Genome-wide association meta-analysis of age at first cannabis use

Camelia C. Minică*, Karin J.H. Verweij, Peter J. van der Most, Hamdi Mbarek, Manon Bernard, Kristel R. van Eijk, Penelope A. Lind, Meng Zhen Liu, Dominique F. Maciejewski, Teemu Palviainen, Cristina Sánchez-Mora, Richard Sherva, Michelle Taylor, Raymond K. Walters, Abdel Abdellaoui, Timothy B. Bigdeli, Susan J.T. Branje, Sandra A. Brown, Miguel Casas, Robin P. CorleyGeorge Davey-Smith, Gareth E. Davies, Erik A. Ehli, Lindsay Farrer, Iryna O. Fedko, Iris Garcia-Martínez, Scott D. Gordon, Catharina A. Hartman, Andrew C. Heath, Ian B. Hickie, Matthew Hickman, Christian J. Hopfer, Jouke Jan Hottenga, René S. Kahn, Jaakko Kaprio, Tellervo Korhonen, Henry R. Kranzler, Ken Krauter, Pol A.C. van Lier, Pamela A.F. Madden, Sarah E. Medland, Michael C. Neale, Wim H.J. Meeus, Grant W. Montgomery, Ilja M. Nolte, Albertine J. Oldehinkel, Zdenka Pausova, Josep A. Ramos-Quiroga, Vanesa Richarte, Richard J. Rose, Jean Shin, Michael C. Stallings, Tamara L. Wall, Jennifer J. Ware, Margaret J. Wright, Hongyu Zhao, Hans M. Koot, Tomas Paus, John K. Hewitt, Marta Ribasés, Anu Loukola, Marco P. Boks, Harold Snieder, Marcus R. Munafò, Joel Gelernter, Dorret I. Boomsma, Nicholas G. Martin, Nathan A. Gillespie, Jacqueline M. Vink, Eske M. Derks

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

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BACKGROUND AND AIMS: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identify associations with genetic variants.

METHODS: A twin-based heritability analysis using 8,055 twins from three cohorts was performed. We then carried-out a genome wide survival meta-analysis of age at first cannabis use in a discovery sample of 24,953 individuals from nine European, North American, and Australian cohorts, and a replication sample of 3,735 individuals.

RESULTS: The twin-based heritability for age at first cannabis use was 38% (95% confidence interval [CI] 19-60%). Shared and unique environmental factors explained 39% (95% CI 20-56%) and 22% (95% CI 16-29%). The genome wide survival meta-analysis identified five SNPs on chromosome 16 within the Calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high LD (r2 >0.8) with the strongest association at the intronic variant rs1574587 (P=4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P=1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been previously associated with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant.

CONCLUSION: Age at cannabis initiation appears to be moderately heritable in Western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.

Original languageEnglish
Pages (from-to)2073-2086
Number of pages14
Issue number11
Early online date13 Jul 2018
Publication statusPublished - Nov 2018


  • Age at first use
  • ATP2C2
  • cannabis initiation
  • genome-wide association
  • heritability
  • substance use

Cohort Studies

  • Netherlands Twin Register (NTR)


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