A large-scale genome-wide association study meta-analysis of cannabis use disorder.
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Johnson Emma C, Demontis Ditte, Thorgeirsson Thorgeir E, Walters Raymond K, Polimanti Renato, Hatoum Alexander S, Sanchez-Roige Sandra, Paul Sarah E, Wendt Frank R, Clarke Toni-Kim, Lai Dongbing, Reginsson Gunnar W, Zhou Hang, He June, Baranger David A A, Gudbjartsson Daniel F, Wedow Robbee, Adkins Daniel E, Adkins Amy E, Alexander Jeffry, Bacanu Silviu-Alin, Bigdeli Tim B, Boden Joseph, Brown Sandra A, Bucholz Kathleen K, Bybjerg-Grauholm Jonas, Corley Robin P, Degenhardt Louisa, Dick Danielle M, Domingue Benjamin W, Fox Louis, Goate Alison M, Gordon Scott D, Hack Laura M, Hancock Dana B, Hartz Sarah M, Hickie Ian B, Hougaard David M, Krauter Kenneth, Lind Penelope A, McClintick Jeanette N, McQueen Matthew B, Meyers Jacquelyn L, Montgomery Grant W, Mors Ole, Mortensen Preben B, Nordentoft Merete, Pearson John F, Peterson Roseann E, Reynolds Maureen D, Rice John P, Runarsdottir Valgerdur, Saccone Nancy L, Sherva Richard, Silberg Judy L, Tarter Ralph E, Tyrfingsson Thorarinn, Wall Tamara L, Webb Bradley T, Werge Thomas, Wetherill Leah, Wright Margaret J, Zellers Stephanie, Adams Mark J, Bierut Laura J, Boardman Jason D, Copeland William E, Farrer Lindsay A, Foroud Tatiana M, Gillespie Nathan A, Grucza Richard A, Harris Kathleen Mullan, Heath Andrew C, Hesselbrock Victor, Hewitt John K, Hopfer Christian J, Horwood John, Iacono William G, Johnson Eric O, Kendler Kenneth S, Kennedy Martin A, Kranzler Henry R, Madden Pamela A F, Maes Hermine H, Maher Brion S, Martin Nicholas G, McGue Matthew, McIntosh Andrew M, Medland Sarah E, Nelson Elliot C, Porjesz Bernice, Riley Brien P, Stallings Michael C, Vanyukov Michael M, Vrieze Scott, Psychiatric Genomics Consortium Substance Use Disorders Workgroup, Davis Lea K, Bogdan Ryan, Gelernter Joel, Edenberg Howard J, Stefansson Kari, Børglum Anders D, Agrawal Arpana
Аннотация
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.