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Genetic risk for Late Onset Alzheimer disease (AD) has been associated with lower cognition and smaller hippocampal volume in healthy young adults. However, it remains unclear whether these and other associations are present during childhood. Using data from 5,556 genomically-confirmed European ancestry youth who completed the baseline session of the ongoing the Adolescent Brain Cognitive Development StudySM (ABCD Study®), our phenome-wide association study estimating associations between indices of genetic risk for late-onset AD (n = 4; AD polygenic risk scores (PRS), APOE rs429358 genotype, AD PRS with the APOE region removed (ADPRS−APOE), and an interaction between ADPRS−APOE and APOE genotype) and 1,687 psychosocial, behavioral, and neural phenotypes revealed no significant associations after correction for multiple testing (all ps > 0.0002; all pfdr>0.07). These data suggest that AD genetic risk may not phenotypically manifest during middle-childhood or that effects are smaller than this sample is powered to detect.

Alcohol expectancies (AEs) are associated with likelihood of alcohol initiation and subsequent alcohol use disorders. It is unclear whether genetic predisposition to alcohol use and/or related traits contributes to shaping how one expects to feel when drinking alcohol. We used the Adolescent Brain Cognitive Development study to examine associations between genetic (i.e., polygenic risk for problematic alcohol use, depression, risk-taking), familial (i.e., parent self-reported alcohol problems), and psychosocial (i.e., adverse childhood experiences, peer use and disapproval toward alcohol) factors and positive and negative AEs in alcohol-naïve children (max analytic N = 6,935). Mixed-effect regression models showed that parental education, importance of the child’s religious beliefs, adverse childhood experiences, peer disapproval of alcohol use, and polygenic liability for risk-taking were associated with positive and/or negative AEs, to varying degrees. Overall, our results suggest several familial and psychosocial predictors of AEs but little evidence of contributions from polygenic liability to problematic alcohol use or related phenotypes.

Substance use disorders (SUDs) are phenotypically and genetically correlated with each other and with other psychological traits characterized by behavioral undercontrol, termed externalizing phenotypes. In this study, we used Genomic Structural Equation Modeling to explore the shared genetic architecture among six externalizing phenotypes and four SUDs used in two previous multivariate GWAS of an externalizing and an addiction risk factor, respectively. Using a preregistered set of criteria, we first evaluated the performance of five confirmatory factor analytic models, including a common factor model, alternative parameterizations of two-factor structures, and a bifactor model. We used a combination of model fit, factor reliability, and model characteristics to adjudicate among the models. We next explored the genetic correlations between factors identified in these models and other relevant psychological traits. We found that a common factor model, in which all externalizing phenotypes and SUDs were influenced by a single dimension of genetic risk best characterized the relationships among our phenotypes. Although two two-factor models also performed well, we found that the factors in those models were very highly correlated with each other (rgS > .87) and similarly genetically correlated with external criteria, suggesting they did not represent meaningfully distinct dimensions. Results from this study can be used to inform future efforts to characterize genetic liability for broad externalizing as well as specific externalizing phenotypes.

Background: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50–70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. Methods: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. Findings: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07–1·15, p=1·84 × 10 −9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86–0·93, p=6·46 × 10 −9). Cannabis use disorder and cannabis use were genetically correlated (r g 0·50, p=1·50 × 10 −21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia. Interpretation: These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder. Funding: National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.

BackgroundDespite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci.MethodsWe performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs). Meta-analysis included seven cohorts: the Million Veteran Program (MVP), Psychiatric Genomics Consortium (PGC), iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N=639,709 (Ncases=20,858) across ancestries. OUD cases were defined as having lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h2SNP) and genetic correlations (rg). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD).ResultsThe EUR meta-analysis identified three genome-wide significant (GWS; p≤5×10−8) lead SNPs—one at FURIN (rs11372849; p=9.54×10−10) and two OPRM1 variants (rs1799971, p=4.92×10−09 ; rs79704991, p=1.37×10−08; r2=0.02). Rs1799971 (p=4.91×10−08) and another OPRM1 variant (rs9478500; p=1.95×10−8; r2=0.03) were identified in the cross-ancestry meta-analysis. Estimated h2SNP was 12.75%, with strong rg with CanUD (rg =0.82; p=1.14×10−47) and AUD (rg=0.77; p=6.36×10−78). The OUD-MTAG resulted in 18 GWS loci, some of which map to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes.ConclusionsWe identified multiple OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. OUD is likely influenced by both OUD-specific loci and loci shared across SUDs.

ImportanceIn light of increasing cannabis use among pregnant women, the Surgeon General of the United States issued an advisory against the use of marijuana during pregnancy on August 29th, 2019.ObjectiveTo determine whether cannabis use during pregnancy is associated with adverse outcomes among offspring.DesignCross-sectional analysis of the baseline session of the ongoing longitudinal Adolescent Brain and Cognitive Development (ABCD) study.SettingData were collected from 22 sites across the United States between 2016 and 2018.ParticipantsChildren ages 9-11 (n=11,489) and their parent or caregiver.ExposurePrenatal marijuana exposure prior to and following maternal knowledge of pregnancy.Main Outcomes and MeasuresChild psychopathology symptomatology (i.e., psychotic-like experiences and internalizing, externalizing, attention, thought, and social problems), cognition, sleep, birth weight, gestational age at birth, body mass index (BMI), and brain structure (i.e., total intracranial volume, white matter volume, gray matter volume). Covariates included familial (e.g., income, familial psychopathology), pregnancy (e.g., prenatal vitamin use, whether the pregnancy was planned), and child (e.g., birth weight, substance use) variables.ResultsAmong 11,489 children (age 9.9±0.6 years; 47.78% female), 655 (5.70%) were prenatally exposed to cannabis in total. Marijuana use prior to (n=648; 5.64%) and following (n=242; 2.11%) maternal knowledge of pregnancy were associated with increased offspring psychopathology characteristics (i.e., psychotic-like experiences and internalizing, externalizing, attention, thought, social, and sleep problems) and BMI as well as reduced cognition, birth weight, and brain structure (i.e., total white and gray mater volumes; all psfdrpsps>0.06).Conclusions and RelevancePrenatal cannabis exposure, and its correlated factors, may increase risk for psychopathology and reduced cognition during middle childhood as well as reduced birthweight. Consistent with recent recommendations by the Surgeon General, marijuana use during pregnancy should be discouraged.