Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium

Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (...

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Bibliographic Details
Published in:	Translational psychiatry Vol. 6; no. 3; p. e769
Main Authors:	Stringer, S, Minică, C C, Verweij, K J H, Mbarek, H, Bernard, M, Derringer, J, van Eijk, K R, Isen, J D, Loukola, A, Maciejewski, D F, Mihailov, E, van der Most, P J, Sánchez-Mora, C, Roos, L, Sherva, R, Walters, R, Ware, J J, Abdellaoui, A, Bigdeli, T B, Branje, S J T, Brown, S A, Bruinenberg, M, Casas, M, Esko, T, Garcia-Martinez, I, Gordon, S D, Harris, J M, Hartman, C A, Henders, A K, Heath, A C, Hickie, I B, Hickman, M, Hopfer, C J, Hottenga, J J, Huizink, A C, Irons, D E, Kahn, R S, Korhonen, T, Kranzler, H R, Krauter, K, van Lier, P A C, Lubke, G H, Madden, P A F, Mägi, R, McGue, M K, Medland, S E, Meeus, W H J, Miller, M B, Montgomery, G W, Nivard, M G, Nolte, I M, Oldehinkel, A J, Pausova, Z, Qaiser, B, Quaye, L, Ramos-Quiroga, J A, Richarte, V, Rose, R J, Shin, J, Stallings, M C, Stiby, A I, Wall, T L, Wright, M J, Koot, H M, Paus, T, Hewitt, J K, Ribasés, M, Kaprio, J, Boks, M P, Snieder, H, Spector, T, Munafò, M R, Metspalu, A, Gelernter, J, Boomsma, D I, Iacono, W G, Martin, N G, Gillespie, N A, Derks, E M, Vink, J M
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 29-03-2016 Nature Publishing Group
Subjects:	45/43 631/208 631/477 692/699/476/5 Adolescent Adult Aged Aged, 80 and over Behavioral Sciences Biological Psychology Carrier Proteins - genetics CD56 Antigen - genetics Cell Adhesion Molecules - genetics Female Genome-Wide Association Study Humans Male Marijuana Abuse - genetics Marijuana Smoking - genetics Medicine Medicine & Public Health Membrane Proteins - genetics Middle Aged Neurosciences Original original-article Pharmacotherapy Potassium Channels - genetics Potassium Channels, Sodium-Activated Psychiatry Young Adult
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Summary:	Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40–48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts ( N =32 330) and four replication samples ( N =5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1 , CADM2 , SCOC and KCNT2 . Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13–20% ( P <0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation ( r g =0.83; P =1.85 × 10 −8 ) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.
Bibliography:	Shared first author. Shared last author.
ISSN:	2158-3188 2158-3188
DOI:	10.1038/tp.2016.36