A large-scale genome-wide association study meta-analysis of cannabis use disorder

Summary 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 (rg 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.Peer reviewe

Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies

First published: 16 February 202

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 x 10(-13)) and African ancestries (rs2066702; P = 2.2 x 10(-9)). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.Peer reviewe

MANAGEMENT AND OUTCOME OF STAGE I SEMINOMA IN ONTARIO.

Purpose: To describe the uptake and use of surveillance andirradiation in stage I seminoma post-orchiectomy in Ontario and to evaluate theimpact of these management strategies on patient outcomes. Background: Testicular cancer is the most common cancer in menbetween the ages of 20 and 44 (1). About half of testicular cancers areseminomas (2). Overall 85% of seminoma patients present with stage I disease with10-year survival over 99%. Adjuvant radiation therapy once constituted thestandard of care but surveillance as a post-orchiectomy management strategy isnow preferred in Ontario (3). Treatment with radiation results in importantlong-term toxicities (2). The actual management patterns and the effect ofthese patterns on seminoma patient outcomes is unknown. This will be the firstphase IV study to describe the management of stage I seminoma and to evaluateit’s effect on patient outcomes. Methods: This is a retrospective, population based cohort studyof seminoma patients in Ontario. Cases of seminoma are identified through theOntario Cancer Registry and linked with patient data from the CanadianInstitute of Health Information and Ontario radiotherapy data. An instrumentalvariable approach will be taken with time and location of treatment as theinstruments. Mantel-Haensel Chi-Squared tests, Student’s T-test, and Log ranktests will be used to find differences in patient characteristics, morbidity andsurvival. The Kaplan-Meier method will be used to model overall survival. Results and Conclusions:Pending data analysis. References: 1. Warde P, Srugeon J,Gospodarowicz M. Testicular Cancer. In: Gunderson L, Tepper J, eds. Clinicalradiation oncology. Philadelphia: Chruchill Livingstone; 2000: 844-862. 2. Nichols CR, Hung A, Corless CL, Foster RS, Roth BJ, Einhorn LH.Testis cancer. In: Kufe DW, Frei III E, Holland JF, Weichselbaum RR, PollockRE, Bast Jr RC, Hong WK, Hait WN, eds. Holland-Frei cancer medicine – 7^thEd.[e-book], Columbia: BC Decker; 2006 [cited 2008 Mar 17]: ch. 99. Availablefrom: Stat!Ref. 3. Chung P, Mayhew LA, Warde P, Winquist E, Lukka H et al. Management of stage I seminoma: Guidelinerecommendations. Cancer Care Ontario, Evidence-Based Series #3-18: Section1; Report date: 30 Jan 2008