A genome-wide study of nearly 25,000 people found age of first cannabis use is 38% heritable with a suggestive genetic link to calcium signaling | Research

The takeaway

A twin-based analysis estimated the heritability of age at first cannabis use at 38%, and a genome-wide association meta-analysis of 24,953 individuals identified a significant association with variants in the ATP2C2 gene on chromosome 16, suggesting calcium signaling plays a role in cannabis initiation timing.

Genetics researchers studying substance use; prevention scientists looking for risk biomarkers; neuroscientists studying calcium signaling and addiction.

38% heritability of age at first cannabis use, with calcium signaling gene ATP2C2 as top hit

What the researchers found

Researchers conducted the largest genome-wide association study of age at first cannabis use to date.

Twin analysis (8,055 twins from three cohorts) estimated heritability at 38% (95% CI 19-60%). Shared environment explained 39% and unique environment 22% of the variation.

The GWAS meta-analysis of 24,953 individuals identified five significant SNPs on chromosome 16 within the ATP2C2 gene (a calcium-transporting ATPase). The strongest association was at rs1574587 (p = 4.09 x 10^-9).

Although these SNPs did not replicate in a smaller sample of 3,735 individuals, the ATP2C2 gene was also significant in gene-based analysis (p = 1.33 x 10^-6).

ATP2C2 has been previously associated with cocaine dependence, and a related gene (ATP2B2) in the same calcium signaling pathway has been linked to opioid dependence, suggesting a shared biological mechanism across substance use disorders.

Why it matters

Earlier cannabis initiation is consistently linked to worse outcomes including dependence and polysubstance use. Finding that timing of first use is substantially heritable (38%) and potentially linked to calcium signaling pathways opens new avenues for understanding and potentially predicting who is at greatest risk.

The numbers in context

Heritability: 38% (95% CI 19-60%). Shared environment: 39%. Unique environment: 22%. 24,953 discovery sample, 3,735 replication. Top SNP: rs1574587 in ATP2C2 (p = 4.09 x 10^-9). Gene-based: ATP2C2 (p = 1.33 x 10^-6).

How the study worked

Twin-based heritability analysis (8,055 twins). GWAS meta-analysis of 24,953 individuals from nine European, North American, and Australian cohorts. Replication sample of 3,735. Gene-based tests. SNP-based heritability estimation.

What this study cannot tell us

Top genetic findings did not replicate in the smaller sample. SNP-based heritability was not significant, suggesting many small genetic effects rather than a few large ones. Only European-ancestry cohorts included. Age at first use is influenced by many environmental factors beyond genetics.

How to read the evidence

Strong. Large multi-cohort meta-analysis with twin heritability validation, though top genetic finding needs further replication.

When this study was published

Published in 2018. Subsequent larger GWAS studies of cannabis traits have expanded these findings.

The bigger picture

This study connects cannabis initiation timing to the same calcium signaling pathway implicated in other substance use disorders. If confirmed, this suggests a shared biological vulnerability to earlier substance initiation across drug types, rather than cannabis-specific genetics.

Questions still open

Will ATP2C2 replicate in larger samples? Does the calcium signaling pathway represent a druggable target for prevention? How do genetic and environmental risk factors interact to determine initiation timing?

Common questions

Does this mean cannabis use is genetic?

The timing of first use is partly genetic (38% heritable), but 62% of the variation is explained by environment. Genetics influence susceptibility, but environment (peer groups, access, norms) plays an equal or larger role in when someone first tries cannabis.

What does calcium signaling have to do with cannabis use?

Calcium signaling is fundamental to how neurons communicate. The ATP2C2 gene is involved in calcium transport, and variants in this gene may affect brain circuits involved in novelty seeking, reward processing, or impulse control, which could influence when someone first tries substances.

Read the original research

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

Addiction (Abingdon, England), 113(11), 2073-2086

View on PubMed ↗Publisher’s paper ↗

Citation

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. (2018). Genome-wide association meta-analysis of age at first cannabis use.. Addiction (Abingdon, England), 113(11), 2073-2086. https://doi.org/10.1111/add.14368