Abstract
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 per day, cessation, and a compound measure of lifetime smoking), alcohol use (drinks per week, alcohol problems, and alcohol dependence), cannabis use (initiation), and coffee consumption (cups per 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 per 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.
| Original language | English |
|---|---|
| Article number | e12849 |
| Journal | Addiction Biology |
| Volume | 26 |
| Issue number | 1 |
| Early online date | 16 Nov 2019 |
| DOIs | |
| Publication status | Published - 31 Jan 2021 |
Acknowledgements
Finally, we would also like to acknowledge all current members of the ADHD Working Group of the Psychiatric Genomics Consortium: Amaia Hervás, A.R. Hammerschlag, Allison Ashley-Koch, Alexandra Philipsen, Alice Charach, Ana Miranda, André Scherag, Andreas Reif, Anke Hinney, Anna Rommel, Anne Wheeler, Richard Anney, Aribert Rothenberger, Barbara Franke, Bru Cormand, Ben Neale, Christine Cornforth, Catharina Hartman, Christie Burton, Claiton Bau, Cristina Sanchez, Danielle Posthuma, Jurgen Deckert, Alysa Doyle, Eugenio Grevet, Edmund Sonuga-Barke, Elizabeth Corfield, Felecia Cerrato, Fernando Mulas, Franziska Degenhardt, Juanita Gamble, Gláucia Chiyoko Akutagava Martins, Gun Peggy Strømstad Knudsen, Hakon Hakonarson, Hans-Christoph Steinhausen, Henrik Larsson, Herber Roeyers, Peter Holmans, Jan Buitelaar, Jan Haavik, Joseph Biederman, Jennifer Crosbie, Jim McGough, Joel Gelernter, Johannes Hebebrand, Jonna Kuntsi, Joseph Sergeant, Josephine Elia, Klaus Peter Lesch, Kate Langley, Luis Rohde, Lindsey Kent, Li Yang, Maria Soler, Meg Mariano, Marieke Klein, Mark Bellgrove, Marta Ribases, Martin Steen Tesli, Joanna Martin, Miguel Casas, Michael Gill, Maria Jesús Arranz Calderón, Manuel Mattheisen, Monica Bayes, Nick Martin, Niels Peter Ole Mors, Ole Andreas Andreassen, Michael O'Donovan, Patrick Sullivan, Paul Arnold, Paul Lichtenstein, Paula Rovira, Preben Bo Mortensen, Pak Sham, Philip Asherson, Julia Pinsonneault, Patrick WL Leung , Irwin Waldman, Rachel Guerra, Josep Antoni Ramos-Quiroga, Ridha Joober, Rachel Lucier, Robert Oades, Richard Ebstein, Russell Schachar, Raymond Walters, Sarah Medland, Sarah Anthony, Sarojini Sengupta, Søren Dalsgaard, Steve Faraone, Hyo-Won Kim, Sandra Loo, Steve Nelson, Søren Dinesen, Susan Smalley, Stefan Johansson, H.C. Steinhausen, Susann Scherag, Tony Altar, Tammy Biondi, Ted Reichborn-Kjennerud, Tetyana Zayats, Anita Thapar, Tim Silk, Tinca Polderman, Tobias Banaschewski, Alexandre Todorov, Yufeng Wang, Nigel Williams, Yanil Zhang, and Ziarih Hawi.Funding
M.R.M. and H.M.S. are members of the UK Centre for Tobacco and Alcohol Studies, a UKCRC Public Health Research: Centre of Excellence. Funding from British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, and National Institute for Health Research, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged. This work was supported by the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council and the University of Bristol (grants MC_UU_12013/6 and MC_UU_12013/7). J.L.T. is supported by a Rubicon grant from the Netherlands Organization for Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek; grant number 446-16-009) as well as a Veni grant (NWO; grant number 016.Veni.195.016). K.J.H.V. and J.L.T. are supported by the Foundation Volksbond Rotterdam. Data handling and analysis on the GenomeDK HPC facility of the ADHD GWAS was supported by National Institute of Mental Health (1U01MH109514-01) and Center for Genomics and Personalized Medicine (grant to A.D.B.). A.D.B.'s research was further supported by the Lundbeck Foundation (Lundbeckfonden, grant nos. R102-A9118 and R155-2014-1724) and by the European Community (EC) Horizon 2020 Programme (Horizon 2020 Framework Programme, grant 667302 (CoCA)). H.M.S. was supported by the Medical Research Council and the University of Bristol (MC_UU_00011/1 and MC_UU_00011/7).
Keywords
- ADHD
- alcohol
- cannabis
- coffee
- Mendelian randomization
- smoking
ASJC Scopus subject areas
- Medicine (miscellaneous)
- Pharmacology
- Psychiatry and Mental health
