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

Emma Johnson, Jouke Hottenga, Lannie Ligthart, Hamdi Mbarek, Yuri Milaneschi, Dorret Boomsma, Arpana Agrawal, Psychiatric Genomics Consortium Substance Use Disorders Workgroup

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1032-1045
Number of pages14
JournalThe Lancet Psychiatry
Volume7
Issue number12
Early online date20 Oct 2020
DOIs
Publication statusPublished - Dec 2020

Funding

TW has acted as an advisor and a lecturer to H Lundbeck A/S. LJB and the spouse of NLS are listed as inventors on Issued US Patent 8 080 371, Markers for Addiction, covering the use of particular SNPs in determining the diagnosis, prognosis, and treatment of addiction. AMM has received research support from Eli Lilly, Janssen, Pfizer, and the Sackler Foundation. HRK is a member of the American Society of Clinical Psychopharmacology's Alcohol Clinical Trials Initiative, which was supported in the last 3 years by AbbVie, Alkermes, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, Pfizer, Arbor, and Amygdala Neurosciences. HRK and JG are named as inventors on PCT patent application number 15/878 640, entitled Genotype-guided dosing of opioid agonists, filed Jan 24, 2018. LD reports untied educational grant funding to research studies of new opioid medications in Australia from Indivior, Mundipharma, Seqirus, and Reckitt Benckiser.

FundersFunder number
University of Otago
University of Connecticut
Washington University in St. Louis
Families for Borderline Personality Disorder Research
Carney Centre for Pharmacogenomics
Virginia Commonwealth University
Johns Hopkins University
Lotto New Zealand
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Aarhus Universitet
AlcGen consortia
University of California, San Diego
Rutgers, The State University of New Jersey
Indiana University
universities and university hospitals of Aarhus and Copenhagen
State University of New York
European Commission
COGA
Icahn School of Medicine at Mount Sinai
Genetics of Alcoholism
University of Iowa
International Cannabis Consortium
Canterbury Medical Research Foundation
Gene Environment Association Studies
Horizon 2020
National Child Health Research Foundation
Howard UniversityU10 AA008401, U01 HG004422
National Human Genome Research InstituteN01HG065403, U01HG006378, U01HG004798, U01HG004446, U01HG004422, R01HG008983, U01HG004438
National Institute on Drug AbuseP60DA011015, R01DA025109, R01DA026911, U01DA041106, R01DA024413, R37DA005147, U01DA041028, U01DA041148, U01DA041025, U01DA041022, R00DA023549, R01DA021905, K02DA032573, R01DA011301, R21DA047527, U01DA024417, T32DA007261, K08DA019951, U24DA041123, U01DA041134, P30DA023026, U01DA041174, R01DA013240, R21DA046791, U01DA041093, R01DA036216, RC2DA028909, R01DA012849, R01DA037904, R01DA035804, R01DA044283, R01DA012845, R01DA019157, U01DA041048, U01DA041089, R01DA034076, U01DA041120, R21DA038504, R01DA012854, U01DA051038, K24DA032555, R01DA013423, P50DA005605, R01DA017305, R01DA016977, R01DA018673, U01DA041117, R01DA019963, U24DA041147, R01DA018432, U01DA041156, R01DA042755, R01DA021913, R01DA012690
National Health and Medical Research Council389927,389875, A7960034, 496682, 339462, A79801419, 389892, 389891, 552485, 241944, DP0770096, 442981, 552498, 496739, DP0212016, 442915, 389938, 1009064, A79906588
National Institute on AgingR01AG061162
National Institute on Alcohol Abuse and AlcoholismR01AA011330, R37AA007728, R01AA017535, R01AA013320, R01AA009367, P50AA011998, R01AA017444, R01AA013321, U10AA008401, F32AA027435, R01AA011408, P20AA017828, R21AA027827, R01AA007535, 58146, K05AA017688, K02AA018755, P50AA022537, R01AA014041, 4844
National Institute of Mental HealthK23MH080230, R01MH063671, R01MH068521, R01MH063970, U01MH109514, R01MH123619, R56MH120736, U01MH109532, K01MH093731, K01MH113848, R01MH117559, T32MH018951, R01MH077874, F32MH122058, R01MH048085, R01MH083094, R01MH066140
National Institute of Child Health and Human DevelopmentR01HD060726, P2CHD066613, P01HD031921, R01HD073342, R01HD093651, R01HD050735, R03HD097630, R01HD074711
Novo Nordisk FondenR01−DA034076, 1U01MH109514–01
Substance Abuse and Mental Health Services AdministrationR01DA026911, 1H79TI081668, R01HD050735, U54EB020403, R21DA046791
US NIDAR00DA023549
Australian National Health and Medical Research Council ResearchN01-HG-65403, R01 DA17305, U01DA041106, U01DA041117, U01DA041028, U01DA041148, U01DA041048, U24DA041123, U01DA041025, U01DA041156, U01DA041134, U01DA041089, U01DA041022, 1135991, U01DA041120, U01DA041174, U01DA041093
National Center for Research ResourcesS10RR025141, UL1RR024975
Center for Education and Drug Abuse ResearchP50 DA005605
National Alliance for Research on Schizophrenia and Depression27676
Wellcome Trust104036/Z/14/Z, 216767/Z/19/Z
Australian Research CouncilR01DA025109, FT110100548, R01MH055557, DP0664638, R01MH068521, 464914, R01MH045268, DP0343921, 619667
National Cancer InstituteP01CA089392
Health Research Council of New Zealand16/600, DA025109, P01-HD031921, DA024413, 11/792, R01HD093651, AA027827, U24DA041147, R01MH117559, DA011015, DA038504, AG061162, DA016977, R01-HD073342, P30DA023026, K02 AA018755, R01 DA018673
Tobacco-Related Disease Research Program of the University of CaliforniaT29KT0526
National Institute of General Medical SciencesRC2GM092618, P50GM115305
Lundbeck FoundationR165–2013–15320, R248–2017–2003, R155–2014–1724, R102-A9118
European Commission, Horizon 2020R01HD060726
Brain and Behavior Research FoundationR21 DA047527, R21 DC018098, 28632
UKRI MRCK01MH113848, MR/S035818/1, MC_PC_17209
Vanderbilt University Medical CenterR01 DA144740, U01HG006378, R01NS032830, U19HL065962, RC2GM092618, U01HG004798, UL1TR000445, S10RR025141, UL1RR024975, P50GM115305, UL1TR002243, R01HD074711
Wellcome Trust Case Control Consortium 2WTCCC-084710, P01-HD31921
National Institutes of HealthHHSN268200782096C
National Center for Advancing Translational SciencesUL1TR000445, UL1TR002243
National Center for Biotechnology InformationR01 DA013423, P01 CA089392, R01 DA019963
National Heart, Lung, and Blood InstituteU19HL065962
National Institute of Biomedical Imaging and BioengineeringU54EB020403
Virginia Tobacco Settlement FoundationDA019951, R01 DA12690, DA013240, DA024417, R01 DA18432, DA042755, AA07728, R01 AA11330, HG008983, MH066140, AA07535, DA037904, R01 DA12849, AA009367, 8520012, DA036216, DA012854, R01 AA017535, DA005147, RC2 DA028909, DA044283, R01 DA019157
Horizon 2020 Framework Programme667302
James Hume Bequest FundR01DA024413, MH077874
National Institute on Deafness and Other Communication DisordersR21DC018098
GENEVA Coordinating CenterU01 HG004446
Fifth Framework ProgrammeQLG2-CT-2002–01254, R01-AA-011408, FP-5, R01-MH-083094, P50-AA-022537, P20-AA-017828
National Institute of Neurological Disorders and StrokeR01NS032830

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