Genome‐wide association meta‐analysis of age at first cannabis use
Authors: Minică Camelia C. , Verweij Karin J. H. , van der Most Peter J. , Mbarek Hamdi , Bernard Manon , van Eijk Kristel R. , Lind Penelope A. , Liu Meng Zhen , Maciejewski Dominique F. , Palviainen Teemu , Sánchez‐Mora Cristina , Sherva Richard , Taylor Michelle , Walters Raymond K. , Abdellaoui Abdel , Bigdeli Timothy B. , Branje Susan J. T. , Brown Sandra A. , Casas Miguel , Corley Robin P. , Davey‐Smith George , Davies Gareth E. , Ehli Erik A. , Farrer Lindsay , Fedko Iryna O. , Garcia‐Martínez Iris , Gordon Scott D. , Hartman Catharina A. , Heath Andrew C. , Hickie Ian B. , Hickman Matthew , Hopfer Christian J. , Hottenga Jouke Jan , Kahn René S. , Kaprio Jaakko , Korhonen Tellervo , Kranzler Henry R. , Krauter Ken , van Lier Pol A. C. , Madden Pamela A. F. , Medland Sarah E. , Neale Michael C. , Meeus Wim H. J. , Montgomery Grant W. , Nolte Ilja M. , Oldehinkel Albertine J. , Pausova Zdenka , Ramos‐Quiroga Josep A. , Richarte Vanesa , Rose Richard J. , Shin Jean , Stallings Michael C. , Wall Tamara L. , Ware Jennifer J. , Wright Margaret J. , Zhao Hongyu , Koot Hans M. , Paus Tomas , Hewitt John K. , Ribasés Marta , Loukola Anu , Boks Marco P. , Snieder Harold , Munafò Marcus R. , Gelernter Joel , Boomsma Dorret I. , Martin Nicholas G. , Gillespie Nathan A. , Vink Jacqueline M. , Derks Eske M. 
Published: July 2018

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 identified associations with genetic variants.

Methods

A twin‐based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome‐wide association 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 3735 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 association meta‐analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium‐transporting ATPase gene (ATP2C2) at P < 5E‐08. All five SNPs are in high linkage disequilibrium (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 associated previously 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.