TY - JOUR
T1 - A large-scale genome-wide association study meta-analysis of cannabis use disorder
AU - Johnson, Emma
AU - Demontis, Ditte
AU - Thorgeirsson, Thorgeir E
AU - Walters, Raymond K
AU - Polimanti, Renato
AU - Hatoum, Alexander S
AU - Sanchez-roige, Sandra
AU - Paul, Sarah E
AU - Wendt, Frank R
AU - Clarke, Toni-kim
AU - Lai, Dongbing
AU - Reginsson, Gunnar W
AU - Zhou, Hang
AU - He, June
AU - Baranger, David A A
AU - Gudbjartsson, Daniel F
AU - Wedow, Robbee
AU - Adkins, Daniel
AU - Adkins, Amy
AU - Alexander, Jeffry
AU - Bacanu, Silviu-alin
AU - Bigdeli, Tim B
AU - Boden, Joseph
AU - Brown, Sandra
AU - Bucholz, Kathleen
AU - Bybjerg-grauholm, Jonas
AU - Corley, Robin P
AU - Degenhardt, Louisa
AU - Dick, Danielle
AU - Domingue, Benjamin
AU - Fox, Louis
AU - Goate, Alison
AU - Gordon, Scott
AU - Hack, Laura
AU - Hancock, Dana
AU - Hartz, Sarah
AU - Hickie, Ian B
AU - Hougaard, David M
AU - Krauter, Kenneth
AU - Lind, Penelope
AU - Mcclintick, Jeanette
AU - Mcqueen, Matthew
AU - Meyers, Jacquelyn
AU - Montgomery, Grant
AU - Mors, Ole
AU - Mortensen, Preben B
AU - Nordentoft, Merete
AU - Pearson, John
AU - Peterson, Roseann
AU - Reynolds, Maureen
AU - Rice, John
AU - Runarsdottir, Valgerdur
AU - Saccone, Nancy
AU - Sherva, Richard
AU - Silberg, Judy
AU - Tarter, Ralph
AU - Tyrfingsson, Thorarinn
AU - Wall, Tamara
AU - Webb, Bradley
AU - Werge, Thomas
AU - Wetherill, Leah
AU - Wright, Margaret J
AU - Zellers, Stephanie
AU - Adams, Mark
AU - Bierut, Laura
AU - Boardman, Jason
AU - Copeland, William
AU - Farrer, Lindsay
AU - Foroud, Tatiana
AU - Gillespie, Nathan
AU - Grucza, Richard
AU - Harris, Kathleen Mullan
AU - Heath, Andrew
AU - Hesselbrock, Victor
AU - Hewitt, John
AU - Hopfer, Christian
AU - Horwood, John
AU - Iacono, William
AU - Johnson, Eric
AU - Kendler, Kenneth
AU - Kennedy, Martin
AU - Kranzler, Henry
AU - Madden, Pamela
AU - Maes, Hermine
AU - Maher, Brion
AU - Martin, Nicholas
AU - Mcgue, Matthew
AU - Mcintosh, Andrew
AU - Medland, Sarah
AU - Nelson, Elliot C
AU - Porjesz, Bernice
AU - Riley, Brien
AU - Stallings, Michael
AU - Vanyukov, Michael
AU - Vrieze, Scott
AU - Davis, Lea K
AU - Bogdan, Ryan
AU - Gelernter, Joel
AU - Edenberg, Howard
AU - Stefansson, Kari
AU - Børglum, Anders D
AU - Agrawal, Arpana
AU - Walters, Raymond K
AU - Polimanti, Renato
AU - Johnson, Emma
AU - Mcclintick, Jeanette
AU - Hatoum, Alexander
AU - He, June
AU - Wendt, Frank
AU - Zhou, Hang
AU - Adams, Mark
AU - Adkins, Amy
AU - Aliev, Fazil
AU - Bacanu, Silviu-alin
AU - Batzler, Anthony
AU - Bertelsen, Sarah
AU - Biernacka, Joanna
AU - Bigdeli, Tim
AU - Chen, Li-shiun
AU - Clarke, Toni-kim
AU - Chou, Yi-ling
AU - Degenhardt, Franziska
AU - Docherty, Anna
AU - Edwards, Alexis
AU - Fontanillas, Pierre
AU - Foo, Jerome
AU - Fox, Louis
AU - Frank, Josef
AU - Giegling, Ina
AU - Gordon, Scott
AU - Hack, Laura
AU - Hartmann, Annette
AU - Hartz, Sarah
AU - Heilmann-heimbach, Stefanie
AU - Herms, Stefan
AU - Hodgkinson, Colin
AU - Hoffman, Per
AU - Hottenga, Jouke
AU - Kennedy, Martin
AU - Alanne-kinnunen, Mervi
AU - Konte, Bettina
AU - Lahti, Jari
AU - Lahti-pulkkinen, Marius
AU - Lai, Dongbing
AU - Ligthart, Lannie
AU - Loukola, Anu
AU - Maher, Brion
AU - Mbarek, Hamdi
AU - Mcintosh, Andrew
AU - Mcqueen, Matthew
AU - Meyers, Jacquelyn
AU - Milaneschi, Yuri
AU - Palviainen, Teemu
AU - Pearson, John
AU - Peterson, Roseann
AU - Ripatti, Samuli
AU - Ryu, Euijung
AU - Saccone, Nancy
AU - Salvatore, Jessica
AU - Sanchez-roige, Sandra
AU - Schwandt, Melanie
AU - Sherva, Richard
AU - Streit, Fabian
AU - Strohmaier, Jana
AU - Thomas, Nathaniel
AU - Wang, Jen-chyong
AU - Webb, Bradley
AU - Wedow, Robbee
AU - Wetherill, Leah
AU - Wills, Amanda
AU - Boardman, Jason
AU - Chen, Danfeng
AU - Choi, Doo-sup
AU - Copeland, William
AU - Culverhouse, Robert
AU - Dahmen, Norbert
AU - Degenhardt, Louisa
AU - Domingue, Benjamin
AU - Elson, Sarah
AU - Frye, Mark
AU - Gäbel, Wolfgang
AU - Hayward, Caroline
AU - Ising, Marcus
AU - Keyes, Margaret
AU - Kiefer, Falk
AU - Kramer, John
AU - Kuperman, Samuel
AU - Lucae, Susanne
AU - Lynskey, Michael
AU - Maier, Wolfgang
AU - Mann, Karl
AU - Männistö, Satu
AU - Müller-myhsok, Bertram
AU - Murray, Alison
AU - Nurnberger, John
AU - Palotie, Aarno
AU - Preuss, Ulrich
AU - Räikkönen, Katri
AU - Reynolds, Maureen
AU - Ridinger, Monika
AU - Scherbaum, Norbert
AU - Schuckit, Marc
AU - Soyka, Michael
AU - Treutlein, Jens
AU - Witt, Stephanie
AU - Wodarz, Norbert
AU - Zill, Peter
AU - Adkins, Daniel
AU - Boden, Joseph
AU - Boomsma, Dorret
AU - Bierut, Laura
AU - Brown, Sandra
AU - Bucholz, Kathleen
AU - Cichon, Sven
AU - Costello, E. Jane
AU - De Wit, Harriet
AU - Diazgranados, Nancy
AU - Dick, Danielle
AU - Eriksson, Johan
AU - Farrer, Lindsay
AU - Foroud, Tatiana
AU - Gillespie, Nathan
AU - Goate, Alison
AU - Goldman, David
AU - Grucza, Richard
AU - Hancock, Dana
AU - Harris, Kathleen Mullan
AU - Heath, Andrew
AU - Hesselbrock, Victor
AU - Hewitt, John
AU - Hopfer, Christian
AU - Horwood, John
AU - Iacono, William
AU - Johnson, Eric
AU - Kaprio, Jaakko
AU - Karpyak, Victor
AU - Kendler, Kenneth
AU - Kranzler, Henry
AU - Krauter, Kenneth
AU - Lichtenstein, Paul
AU - Lind, Penelope
AU - Mcgue, Matt
AU - Mackillop, James
AU - Madden, Pamela
AU - Maes, Hermine
AU - Magnusson, Patrik
AU - Martin, Nicholas
AU - Medland, Sarah
AU - Montgomery, Grant
AU - Nelson, Elliot
AU - Nöthen, Markus
AU - Palmer, Abraham
AU - Pederson, Nancy
AU - Penninx, Brenda
AU - Porjesz, Bernice
AU - Rice, John
AU - Rietschel, Marcella
AU - Riley, Brien
AU - Rose, Richard
AU - Rujescu, Dan
AU - Shen, Pei-hong
AU - Silberg, Judy
AU - Stallings, Michael
AU - Tarter, Ralph
AU - Vanyukov, Michael
AU - Vrieze, Scott
AU - Wall, Tamara
AU - Whitfield, John
AU - Zhao, Hongyu
AU - Neale, Benjamin
AU - Gelernter, Joel
AU - Edenberg, Howard
AU - Agrawal, Arpana
AU - Psychiatric Genomics Consortium Substance Use Disorders Workgroup
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85095443055&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85095443055&partnerID=8YFLogxK
U2 - 10.1016/S2215-0366(20)30339-4
DO - 10.1016/S2215-0366(20)30339-4
M3 - Article
SN - 2215-0366
VL - 7
SP - 1032
EP - 1045
JO - The Lancet Psychiatry
JF - The Lancet Psychiatry
IS - 12
ER -