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Investigating causality between liability to ADHD and substance use, and liability to substance use and ADHD risk, using Mendelian randomization

Research output: Contribution to journalArticle

Original languageEnglish
Article numbere12849
Number of pages11
JournalAddiction Biology
DateAccepted/In press - 5 Oct 2019


Attention-deficit hyperactivity disorder (ADHD) has consistently been associated with substance use, but the nature of this association is not fully understood. To inform intervention development and public health messages, a vital question is whether there are causal pathways from ADHD to substance use and/or vice versa. We applied bidirectional Mendelian randomization, using summary-level data from the largest available genome-wide association studies (GWAS) on ADHD, smoking (initiation, cigarettes/day, cessation, and a compound measure of lifetime smoking), alcohol use (drinks/week, alcohol problems, and alcohol dependence), cannabis use (initiation) and coffee consumption (cups/day). Genetic variants robustly associated with the ‘exposure’ were selected as instruments and identified in the ‘outcome’ GWAS. Effect estimates from individual genetic variants were combined with inverse-variance weighted regression and five sensitivity analyses (weighted median, weighted mode, MR-Egger, generalized summary-data-based-MR, and Steiger filtering). We found evidence that liability to ADHD increases likelihood of smoking initiation and heaviness of smoking among smokers, decreases likelihood of smoking cessation, and increases likelihood of cannabis initiation. There was weak evidence that liability to ADHD increases alcohol dependence risk, but not drinks/week or alcohol problems. In the other direction, there was weak evidence that smoking initiation increases ADHD risk, but follow-up analyses suggested a high probability of horizontal pleiotropy. There was no clear evidence of causal pathways between ADHD and coffee consumption. Our findings corroborate epidemiological evidence, suggesting causal pathways from liability to ADHD to smoking, cannabis use, and, tentatively, alcohol dependence. Further work is needed to explore the exact mechanisms mediating these causal effects.

    Structured keywords

  • Tobacco and Alcohol

    Research areas

  • ADHD, Smoking, Alcohol, Cannabis, Coffee, Mendelian randomization

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  • Treur_et_al-2019-Addiction_Biology

    Rights statement: This is the final published version of the article (version of record). It first appeared online via Wiley at . Please refer to any applicable terms of use of the publisher.

    Final published version, 670 KB, PDF document

    Licence: CC BY


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