Background and Aims:Substance use disorders (SUDs) are heritable and share genetic variance with externalizing and internalizing psychopathology. Although recent gene identification efforts have demonstrated the value of modeling the shared genetic architecture among SUDs and externalizing, most research has thus far failed to account for overlap with internalizing. In this study, we aim to characterize the genetic relationships of both externalizing and internalizing with SUDs. Design and setting:We used genome-wide association study (GWAS) summary statistics derived from previously published studies of externalizing, internalizing, and SUD outcomes to quantify the genetic overlap between these phenotypes. We characterize this overlap using omnibus, partial, and local genetic correlations, estimates of their shared polygenic effects, genetic causality models, polygenic score (PGS) analyses, and estimates of each SUDs residual variance derived from models in Genomic SEM. Participants:We used GWAS summary statistics from individuals whose genomes were most similar to those from reference panels sampled from Europe (Ns ranged from 45,395 to 1,565,618) and Africa (Ns ranged from 30,000 to 122,571). For polygenic scores analyses, we used data from individuals of European and African ancestry groups available in the Collaborative Study on the Genetics of Alcoholism (COGA) sample (N Maximum = 7,394 for European-like genomes and 3,238 for African-like genomes). Measurements:Measurements in this study include GWAS summary statistics for externalizing, internalizing, and four substance use disorders: problematic alcohol use (PAU), cannabis use disorder (CUD), opioid use disorder (OUD), and tobacco use disorder (TUD). SUD outcomes in COGA were DSM-IV symptom counts of AUD, CUD, and OUD and scores on the Fagerstrom Test for Nicotine Dependence. Findings:We found strong genetic relationships of externalizing and, to a lesser extent, internalizing with all SUDs across methods. Despite their more modest associations, internalizing emerged as an important genetic correlate of SUDs. After accounting for variance shared with externalizing, partial genetic correlations between internalizing and SUDs were attenuated but, with the exception of TUD, still significant. Similarly, the PGSINT accounted for a statistically significant increase in variance over and above PGSEXT. Two SUD specific patterns emerged such that TUD was least associated with both psychopathology spectra and OUD was most strongly related to internalizing relative to other SUDs. Conclusions:From these findings we conclude that shared genetic influences may explain comorbidity observed between SUDs and internalizing disorders and suggest that genetic risk for internalizing should be incorporated into SUD identification and prevention efforts. Future gene identification efforts should study SUDs in the context of both externalizing and internalizing psychopathology.

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.

Personality traits describe stable differences in how people think, feel and behave, and how they interact with and experience their social and physical environments1,2. Many questions remain unanswered about associations between DNA and personality traits, such as their robustness, their generalizability and the biological and social pathways through which they act. Here we meta-analyse data across 46 cohorts comprising 611,037 to 1.14 million participants with European-like and African-like genomes for genome-wide association studies (GWAS) of the Big Five personality traits (extraversion, agreeableness, conscientiousness, neuroticism and openness to experience), and data from up to 50,725 participants for within-family GWAS. We identify 1,260 lead genetic variants associated with personality, including 824 novel variants3. Common genetic variants explain a moderate 4.8-9.3% of the variance in measures of each trait, and 9.3-13.3% among instruments with typical measurement reliability. Genetic associations with personality are highly consistent but not identical across geography, reporter (self versus close other), age group and measurement instrument, and we find minimal spousal assortment for personality in recent history. In contrast to many other social and behavioural traits4,5, within-family GWAS and polygenic index analyses indicate that genetic associations with personality are minimally confounded by the shared family environment. Polygenic prediction, genetic correlation and Mendelian randomization analyses indicate that personality traits have widespread, potentially causal associations with consequential behaviours and life outcomes. Overall, we find that the genetic architecture of personality is robustly generalizable, minimally confounded and widely relevant to human experience.

Importance:Cannabis use remains prevalent in youth despite concerns regarding its potential impact on cognitive function. Unraveling whether the association between cannabis use and cognition is partially due to preexisting differences or primarily related to use is vital to understanding underlying mechanisms. Objective:To estimate the longitudinal association between cannabis initiation and cognitive trajectories, indexed by task performance and P3 event-related potential (ERP), and to estimate whether baseline cognition is associated with cannabis initiation. Design:Data were analyzed from the ongoing longitudinal Collaborative Study on the Genetics of Alcoholism (COGA) cohort, which was followed up approximately every 2-5 years from 2004 to 2025. Setting:6 sites across the United States. Participants:Adolescent and young adult offspring of past COGA participants and control families who reported on their cannabis use and who had Visual Oddball (VOP) performance and P3 ERP data (N=4814; 52.4% female, 68.4% white) were grouped based on the timing of cognitive data collection relative to cannabis initiation into Pre-onset (n=2,449; ≥1 assessment) and Post-onset (n=998; ≥3 assessments) subsamples. Main Outcomes and Measures:VOP measures include performance accuracy (%), reaction times (ms), and P3 amplitude (μV) and latency (ms) during target trials. Cannabis measures included lifetime use of cannabis (i.e., ever used) and age at first use. Results:High P3 amplitude, and prolonged P3 latency and reaction time were associated with a reduced hazard of cannabis initiation (All Hazards Ratio, [H.R.s]< 0.91, p's<.008). Following initiation, cannabis use was associated with steeper declines in P3 amplitude (b=-0.29, p=0.02) and stabilized reaction time (b=0.35; p=0.005). Steeper decline in P3 amplitude (i.e., slope) was associated with greater cannabis progression (e.g., Cannabis Use Disorder, Odds Ratio, [O.R.]=2.34, p<.001), whereas steeper decline in reaction time was associated with reduced progression (O.R.=.79, p=.002). Conclusion:Baseline P3 indices and reaction time were associated with cannabis initiation, while cannabis use was associated with subsequent changes in P3 amplitude and reaction time trajectories. These findings indicate that accelerated neurodevelopment may modify the likelihood of cannabis initiation which, in turn, may further contribute to neurocognitive changes that deepen cannabis involvement. Key Points:Question: Are associations between cannabis use and cognition attributable to preexisting neurodevelopmental differences, related to cannabis use, or reciprocal processes?Findings: In this longitudinal cohort study of participants from the Collaborative Study on the Genetics of Alcoholism (COGA), high P3 amplitude and prolonged P3 latency and reaction time were associated with reduced risk of cannabis initiation. Following initiation, cannabis use was associated with steeper declines in P3 amplitude and faster but stabilized reaction time.Meaning: Accelerated neurodevelopment may modify the likelihood of cannabis initiation which, in turn, further contribute to neurocognitive changes that deepen cannabis involvement and make it problematic.

Suicidal thoughts and behaviors originate from heterogeneous mechanisms, including behavioral disinhibition characteristic of "externalizing" disorders (e.g., substance use disorders, antisocial personality disorder, etc.). Prior work has demonstrated strong genetic overlap between externalizing and suicide attempts. In the current analysis, we investigate the co-occurrence between a broader array of suicide phenotypes (i.e., suicide deaths, non-fatal attempts, suicidal ideation) and the externalizing spectrum using data from the Million Veteran Program (MVP) Cohort. We leverage the large-scale MVP database to (1) estimate a latent genomic factor for externalizing comprised of MVP data (MVP-EXT) using genomic structural equation modeling (GenomicSEM), (2) validate these results against prior externalizing models and other traits, (3) examine the genetic overlap between externalizing and suicide outcomes using multiple approaches (e.g., genetic correlations, polygenic scores, and post mortem brain tissue of suicide deaths), and (4) explore whether phenotypic externalizing is prospectively associated with death by suicide. We identify 155 loci in our meta-analysis of European-like (EUR-like, N = 310,498) and African-like (AFR-like, N = 99,949) MVP participants. MVP-EXT showed a strong genetic correlation with a prior, non-MVP externalizing factor (rG = 0.87, 95% CI = 0.83, 0.91) and suicide attempt in both EUR-like (rG = 0.67, 95% CI = 0.60, 0.74) and AFR-like (rG = 0.62, 95% CI = 0.42, 0.81) veterans. MVP-EXT polygenic scores were associated with suicidal ideation (OR = 1.09, 95% CI = 1.05, 1.13) and suicide attempts (OR = 1.20, 95% CI = 1.13, 1.27) in independent cohorts. MVP-EXT associated genes showed significant enrichment particularly within inhibitory neurons in suicide deaths compared to deaths from other causes. A phenotypic score for externalizing was prospectively associated with death by suicide in MVP (HR = 1.39, 95% CI = 1.33, 1.45). In total, our results reiterate that, while the relation between suicide with internalizing disorders has generally received more attention, externalizing is an important risk factor for suicide related behaviors. Greater attention should be paid to these problems as potential antecedents of suicide-related behaviors.

Ongoing efforts to identify genes involved in substance use disorders (SUDs) often focus on individual disorders despite high rates of co-occurrence with each other and other externalizing traits. Here, we investigate whether incorporating data on other externalizing traits can boost power to detect without sacrificing specificity of SUD genetic signal. We used multivariate genomic analyses and downstream biological annotation and genetic association analyses to explore this question. We found that joint analysis of SUDs and other externalizing traits resulted in increased insights into the neurobiology of broad and substance-specific SUD risk. We found no evidence of loss of specificity for SUD genetic signal but note improvements in our ability to characterize the neurobiology of broad and substance-specific SUD genetic effects. Our findings suggest that genetic risk for SUDs operates largely via pathways shared with other behaviors characterized by behavioral disinhibition, with additional substance-specific risk, and that modeling this shared disposition improves gene discovery.

Objective Understanding how genetic risk unfolds across development will be important for using genetics to inform prevention and early intervention. The current study leverages information from 5 large datasets to characterize behavioral manifestations of a genetic liability toward externalizing from ages 6 months to 26 years. Method We used polygenic scores (PGS) derived from a multivariate genome-wide association study (GWAS) of externalizing that identified hundreds of significantly associated genetic variants (EXTPGS) to estimate associations of genetic liability with relevant phenotypes within and across developmental periods, ranging from toddlerhood to early adulthood. We used data from 5 population- and family-based datasets spanning 3 countries. Results The EXTPGS was significantly associated with a breadth of externalizing phenotypes from toddlerhood to early adulthood. Higher EXTPGS was consistently associated with measures of impulsivity from early adolescence to early adulthood. Individuals with higher EXTPGS were more likely to experience conduct problems and symptoms of oppositional defiant and attention-deficit/hyperactivity disorders. Furthermore, the EXTPGS was associated with higher levels of substance use and problems beginning in early adolescence through early adulthood, including alcohol and illicit drug use. There was minimal evidence for sex interactions. Conclusion A genetic liability toward externalizing is associated a wide array of behaviors and psychiatric/substance use outcomes beginning as early as childhood and through emerging adulthood. The early emergence and breadth of behaviors associated with a genetic liability toward externalizing could inform prevention and intervention.

Alcohol use disorder (AUD) and related health conditions result from a complex interaction of genetic, neural and environmental factors, with differential impacts across the lifespan. From its inception, the Collaborative Study on the Genetics of Alcoholism (COGA) has focused on the importance of brain function as it relates to the risk and consequences of alcohol use and AUD, through the examination of noninvasively recorded brain electrical activity and neuropsychological tests. COGA's sophisticated neurophysiological and neuropsychological measures, together with rich longitudinal, multi-modal family data, have allowed us to disentangle brain-related risk and resilience factors from the consequences of prolonged and heavy alcohol use in the context of genomic and social-environmental influences over the lifespan. COGA has led the field in identifying genetic variation associated with brain functioning, which has advanced the understanding of how genomic risk affects AUD and related disorders. To date, the COGA study has amassed brain function data on over 9871 participants, 7837 with data at more than one time point, and with notable diversity in terms of age (from 7 to 97), gender (52% female), and self-reported race and ethnicity (28% Black, 9% Hispanic). These data are available to the research community through several mechanisms, including directly through the NIAAA, through dbGAP, and in collaboration with COGA investigators. In this review, we provide an overview of COGA's data collection methods and specific brain function measures assessed, and showcase the utility, significance, and contributions these data have made to our understanding of AUD and related disorders, highlighting COGA research findings.

The collaborative study on the genetics of alcoholism (COGA) is a multi-site, multidisciplinary project with the goal of identifying how genes are involved in alcohol use disorder and related outcomes, and characterizing how genetic risk unfolds across development and in conjunction with the environment and brain function. COGA is a multi-generational family-based study in which probands were recruited through alcohol treatment centers, along with a set of community comparison families. Nearly 18,000 individuals from >2200 families have been assessed over a period of over 30 years with a rich phenotypic battery that includes semi-structured psychiatric interviews and questionnaire measures, along with DNA collection and electrophysiological data on a large subset. Participants range in age from 7 to 97, with many having longitudinal assessments, providing a valuable opportunity to study alcohol use and problems across the lifespan. Here we provide an overview of data collection methods for the COGA sample, and details about sample characteristics and comorbidity. We also review key research findings that have emerged from analyses of the COGA data. COGA data are available broadly to researchers, and we hope this overview will encourage further collaboration and use of these data to advance the field.

Alcohol Use Disorder is a complex genetic disorder, involving genetic, neural, and environmental factors, and their interactions. The Collaborative Study on the Genetics of Alcoholism (COGA) has been investigating these factors and identified putative alcohol use disorder risk genes through genome-wide association studies. In this review, we describe advances made by COGA in elucidating the functional changes induced by alcohol use disorder risk genes using multimodal approaches with human cell lines and brain tissue. These studies involve investigating gene regulation in lymphoblastoid cells from COGA participants and in post-mortem brain tissues. High throughput reporter assays are being used to identify single nucleotide polymorphisms in which alternate alleles differ in driving gene expression. Specific single nucleotide polymorphisms (both coding or noncoding) have been modeled using induced pluripotent stem cells derived from COGA participants to evaluate the effects of genetic variants on transcriptomics, neuronal excitability, synaptic physiology, and the response to ethanol in human neurons from individuals with and without alcohol use disorder. We provide a perspective on future studies, such as using polygenic risk scores and populations of induced pluripotent stem cell-derived neurons to identify signaling pathways related with responses to alcohol. Starting with genes or loci associated with alcohol use disorder, COGA has demonstrated that integration of multimodal data within COGA participants and functional studies can reveal mechanisms linking genomic variants with alcohol use disorder, and potential targets for future treatments.

This review describes the genetic approaches and results from the family-based Collaborative Study on the Genetics of Alcoholism (COGA). COGA was designed during the linkage era to identify genes affecting the risk for alcohol use disorder (AUD) and related problems, and was among the first AUD-focused studies to subsequently adopt a genome-wide association (GWAS) approach. COGA's family-based structure, multimodal assessment with gold-standard clinical and neurophysiological data, and the availability of prospective longitudinal phenotyping continues to provide insights into the etiology of AUD and related disorders. These include investigations of genetic risk and trajectories of substance use and use disorders, phenome-wide association studies of loci of interest, and investigations of pleiotropy, social genomics, genetic nurture, and within-family comparisons. COGA is one of the few AUD genetics projects that includes a substantial number of participants of African ancestry. The sharing of data and biospecimens has been a cornerstone of the COGA project, and COGA is a key contributor to large-scale GWAS consortia. COGA's wealth of publicly available genetic and extensive phenotyping data continues to provide a unique and adaptable resource for our understanding of the genetic etiology of AUD and related traits.

Behaviors and disorders related to self-regulation, such as substance use, antisocial conduct, and ADHD, are collectively referred to as externalizing and have a shared genetic liability. We applied a multivariate approach that leverages genetic correlations among externalizing traits for genome-wide association analyses. By pooling data from ~1.5 million people, our approach is statistically more powerful than single-trait analyses and identifies more than 500 genetic loci. The identified loci were enriched for genes expressed in the brain and related to nervous system development. A polygenic score constructed from our results captures variation in a broad range of behavioral and medical outcomes that were not part of our genome-wide analyses, including traits that until now lacked well-performing polygenic scores, such as opioid use disorder, suicide, HIV infections, criminal convictions, and unemployment. Our findings are consistent with the idea that persistent difficulties in self-regulation can be conceptualized as a neurodevelopmental condition.