Genetic support of a causal relationship between cannabis use and educational attainment: a two-sample Mendelian randomization study of European ancestry

Abstract

Background and aims: Excessive cannabis use may lead to lower educational attainment. However, this association may be due to confounders and reverse causality. We tested the potential causal relationship between cannabis use disorder (CUD) or life-time cannabis use (LCU) and educational attainment.

Design: Bidirectional two-sample Mendelian randomization (MR) study was conducted. Our primary method was inverse-variance weighted (IVW) MR, with a series of sensitivity analyses. Multivariable MR (MVMR) was performed to estimate any direct effect independent of intelligence, smoking initiation or attention deficit hyperactivity disorder (ADHD).

Setting and participants: European ancestry individuals. The sample sizes of the genome-wide association study ranged from 55 374 to 632 802 participants.

Measurements: Genetic variants of CUD, LCU or educational attainment.

Findings: Using univariable MR, we found evidence of a potential causal effect of genetic liability to CUD on a lower educational attainment [MR, 95% confidence interval (CI)_{inverse variance weighted (IVW)} = -1.2 month (-1.9 month, -0.5 month); P = 0.0008]. However, we found no evidence of an effect of genetic liability to LCU on educational attainment [MR, 95% CI_IVW = 0.5 month (-1.5 month, 2.6 month), P = 0.6032]. Reverse direction analysis suggested that genetic liability to higher educational attainment had a potential causal effect on lower risk of CUD [odds ratio (OR), 95% CI_IVW = 0.39 (0.29, 0.52), P = 1.69 × 10^-10 ]. We also found evidence of potential causal effect from genetic liability to higher educational attainment to higher risk of LCU [OR, 95% CI_IVW = 1.35 (1.11, 1.66), P = 0.0033].

Conclusions: Genetic liability to cannabis use disorder may lead to lower educational attainment. Genetic liability to higher educational attainment may also lead to higher life-time cannabis use risk and lower cannabis use disorder risk. However, the bidirectional effect between cannabis use disorder and educational attainment may be due to shared risk factors (e.g. attention-deficit hyperactivity disorder).

Keywords: Cannabis use disorder; causal inference; educational attainment; life-time cannabis use; multivariable Mendelian randomization; univariable Mendelian randomization.