A Multivariate Genome-Wide Association Study Reveals Neural Correlates and Common Biological Mechanisms of Psychopathology Spectra.

There is considerable comorbidity across externalizing and internalizing behavior dimensions of psychopathology. We applied genomic structural equation modeling (gSEM) to genome-wide association study (GWAS) summary statistics to evaluate the factor structure of externalizing and internalizing psychopathology across 16 traits and disorders among European-ancestry individuals (n's = 16,400 to 1,074,629). We conducted GWAS on factors derived from well-fitting models. Downstream analyses served to identify biological mechanisms, explore drug repurposing targets, estimate genetic overlap between the externalizing and internalizing spectra, and evaluate causal effects of psychopathology liability on physical health. Both a correlated factors model, comprising two factors of externalizing and internalizing risk, and a higher-order single-factor model of genetic effects contributing to both spectra demonstrated acceptable fit. GWAS identified 409 lead single nucleotide polymorphisms (SNPs) associated with externalizing and 85 lead SNPs associated with internalizing, while the second-order GWAS identified 256 lead SNPs contributing to broad psychopathology risk. In bivariate causal mixture models, nearly all externalizing and internalizing causal variants overlapped, despite a genetic correlation of only 0.37 (SE = 0.02) between them. Externalizing genes showed cell-type specific expression in GABAergic, cortical, and hippocampal neurons, and internalizing genes were associated with reduced subcallosal cortical volume, providing insight into the neurobiological underpinnings of psychopathology. Genetic liability for externalizing, internalizing, and broad psychopathology exerted causal effects on pain, general health, cardiovascular diseases, and chronic illnesses. These findings underscore the complex genetic architecture of psychopathology, identify potential biological pathways for the externalizing and internalizing spectra, and highlight the physical health burden of psychiatric comorbidity.

Multi-ancestry Whole-exome Sequencing Study of Alcohol Use Disorder in Two Cohorts.

Alcohol use disorder (AUD) is a leading cause of death and disability worldwide. There has been substantial progress in identifying genetic variants underlying AUD. However, there are few whole-exome sequencing (WES) studies of AUD. We analyzed WES of 4,530 samples from the Yale-Penn cohort and 469,835 samples from the UK Biobank (UKB). After quality control, 1,420 AUD cases and 619 controls of European ancestry (EUR) and 1,142 cases and 608 controls of African ancestry (AFR) from Yale-Penn were retained for subsequent analyses. WES data from 415,617 EUR samples (12,861 cases), 6,142 AFR samples (130 cases) and 4,607 South Asian (SAS) samples (130 cases) from UKB were also analyzed. Single-variant association analysis identified the well-known functional variant rs1229984 in ADH1B ( P =4.88×10 -31 ) and several other common variants in ADH1C . Gene-based tests identified ADH1B ( P =1.00×10 -31 ), ADH1C ( P =5.23×10 -7 ), CNST ( P =1.19×10 -6 ), and IFIT5 (3.74×10 -6 ). This study extends our understanding of the genetic basis of AUD.

Cost-Effective and Scalable Clonal Hematopoiesis Assay Provides Insight into Clonal Dynamics.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related phenomenon in which hematopoietic stem cells acquire mutations in a select set of genes commonly mutated in myeloid neoplasia which then expand clonally. Current sequencing assays to detect CHIP mutations are not optimized for the detection of these variants and can be cost-prohibitive when applied to large cohorts or to serial sequencing. In this study, an affordable (approximately US $8 per sample), accurate, and scalable sequencing assay for CHIP is introduced and validated. The efficacy of the assay was demonstrated by identifying CHIP mutations in a cohort of 456 individuals with DNA collected at multiple time points in Vanderbilt University's biobank and quantifying clonal expansion rates over time. A total of 101 individuals with CHIP/clonal cytopenia of undetermined significance were identified, and individual-level clonal expansion rate was calculated using the variant allele fraction at both time points. Differences in clonal expansion rate by driver gene were observed, but there was also significant individual-level heterogeneity, emphasizing the multifactorial nature of clonal expansion. Additionally, the study explores mutation co-occurrence and clonal competition between multiple driver mutations.

Mapping Psychosis Risk States onto the Hierarchical Taxonomy of Psychopathology Using Hierarchical Symptom Dimensions.

Clinical high risk for psychosis (CHR) is a transdiagnostic risk state. However, it is unclear how risk states such as CHR fit within broad transdiagnostic models such as the Hierarchical Taxonomy of Psychopathology (HiTOP). In this study, a hierarchical dimensional symptom structure was defined by unfolding factor analysis of self-report data from 3,460 young adults (mage=20.3). A subsample (n=436) completed clinical interviews, 85 of whom met CHR criteria. Regression models examined relationships between symptom dimensions, CHR status, and clinician-rated symptoms. CHR status was best explained by a reality distortion dimension, with contributions from internalizing dimensions. Positive and negative attenuated psychotic symptoms were best explained by multiple psychotic and nonpsychotic symptom dimensions including reality distortion, distress, fear, detachment, and mania. Attenuated psychotic symptoms are a complex presenting problem warranting comprehensive assessment. HiTOP can provide both diagnostic precision and broad transdiagnostic coverage, making it a valuable resource for use with at-risk individuals.

Chemical codes promote selective compartmentalization of proteins.

Cells have evolved mechanisms to distribute ∼10 billion protein molecules to subcellular compartments where diverse proteins involved in shared functions must efficiently assemble. Such assembly is presumed to unfold as a result of specific interactions between biomolecules; however, recent evidence suggests that distinctive chemical environments within subcellular compartments may also play an important role. Here, we test the hypothesis that protein groups with shared functions also share codes that guide them to compartment destinations. To test our hypothesis, we developed a transformer large language model, called ProtGPS, that predicts with high performance the compartment localization of human proteins excluded from the training set. We then demonstrate ProtGPS can be used for guided generation of novel protein sequences that selectively assemble into specific compartments in cells. Furthermore, ProtGPS predictions were sensitive to disease-associated mutations that produce changes in protein compartmentalization, suggesting that this type of pathogenic dysfunction can be discovered in silico. Our results indicate that protein sequences contain not only a folding code, but also a previously unrecognized chemical code governing their distribution in specific cellular compartments.

Acetate Assistance in Regioselective Hydroamination of Allenamides: A Combined Experimental and Density Functional Theory Study.

A key factor in the development of selective nucleophilic addition to allenamides is controlling the reactivity of electrophilic intermediates, which is generally achieved using an electrophilic activator via conjugated iminium intermediates. In this combined experimental and computational study, we show that a general and highly chemoselective hydroamination of allenamides can be accomplished using a combination of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and NaOAc. Experimental mechanistic studies revealed that HFIP mediates proton transfer to activate the allenamide, while the acetate additive significantly contributes to N-selective interception. This strategy enables a general hydroamination of allenamides without the use of metals. We demonstrated that various functionalized 1,3-diamines could be readily synthesized and diversified into value-added structural motifs. Detailed mechanistic investigations using the density functional theory revealed the role of NaOAc in the formation of reactive electrophilic intermediates, which ultimately governed the selective formation of 1,3-diamine products. Critically, calculations of the potential energy surface around the proton-transfer transition state revealed that two different reactive electrophilic intermediates were formed when NaOAc was added.

Multi-ancestry meta-analysis of tobacco use disorder identifies 461 potential risk genes and reveals associations with multiple health outcomes.

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviours and although strides have been made using genome-wide association studies to identify risk variants, most variants identified have been for nicotine consumption, rather than TUD. Here we leveraged four US biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records) in 653,790 individuals (495,005 European, 114,420 African American and 44,365 Latin American) and data from UK Biobank (ncombined = 898,680). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviours in children and hundreds of medical outcomes, including HIV infection, heart disease and pain. This work furthers our biological understanding of TUD and establishes electronic health records as a source of phenotypic information for studying the genetics of TUD.

Reductions in World Health Organization risk drinking level are associated with improvements in sleep problems among individuals with alcohol use disorder.

AIMS: Among individuals with alcohol use disorder (AUD), sleep disturbances are pervasive and contribute to the etiology and maintenance of AUD. However, despite increased attention toward the relationship between alcohol use and sleep, limited empirical research has systematically examined whether reductions in drinking during treatment for AUD are associated with improvements in sleep problems. METHODS: We used data from a multisite, randomized, controlled trial that compared 6 months of treatment with gabapentin enacarbil extended-release with placebo for adults with moderate-to-severe AUD (N = 346). The Timeline Follow-back was used to assess WHO risk drinking level reductions and the Pittsburgh Sleep Quality Index was used to assess sleep quality over the prior month at baseline and the end of treatment. RESULTS: Sleep problem scores in the active medication and placebo groups improved equally. Fewer sleep problems were noted among individuals who achieved at least a 1-level reduction (B = -0.99, 95% confidence interval (CI) [-1.77, -0.20], P = .014) or at least a 2-level reduction (B = -0.80, 95% CI [-1.47, -0.14], P = .018) in WHO risk drinking levels at the end of treatment. Reductions in drinking, with abstainers excluded from the analysis, also predicted fewer sleep problems at the end of treatment (1-level: B = -1.01, 95% CI [-1.83, -0.20], P = .015; 2-level: B = -0.90, 95% CI [-1.59, -0.22], P = .010). CONCLUSIONS: Drinking reductions, including those short of abstinence, are associated with improvements in sleep problems during treatment for AUD. Additional assessment of the causal relationships between harm-reduction approaches to AUD and improvements in sleep is warranted.

A regulatory focus theory perspective on the dynamics between action and power.

Building on the strong consensus that the experience of power motivates individuals to take action, prior research postulates a positively reinforcing cycle wherein taking action leads to power, which in turn leads to subsequent actions. Applying regulatory focus theory, we differentiate between promotion-oriented and prevention-oriented actions to develop a within-person theory of when and why promotion-oriented and prevention-oriented actions should relate to power, and vice-versa. Across two studies, we find that when employees engaged in promotive voice behaviors, they were more likely to experience a sense of power; this effect was amplified for employees with trait promotion focus. When employees engaged in prohibitive voice behaviors, employees with trait prevention focus were less likely to experience a sense of power. The experience of power subsequently motivated employees to engage in promotive voice behaviors, but not prohibitive voice behaviors. By elucidating the differences between promotion and prevention pathways of action and power, our research challenges the notion that action and power positively reinforce each other. We discuss the theoretical and practical implications of our findings. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Reductions in World Health Organization Risk Drinking Level Are Associated With Reductions in Alcohol Use Disorder Diagnosis and Criteria: Evidence From an Alcohol Pharmacotherapy Trial.

OBJECTIVES: This study aimed to evaluate the validity of World Health Organization (WHO) risk drinking level reductions as meaningful endpoints for clinical practice and research. This study examined whether such reductions were associated with a lower likelihood of a current alcohol use disorder (AUD) diagnosis and fewer AUD criteria. METHODS: We conducted a secondary data analysis to address these objectives using data from a multisite randomized controlled trial of gabapentin enacarbil extended release in treating moderate to severe AUD among adults (N = 346). Participants received gabapentin enacarbil extended release or placebo for 6 months. The timeline follow-back was used to assess WHO risk drinking level reductions, and the Mini-International Neuropsychiatric Interview was used to assess Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) AUD diagnosis and criteria at baseline (past year) and end of treatment (past month). RESULTS: Most participants (80.1%) achieved at least a 1-level reduction in the WHO risk drinking levels from baseline to end of treatment, and nearly half of participants (49.8%) achieved at least a 2-level reduction. At least a 1-level reduction or at least a 2-level reduction in WHO risk drinking level predicted lower odds of an active AUD diagnosis (1-level: odds ratio, 0.74 [95% confidence interval (CI), 0.66-0.84]; 2-level: odds ratio, 0.71 [95% CI, 0.64-0.79]) and fewer AUD criteria (1-level: B, -1.66 [95% CI, -2.35 to -0.98]; 2-level: B, -1.76 [95% CI, -2.31 to -1.21]) at end of treatment. CONCLUSIONS: World Health Organization risk drinking level reductions correlate with Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) AUD diagnosis and criteria, providing further evidence for their use as endpoints in alcohol intervention trials, which has potential implications for broadening the base of AUD treatment.

Genomic evolution shapes prostate cancer disease type.

The development of cancer is an evolutionary process involving the sequential acquisition of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues. We investigated the genomic evolution of prostate cancer through the application of three separate classification methods, each designed to investigate a different aspect of tumor evolution. Integrating the results revealed the existence of two distinct types of prostate cancer that arise from divergent evolutionary trajectories, designated as the Canonical and Alternative evolutionary disease types. We therefore propose the evotype model for prostate cancer evolution wherein Alternative-evotype tumors diverge from those of the Canonical-evotype through the stochastic accumulation of genetic alterations associated with disruptions to androgen receptor DNA binding. Our model unifies many previous molecular observations, providing a powerful new framework to investigate prostate cancer disease progression.

The complex polyploid genome architecture of sugarcane.

Sugarcane, the world's most harvested crop by tonnage, has shaped global history, trade and geopolitics, and is currently responsible for 80% of sugar production worldwide1. While traditional sugarcane breeding methods have effectively generated cultivars adapted to new environments and pathogens, sugar yield improvements have recently plateaued2. The cessation of yield gains may be due to limited genetic diversity within breeding populations, long breeding cycles and the complexity of its genome, the latter preventing breeders from taking advantage of the recent explosion of whole-genome sequencing that has benefited many other crops. Thus, modern sugarcane hybrids are the last remaining major crop without a reference-quality genome. Here we take a major step towards advancing sugarcane biotechnology by generating a polyploid reference genome for R570, a typical modern cultivar derived from interspecific hybridization between the domesticated species (Saccharum officinarum) and the wild species (Saccharum spontaneum). In contrast to the existing single haplotype ('monoploid') representation of R570, our 8.7 billion base assembly contains a complete representation of unique DNA sequences across the approximately 12 chromosome copies in this polyploid genome. Using this highly contiguous genome assembly, we filled a previously unsized gap within an R570 physical genetic map to describe the likely causal genes underlying the single-copy Bru1 brown rust resistance locus. This polyploid genome assembly with fine-grain descriptions of genome architecture and molecular targets for biotechnology will help accelerate molecular and transgenic breeding and adaptation of sugarcane to future environmental conditions.

A multi-ancestry genetic study of pain intensity in 598,339 veterans.

Chronic pain is a common problem, with more than one-fifth of adult Americans reporting pain daily or on most days. It adversely affects the quality of life and imposes substantial personal and economic costs. Efforts to treat chronic pain using opioids had a central role in precipitating the opioid crisis. Despite an estimated heritability of 25-50%, the genetic architecture of chronic pain is not well-characterized, in part because studies have largely been limited to samples of European ancestry. To help address this knowledge gap, we conducted a cross-ancestry meta-analysis of pain intensity in 598,339 participants in the Million Veteran Program, which identified 126 independent genetic loci, 69 of which are new. Pain intensity was genetically correlated with other pain phenotypes, level of substance use and substance use disorders, other psychiatric traits, education level and cognitive traits. Integration of the genome-wide association studies findings with functional genomics data shows enrichment for putatively causal genes (n = 142) and proteins (n = 14) expressed in brain tissues, specifically in GABAergic neurons. Drug repurposing analysis identified anticonvulsants, ß-blockers and calcium-channel blockers, among other drug groups, as having potential analgesic effects. Our results provide insights into key molecular contributors to the experience of pain and highlight attractive drug targets.

The hierarchical taxonomy of psychopathology in clinical high risk for psychosis: Validation and extension.

The Hierarchical Taxonomy of Psychopathology (HiTOP) consortium's transdiagnostic dimensional model of psychopathology has considerable support; however, this model has been underresearched in individuals at clinical high risk for psychosis (CHR-P), a population that may advance the model. CHR-P individuals not only have attenuated psychotic symptoms that vary in severity, but also have many comorbid diagnoses and varied clinical outcomes, including disorders with uncertain relations to HiTOP (e.g., obsessive-compulsive disorder). The present study used self-report and interview data from North American Prodrome Longitudinal Study-3 (710 CHR, 96 controls) to replicate the HiTOP model and test specific hypotheses regarding disorders with uncertain relations to its dimensions. Additionally, the present study examined the HiTOP model in relation to childhood trauma, declines in social functioning, and development of full psychosis. Confirmatory factor analysis indicated that the HiTOP model's fit was nearly adequate (e.g., comparative fit index = .89), though several theory-relevant modifications were indicated. Additionally, specific tests were conducted to gain a more fine-grained perspective on how disorders with less clear prior evidence were related to the HiTOP model. Notable findings from these analyses include bipolar spectrum disorders relating to the psychosis super spectrum (i.e., .39 loading), and obsessive-compulsive disorder showing a complex pattern of loadings (e.g., internalizing and psychosis). The final model parsimoniously accounted for childhood trauma (e.g., super spectra rs = .22-.32), associations with current functioning, and predicted future conversion to a psychotic disorder (e.g., super spectra R² = .13). Overall, these results inform the HiTOP model and suggest its promise for CHR-P research. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Identification of Psychosis Risk and Diagnosis of First-Episode Psychosis: Advice for Clinicians.

Early detection of psychotic-spectrum disorders among adolescents and young adults is crucial, as the initial years after psychotic symptom onset encompass a critical period in which psychosocial and pharmacological interventions are most effective. Moreover, clinicians and researchers in recent decades have thoroughly characterized psychosis-risk syndromes, in which youth are experiencing early warning signs indicative of heightened risk for developing a psychotic disorder. These insights have created opportunities for intervention even earlier in the illness course, ideally culminating in the prevention or mitigation of psychosis onset. However, identification and diagnosis of early signs of psychosis can be complex, as clinical presentations are heterogeneous, and psychotic symptoms exist on a continuum. When a young person presents to a clinic, it may be unclear whether they are experiencing common, mild psychotic-like symptoms, early warning signs of psychosis, overt psychotic symptoms, or symptoms better accounted for by a non-psychotic disorder. Therefore, the purpose of this review is to provide a framework for clinicians, including those who treat non-psychotic disorders and those in primary care settings, for guiding identification and diagnosis of early psychosis within the presenting clinic or via referral to a specialty clinic. We first provide descriptions and examples of first-episode psychosis (FEP) and psychosis-risk syndromes, as well as assessment tools used to diagnose these conditions. Next, we provide guidance as to the differential diagnosis of conditions which have phenotypic overlap with psychotic disorders, while considering the possibility of co-occurring symptoms in which case transdiagnostic treatments are encouraged. Finally, we conclude with an overview of early detection screening and outreach campaigns, which should be further optimized to reduce the duration of untreated psychosis among youth.

The Use of Intralipid Infusions in the Prevention of Embryo Implantation Failure.

Intralipids have been suggested to suppress uterine natural killer cell activity, which could potentially improve implantation rates in women with recurrent loss. We report a case of a 41-year-old African woman with recurrent pregnancy loss who had elevated uterine killer cell activity and for whom intralipid infusion was used to achieve pregnancy. We recommend routine uterine natural killer cell testing for women with recurrent pregnancy loss and further research on newer intravenous lipid emulsions in fertility medicine.

MR-Safe Cartesian Platform for Active Cardiac Shimming: Preliminary Validation.

OBJECTIVE: Implanted Cardioverter Defibrillators (ICDs) induce a large (100 parts per million) inhomogeneous magnetic field in the magnetic resonance imaging (MRI) scanner which cannot be corrected by the scanner's built-in shim coils, leading to significant image artifacts that can make portions of the heart unreadable. To compensate for the field inhomogeneity, an active shim coil capable of countering the field deviation in user-defined regions was designed that must be optimally placed at patient-specific locations. We aim to develop and evaluate an MR-safe robotic solution for automated shim coil positioning. METHODS: We designed and fabricated an MR-safe Cartesian platform that holds the shim coil inside the scanner. The platform consists of three lead screw stages actuated by pneumatic motors, achieving decoupled translations of 140 mm in each direction. The platform is made of plastics and fiberglass with the control electronics placed outside the scanner room, ensuring MR safety. Mechanical modeling was derived to provide design specifications. RESULTS: Experiments show that the platform achieves less than 2 mm average motion error and 0.5 mm repeatability in all directions, and reduces the adjustment time from > 5 min to a few seconds. Phantom and animal trials were conducted, showing that the proposed system is able to position a heavy shim coil (> 3 kg) for improved ICD artifact suppression. CONCLUSION: This robotic platform provides an effective method for reliable shim coil positioning inside the scanner. SIGNIFICANCE: This work contributes to improving cardiac MRI quality that could facilitate accurate diagnosis and treatment planning for patients with implanted ICDs.

Pleiotropy and genetically inferred causality linking multisite chronic pain to substance use disorders.

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.

Single Nucleotide Polymorphisms in Coronary Microvascular Dysfunction.

Coronary microvascular dysfunction is an underdiagnosed pathologic process that is associated with adverse clinical outcomes. There are data to suggest that coronary microvascular dysfunction, in some cases, may be genetically determined. We present an updated review of single nucleotide polymorphisms in coronary microvascular dysfunction.

Genetic and non-genetic predictors of risk for opioid dependence.

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.