of all-cause dementia (hazard ratio = 1.56, 95% confidence interval [CI]: 1.39 to 1.76), Alzheimer's disease, and vascular dementia. MR supported a potential causal link between genetic liability to OUD and dementia (inverse variance weighted odds ratio = 1.77, 95% CI: 1.43 to 2.19). Genetic variation in the μ-opioid receptor gene was also associated with dementia risk. No PRS associations were found with brain structure. DISCUSSION:These findings suggest a potential causal role for OUD in dementia, implicating μ-opioid receptor pathways in neurodegeneration.

Migraine is a leading cause of disability 1 , yet preventive treatment remains largely empirical despite the availability of several mechanistically distinct therapies 2 . Genetic data can clarify mechanisms and therapeutic hypotheses when association signals are integrated with molecular and clinical data 3 . We meta-analyzed migraine GWAS data from 12 European ancestry cohorts (206,893 cases and 2,093,175 controls) and four African ancestry cohorts (22,115 cases and 178,626 controls). We identified 311 lead variants in European-ancestry analyses and 316 lead variants in trans-ancestry analysis. Fine-mapping and transcriptome-wide analyses prioritized variants and genes implicated in sensory neuronal signaling, vascular tone, and immune regulation, with convergent evidence at several established loci including TRPM8 and PHACTR1 4 . Drug-repurposing analyses identified therapeutic targets and compounds, including established migraine treatments and candidates requiring experimental validation. Genetic correlations, Mendelian randomization, and a phenome-wide scan linked migraine liability to psychiatric, pain, and gastrointestinal phenotypes. Together, these findings expand the known genetic architecture of migraine across ancestries and provide a genetics-led map connecting association signals with biological pathways, multimorbidity and candidate therapeutic mechanisms, providing a foundation for future functional and translational studies.

Outreach in psychiatric genetics bridges the gaps across research advancements, clinical practice, and public understanding. Effective communication with a range of audiences faces multiple challenges, including the complex nature of psychiatric disorders and of genetic findings, the chronicled and ongoing misuse of genetic data, and the rapid growth of direct-to-consumer genetic testing. This is particularly true in the internet and social media era, which has accelerated the spread of inaccurate information with serious consequences, including perpetuating stigma and increasing shame. Yet a significant gap remains in outreach: a recent survey found that only 51% of psychiatric genetics researchers participate in outreach, largely attributed to their perceived lack of skill and support. The Psychiatric Genomics Consortium (PGC) developed an Outreach Committee to organize and catalyze initiatives including: the Worldwide Lab, an online seminar series covering new and important approaches that is then posted on YouTube; the PGC Video Textbook, which has resources for clinicians, researchers, educators, and the broader public; patient and family engagement programs; and social media campaigns designed to inform both researchers and affected communities about new developments in psychiatric genetics. These initiatives were developed to demystify psychiatric genetics research and empower broad audiences with reliable, actionable information. Along with research and traditional teaching, the psychiatric genomics community should continue to prioritize and recognize engagement as a core component of our academic mission and values.

OBJECTIVES:To investigate the relationship between alcohol consumption and dementia. DESIGN:Prospective cohort and case-control analyses combined with linear and non-linear Mendelian randomisation. SETTING:Two large-scale population-based cohorts: the US Million Veteran Programme and the UK Biobank. Genetic analyses used summary statistics from genome-wide association studies (GWAS). PARTICIPANTS:559 559 adults aged 56-72 years at baseline were included in observational analyses (mean follow-up: 4 years in the US cohort; 12 years in the UK cohort). Genetic analyses used summary data from multiple large GWAS consortia (2.4 million participants). MAIN OUTCOME MEASURES:Incident all-cause dementia, determined through health record linkage, and genetic proxies. RESULTS:During follow-up, 14 540 participants developed dementia and 48 034 died. Observational phenotype-only analyses revealed U-shaped associations between alcohol and dementia risk: higher risk was observed among non-drinkers, heavy drinkers (>40 drinks per week; HR 1.41, 95% CI 1.15 to 1.74), and those with alcohol use disorder (AUD) (HR 1.51, 95% CI 1.42 to 1.60) compared with light drinkers. In contrast, Mendelian randomisation genetic analysis identified a monotonic increase in dementia risk with greater alcohol consumption. A 1 SD increase in log-transformed drinks per week was associated with a 15% dementia increase (inverse-variance weighted (IVW) OR 1.15, 95% CI 1.03 to 1.27). A twofold increase in AUD prevalence was associated with a 16% increase in dementia risk (IVW OR 1.16, 95% CI 1.03 to 1.30). Alcohol intake increased dementia, but individuals who developed dementia also experienced a decline in alcohol intake over time, suggesting reverse causation-where early cognitive decline leads to reduced alcohol consumption-underlies the supposed protective alcohol effects in observational studies. CONCLUSIONS:These findings provide evidence for a relationship between all types of alcohol use and increased dementia risk. While correlational observational data suggested a protective effect of light drinking, this could be in part attributable to reduced drinking seen in early dementia; genetic analyses did not support any protective effect, suggesting that any level of alcohol consumption may contribute to dementia risk. Public health strategies that reduce the prevalence of alcohol use disorder could potentially lower the incidence of dementia by up to 16%.

Abstract Stimulant use disorder (StimUD) is a significant public health problem, but genetic studies have been limited by small sample sizes. We conducted genome-wide association studies (GWAS) of StimUD in the Million Veteran Program (MVP) and All of Us (AOU), followed by meta-analysis with FinnGen and 10 additional datasets, for a total of 709,369 individuals (N cases =33,977, N controls =675,392) in four broad ancestry groups: European (EUR) (N cases =22,564, N controls =624,672), African (AFR) (N cases =7,574, N controls =34,189), Admixed American (AMR) (N cases =3,657, N controls =15,698), and East Asian (EAS) (N cases =182, N controls =833). Population-specific SNP heritability was 6.1% in EUR and 2.4% in AFR. We discovered a total of 19 genome-wide-significant loci, six in EUR, including DRD2 *rs5794864, P =7.32×10 −10 , one in AFR, five in a multi-ancestry meta-analysis, including CHRNA5 *rs55781567, P =3.27×10 −9 , two in a male-only meta-analysis, including FTO *rs8057044, P =9.50×10 −9 , and five in a meta-analysis of sex-stratified results. In a hold-out AOU subsample (N EUR =18,841, N AFR =12,263, N AMR =9,739), ancestry-specific polygenic risk scores were significantly associated with StimUD in EUR (OR=3.28, 95% confidence interval (CI)=2.89-3.71) and AMR (OR=2.01, 95% CI=1.71-2.37). Transcriptome-wide association studies, fine-mapping, and colocalization analyses prioritized additional genes (e.g., GPX1 , BSN ). Genetic correlation, Mendelian randomization, and causal mixture analyses revealed relationships with other substance use and use disorder phenotypes, including cannabis use disorder (r g =0.94, P =5.43×10 −237 ) and opioid use disorder (r g =1.01, P =4.40×10 −107 ), and other psychiatric traits, including anxiety, depression, neuroticism, and attention-deficit/hyperactivity disorder. This is the first well-powered GWAS of StimUD, and it offers significant insights into disease biology.

Abstract We explore the genetic mechanisms underlying fibromyalgia, a chronic heritable syndrome. We conduct genome-wide association studies (GWAS) of fibromyalgia in European, African, and Latin American ancestry subjects, combining data from several cohorts (85,139 cases; 1,642,433 controls). We also conduct a multi-trait analysis of GWAS (MTAG), leveraging pain GWAS to enhance power for fibromyalgia analyses. We apply a series of methods to analyze genetic association between fibromyalgia and psychological and physiological phenotypes. We find 10 genomic loci that are associated with fibromyalgia in European ancestry subjects, one in African, 12 cross-ancestry, and 45 in the European ancestry MTAG; most of these were previously associated with pain, cognitive function, autoimmune response, or general health measures. We show a moderate negative genetic correlation between fibromyalgia and physical activity, and strong genetic correlations with chronic pain, post-traumatic stress disorder, and depression (r g ≥0.69). Genomic structural equation modeling places fibromyalgia in the context of psychiatric, medical, and lifestyle phenotypes, mostly as pain- and autoimmune-related trait. Local genetic correlations and genetic causality point to neuronal mechanisms that provide a strong basis for some of the main characteristics of fibromyalgia and its comorbidities. These findings provide potential targets for future studies to improve diagnosis and treatment of fibromyalgia.

Externalizing spectrum disorders-spanning attention-deficit/hyperactivity disorder, conduct disorder, substance use disorders, and other disorders characterized by disinhibition-frequently co-occur within individuals due, in part, to shared genetic etiology. To advance understanding of this genetic architecture, we conducted a multi-ancestry, multivariate genome-wide association analysis of more than 4 million individuals, identifying 1,294 genomic regions linked to an externalizing factor. Fine-mapping and gene prioritization efforts identified 961 effector genes, with the putative causal variant associations showing robust replication in the All of Us Research Program sample. Bioinformatic analyses revealed a broadly distributed neural architecture with early and sustained involvement of GABAergic and glutamatergic neurons. Drug repurposing analyses further highlighted the role of GABAA receptors, as well as dopaminergic signaling, excitatory-inhibitory balance, and neurosteroid pathways. A genome-wide polygenic index predicted ~12% of the variance in externalizing in independent cohorts of individuals with European-like ancestry, compared to ~3% in individuals with African-like ancestry, and was associated with myriad health and life outcomes. Together, these findings map the shared genetic etiology of externalizing psychopathology and identify neurodevelopmental and synaptic mechanisms with translational relevance.

Fibromyalgia is a chronic heritable syndrome, with little prior genetic work taking a syndromic approach. In this study we aimed to discover genetic mechanisms underlying fibromyalgia. We conducted genome-wide association studies (GWAS) of fibromyalgia in subjects of European (EUR), African (AFR) and Latin American (AMR) ancestries, combining data from several samples (total N, 85,139 cases; 1,642,433 controls). We also conducted a multi-trait analysis of GWAS (MTAG), leveraging pain summary statistics to achieve enhanced power for fibromyalgia analyses. We then applied a series of post-GWAS methods to analyze the genetic association between fibromyalgia and a variety of psychological and physiological phenotypes. We found 10 genome-wide significant (GWS) loci associated with fibromyalgia in EUR, 1 in AFR, 12 cross-ancestry, and 45 in the EUR MTAG. Most of these loci were previously associated with pain, cognitive function, autoimmune response, or general health measures like BMI and blood pressure. Genetic correlation analysis revealed a moderate negative correlation with physical activity, and strong genetic correlations with chronic pain, PTSD and depression (rg ≥ 0.69). Genomic structural equation modeling helped to place fibromyalgia in the context of a set of psychiatric, medical, and lifestyle traits. Additional findings regarding local genetic correlations and genetic causality point to genetic mechanisms that provide a strong basis for some of the main characteristics of fibromyalgia and its comorbidities. These findings provide potential targets for future studies to improve diagnosis and treatment of fibromyalgia. ### Competing Interest Statement JG is paid for editorial work by the journal Complex Psychiatry. All other authors report no conflicts. MBS has in the past 3 years received consulting income from atai Life Sciences, BigHealth, Biogen, Bionomics, Boehringer Ingelheim, Delix Therapeutics, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, Karuna Therapeutics, Lundbeck, Lykos Therapeutics, NeuroTrauma Sciences, Newleos Therapeutics, Otsuka US, PureTech Health, Roche/Genentech, Sage Therapeutics, Seaport Therapeutics, and Transcend Therapeutics. Dr. Stein has stock options in EpiVario, Newleos Therapeutics, and Oxeia Biopharmaceuticals. He has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). He has also received research support from the National Institutes of Health, the Department of Veterans Affairs, and the Department of Defense. He is on the scientific advisory board of the Brain and Behavior Research Foundation and the Anxiety and Depression Association of America. ### Funding Statement This research is based in part on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by MVP000 as well as 5IO1CX001849. More details regarding this consortium are provided in the Supplementary Information. This publication does not represent the views of the Department of Veterans Affairs or the United States Government. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All of Us, The Million Veteran Program, UK Biobank, Finngen I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data will be made available upon publication

Increasing prevalence of cannabis use and cannabis use disorder (CanUD) may increase risk for psychiatric disorders. We evaluated the relationships between these cannabis traits and a range of psychiatric traits, running global and local genetic correlations, genomic structural equation modeling, colocalization analyses and Mendelian randomization analyses for causality. Global genetic analyses identified significantly different correlations between CanUD and cannabis use. A variant in strong linkage disequilibrium to one regulating CHRNA2 was significantly shared by CanUD and schizophrenia in colocalization analysis and included in a significant region in local genetic correlations between these traits. A three-factor model from genomic structural equation modeling showed that CanUD and cannabis use partially map together onto a factor with major depressive disorder and ADHD. In terms of causality, CanUD showed bidirectional causal relationships with most tested psychiatric disorders, differently from cannabis use. Increasing use of cannabis can increase rates of psychiatric disorders over time, especially in individuals who progress from cannabis use to CanUD.

Differences in sleep duration, quality, and timing are associated with variation in cognition, health outcomes, and quality of life. Genetic studies may help explain the underlying mechanisms of sleep and its relationships to other conditions. Our previous work highlighted risk loci associated with short (<6hrs) and long sleep (>9hrs), using data from the UK Biobank and the Million Veteran Program. We build on this work by conducting a genome wide association study (GWAS) and multi-ancestry meta-analysis of sleep duration as a quantitative trait. We used LD score regression (LDSC) to evaluate the correlation between sleep duration and other traits, and genomic structural equation modelling (genomicSEM) to consider the relationships between traits of interest. We identify 234 independent genome-wide significant loci for sleep duration, of which 143 are novel. The average impact of each risk variant amounts to approximately ±0.86minutes (sd=0.19), with a sum total of ± 220.5 minutes across all genome-wide significant loci. We support previous findings showing the most strongly associated gene is PAX8. Linkage disequilibrium score regression shows that the genetic architecture of sleep duration is largely distinct from other measures of sleep quality and sleep disorders. We see several examples of negative correlation between deleterious traits and the quantitative measure of sleep duration reported here, contrasting with positive associations with long and short sleep (e.g., depression, ADHD, cannabis use disorder, smoking). We derive genomic-SEM models that show short and long sleep load on separate factors, as does overall sleep duration loading alone. This is the largest available GWAS of sleep duration, and the first to extend analyses outside of European ancestry populations. We identify novel loci for sleep duration and provide insight to the shared and unique genetic architecture across multiple sleep and neuropsychiatric traits.

OBJECTIVE:Quantifying the contribution of environmental and genetic factors to alcohol use disorder (AUD) criterion count across different ancestries may provide insight into the biopsychosocial etiology of AUD. Although polygenic risk prediction represents an important future application, its utility may be enhanced when considered in the context of environmental predictors. The authors used large African- and European-ancestry samples to examine how genetic, psychiatric, and environmental factors predict AUD criterion count. METHODS:The authors analyzed data from 11,021 individuals in the Yale-Penn Study sample: 5,843 of African ancestry (AFR) and 5,178 of European ancestry (EUR). Polygenic risk scores (PRSs) were generated from genome-wide association studies of problematic alcohol use (PAU). Generalized linear regression and relative importance analyses determined the independent and interactive effects of environmental and genetic factors on AUD criterion count. RESULTS:PRSs for PAU were positively associated with AUD criterion count in both ancestries and predicted 1.9% of AUD criterion count in the EUR sample and 1.3% in the AFR sample. A combination of education, substance use in the household before age 13, annual household income, and male sex explained 73.1% of the variance in AUD criterion count in the AFR sample and 58.9% in the EUR sample. Among examined psychiatric disorders, posttraumatic stress disorder explained the most variance (10.0% in AFR, 9.4% in EUR), followed by anxiety disorders (3.4% in AFR, 6.2% in EUR) and major depressive disorder (1.3% in AFR, 2.1% in EUR). In the EUR sample, education level moderated the relationship between PRS for PAU and AUD criterion count. CONCLUSIONS:In both African and European ancestry groups, environmental factors explained the majority of the variance in AUD criterion count, but polygenic risk was also a statistically significant predictor. These findings may help inform clinical, research, and policy efforts to mitigate AUD risk.

BACKGROUND:Genetic research on nicotine dependence has utilized multiple assessments that are in weak agreement. METHODS:We conducted a genome-wide association study (GWAS) of nicotine dependence defined using the Diagnostic and Statistical Manual of Mental Disorders (DSM-NicDep) in 61,861 individuals (47,884 of European ancestry [EUR], 10,231 of African ancestry, and 3,746 of East Asian ancestry) and compared the results to other nicotine-related phenotypes. RESULTS:We replicated the well-known association at the CHRNA5 locus (lead single-nucleotide polymorphism [SNP]: rs147144681, p = 1.27E-11 in EUR; lead SNP = rs2036527, p = 6.49e-13 in cross-ancestry analysis). DSM-NicDep showed strong positive genetic correlations with cannabis use disorder, opioid use disorder, problematic alcohol use, lung cancer, material deprivation, and several psychiatric disorders, and negative correlations with respiratory function and educational attainment. A polygenic score of DSM-NicDep predicted DSM-5 tobacco use disorder criterion count and all 11 individual diagnostic criteria in the independent National Epidemiologic Survey on Alcohol and Related Conditions-III sample. In genomic structural equation models, DSM-NicDep loaded more strongly on a previously identified factor of general addiction liability than a "problematic tobacco use" factor (a combination of cigarettes per day and nicotine dependence defined by the Fagerström Test for Nicotine Dependence). Finally, DSM-NicDep showed a strong genetic correlation with a GWAS of tobacco use disorder as defined in electronic health records (EHRs). CONCLUSIONS:Our results suggest that combining the wide availability of diagnostic EHR data with nuanced criterion-level analyses of DSM tobacco use disorder may produce new insights into the genetics of this disorder.

Physical activity (PA) is one of the most fundamental traits in the animal kingdom, has pervasive health benefits, and is genetically influenced. Using data from the Million Veteran Program, we conducted genetic analyses of leisure, work and home-time PA. For leisure, we included 189,812 individuals of European ancestry (SNP-based heritability (h2) = 0.083 ± 0.005), 27,044 of African ancestry (h2 = 0.034 ± 0.017) and 10,263 of Latin American ancestry (h2 = 0.083 ± 0.036) in a cross-ancestry meta-analysis with UK Biobank data, identifying 70 lead variants. Leisure-time PA was genetically distinct from PA at home or work, with the latter two showing less health benefit with respect to health outcomes and lifespan. Mendelian randomization analyses showed a protective role of leisure-time PA against COVID-19 hospitalization (β = -0.067 ± 0.016; P = 2.8 × 10-5), and with other traits including cardiovascular and respiratory system diseases, metabolic traits and aging. These findings provide new insights into the biology of PA, showing specific causal health benefits of leisure-time PA.

Erectile dysfunction is attributable to numerous biological and psychological issues, and its prevalence increases with age. We conducted genome-wide association studies of erectile dysfunction in AllofUs subjects of European and African ancestry, then meta-analyzed our findings with published datasets [N European = 913,194 (136,867 cases); N African = 125,315 (51,599 cases)]. We identified 40 independent variants in Europeans, two in Africans, and 51 cross-ancestry. In all analyses, the strongest effect variants mapped to a non-coding region known to regulate SIM1 , previously associated with erectile dysfunction: rs78677597 (Europeans) (p = 5.32 × 10 −139 ), and rs17185536 (Africans (p = 1.17 × 10 −9 ) and cross-ancestry (p = 5.3 × 10 −138 )). Genetic correlations with psychiatric and health traits were moderate. Positive associations with phenotypes related to sexual drive may reflect ascertainment bias. This study is consistent with indications that erectile dysfunction is a complex trait influenced by multiple factors. Our findings emphasize the need to investigate genetic risk – SIM1 in particular further – to understand the mechanism through which they affect erectile function.

This study investigated the genetic and epigenetic mechanisms underlying the comorbidity of five substance dependence diagnoses (SDs; alcohol, AD; cannabis, CaD; cocaine, CoD; opioid, OD; tobacco, TD). A latent class analysis (LCA) was performed on 22,668 individuals from six cohorts to identify comorbid DSM-IV SD patterns. In subsets of this sample, we tested SD-latent classes with respect to polygenic overlap of psychiatric and psychosocial traits in 7659 individuals of European descent and epigenome-wide changes in 886 individuals of African, European, and Admixed-American descents. The LCA identified four latent classes related to SD comorbidities: AD + TD, CoD + TD, AD + CoD + OD + TD (i.e., polysubstance addiction, 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). In conclusion, 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.

Objective To examine the causal relationship between alcohol use and dementia risk across multiple ancestry groups. Design We triangulated evidence from observational and univariable and multivariable Mendelian randomization. Setting and participants Cross-ancestry observational analyses were conducted in two large prospective studies: the US Million Veteran Program and UK Biobank. One- and two-sample univariable and multivariable Mendelian randomization used de novo data from a genome-wide association study in Million Veteran Program plus publicly available data. Main outcome measure All-cause dementia. Results Among 559,559 participants (aged 56-72 years old at baseline) included in observational analyses, 14,540 received developed dementia and 48,034 died during follow-up. Observational associations between alcohol and dementia were U-shaped. Non-, heavy (>40 drinks per week - hazard ratio (HR)1.41; 95% confidence interval [CI], 1.15 to 1.74]) and dependent (1.51[1.42-1.60]) drinkers were at higher dementia risk than light drinkers. In contrast, genetic analyses revealed a monotonically increasing association between alcohol dose and dementia, with no evidence supporting a protective effect of any level of drinking. A two-fold increase in genetically-predicted alcohol use disorder prevalence was associated with a 16% increase in dementia cases (IVW OR=1.16[1.03-1.30]), and a one standard deviation increase in log-transformed drinks per week was associated with a 15% increase (IVW OR=1.15[1.03-1.27]). Conclusions Alcohol consumption has a causal role for dementia. These findings challenge a purported protective effect of moderate drinking. Reducing alcohol use could be an effective dementia prevention strategy. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research used data from the Million Veteran Program and was supported by funding from the Department of Veterans Affairs Office of Research and Development, Million Veteran Program Grant #I01CX001849, and the VA Cooperative Studies Program (CSP) study #575B, and MVP025. This publication does not represent the views of the Department of Veterans Affairs or the United States Government. AT is supported by the Wellcome Trust (216462/Z/19/Z). SBu is supported by the Wellcome Trust (225790/Z/22/Z) and the United Kingdom Research and Innovation Medical Research Council (MC\_UU\_00002/7). This research was supported by the National Institute for Health Research Cambridge Biomedical Research Centre (NIHR203312). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This research was conducted according to the guidelines of the Declaration of Helsinki and approved by the Department of Veteran Affairs Central IRB (protocol code MVP001, approved in 2010). Written informed consent has been obtained from the participants in accordance with all VA policies and under the authority of the VA Central IRB.UKB received ethical approval from the Research Ethics Committee (reference 11/NW/0382), and all participants provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Access to UK Biobank data is available following a successful application. Access to Million Veteran Program summary statistics is available through via dbGAP.

Background The impact of alcohol use on dementia risk remains contentious. Methodological limitations of previous studies have made distinguishing causation from confounding difficult. Mendelian randomization is a quasi-experimental method that can estimate causal effects via genetics. Methods We estimated dose-response relationships between alcohol and dementia in observational and genetic analyses. First, we pooled and harmonized individual-level phenotype data from two prospective cohort studies: the US Million Veteran Program (MVP) and UK Biobank (UKB; mean follow-up 4 and 12 years respectively). Associations were examined using Cox regression analysis and results combined using random-effects meta-analysis. We compared these findings with genetic associations between alcohol use and dementia (calculated de novo) using data from 2.4 million participants using Mendelian randomization. Results 559,559 participants (247,136 from MVP and 312,423 from UKB) aged 56-72 years old at baseline were included in observational analyses. 14,540 developed dementia and 48,034 died during follow-up. Observational associations between alcohol and dementia were U-shaped, meaning that nondrinkers, heavy (>40 drinks per week) drinkers (hazard ratio=1.41[1.15 to 1.74]) and dependent drinkers (1.51[1.42-1.60]) were all at higher dementia risk compared with light drinkers. In contrast, genetic analyses revealed a monotonically increasing association between alcohol dose and dementia, with no evidence supporting a protective effect of any level of drinking. A two-fold increase in genetically-predicted alcohol use disorder prevalence was associated with a 16 % increase in dementia cases (IVW OR=1.16[1.03-1.30]), and a one standard deviation increase in log-transformed drinks per week was associated with a 15 % increase (IVW OR=1.15[1.03-1.27]). Discussion Alcohol consumption has a causal role for dementia. Halving the population prevalence of alcohol use disorder would lead to a 16 % reduction in dementia cases.

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, Neffective = 387,649) and from the Million Veteran Program and the Psychiatric Genomics Consortium meta-analyses for alcohol use disorder (AUD, Neffective = 296,974), cannabis use disorder (CanUD, Neffective = 161,053), opioid use disorder (OUD, Neffective = 57,120), and problematic tobacco use (PTU, Neffective = 270,120). SNP-based heritability was estimated for each of the traits and genetic correlation (rg) 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 (rg = 0.26, p = 7.55 × 10−18), CanUD (rg = 0.37, p = 8.21 × 10−37), OUD (rg = 0.20, p = 1.50 × 10−3), and PTU (rg = 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 (ppleiotropy = 2.69 × 10−8), and CADM2 rs1248857 (ppleiotropy = 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.

Background:The long-term impact of opioid use disorder (OUD) on brain health has been little explored although of potentially high public health importance. Objectives:To investigate the potential causal impact of OUD on later life brain health outcomes, including dementia, stroke and brain structure. Methods:Observational and Mendelian randomization (MR) analyses were conducted. Participants included in observational analyses were enrolled in the US Million Veteran Program (MVP). Cox proportional hazards were used to examine the association between electronic health record (EHR)-derived diagnoses of OUD and incident dementia in European and African ancestry populations. Two-sample MR was applied to explore the association between genetic predisposition to OUD and dementia, as well as key endophenotypes including brain structure. Several analyses were used for insight into aetiological pathways, including cis-MR to assess the impact of genetically-proxied opioid receptor perturbation, Bayesian colocalization, and polygenic risk score analyses of longitudinal brain changes in non-opioid users from the Lifebrain project (n=229). Results:Amongst 222,518 MVP participants, 8397 developed dementia during follow up. Participants with OUD (n=9,399) were younger and more likely to be male. In observational analyses, OUD was associated with a higher risk of incident all-cause dementia (hazard ratio [HR]=1.56, 95% confidence interval [CI] [1.39,1.76];p=2.23×10 -13 ), Alzheimer's [HR=1.40[1.04,1.87]; p=0.02) and vascular dementia (HR=1.49[1.19,1.86];p=0.0004). In the genetic analysis, genetically-proxied OUD also associated with higher dementia risk. A doubling in genetically-proxied OUD prevalence was associated with a 77% increase in odds of dementia (IVW OR=1.77[1.43,2.19];p=1.69×10 ⁻⁷ ). Variation in μ-opioid receptor genes were strongly associated with dementia risk. No significant associations were observed with brain structure in non-opioid users, nor in lower powered non-European ancestry groups. Conclusions:These findings suggest a potential causal impact of opioid use disorder on dementia. Genetic analyses supported an aetiological role of μ-opioid receptor pathways. Further pharmacovigilance and investigation into the long-term effects of opioids on brain health are warranted.