A large-scale genome-wide association study meta-analysis of cannabis use disorder.
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.
Johnson, EC; Demontis, D; Thorgeirsson, TE; Walters, RK; Polimanti, R; Hatoum, AS; Sanchez-Roige, S; Paul, SE; Wendt, FR; Clarke, T-K; Lai, D; Reginsson, GW; Zhou, H; He, J; Baranger, DAA; Gudbjartsson, DF; Wedow, R; Adkins, DE; Adkins, AE; Alexander, J; Bacanu, S-A; Bigdeli, TB; Boden, J; Brown, SA; Bucholz, KK; Bybjerg-Grauholm, J; Corley, RP; Degenhardt, L; Dick, DM; Domingue, BW; Fox, L; Goate, AM; Gordon, SD; Hack, LM; Hancock, DB; Hartz, SM; Hickie, IB; Hougaard, DM; Krauter, K; Lind, PA; McClintick, JN; McQueen, MB; Meyers, JL; Montgomery, GW; Mors, O; Mortensen, PB; Nordentoft, M; Pearson, JF; Peterson, RE; Reynolds, MD; Rice, JP; Runarsdottir, V; Saccone, NL; Sherva, R; Silberg, JL; Tarter, RE; Tyrfingsson, T; Wall, TL; Webb, BT; Werge, T; Wetherill, L; Wright, MJ; Zellers, S; Adams, MJ; Bierut, LJ; Boardman, JD; Copeland, WE; Farrer, LA; Foroud, TM; Gillespie, NA; Grucza, RA; Harris, KM; Heath, AC; Hesselbrock, V; Hewitt, JK; Hopfer, CJ; Horwood, J; Iacono, WG; Johnson, EO; Kendler, KS; Kennedy, MA; Kranzler, HR; Madden, PAF; Maes, HH; Maher, BS; Martin, NG; McGue, M; McIntosh, AM; Medland, SE; Nelson, EC; Porjesz, B; Riley, BP; Stallings, MC; Vanyukov, MM; Vrieze, S; Psychiatric Genomics Consortium Substance Use Disorders Workgroup, ; Davis, LK; Bogdan, R; Gelernter, J; Edenberg, HJ; Stefansson, K; Børglum, AD; Agrawal, A
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