Objective Smoking has been widely studied as a susceptibility factor for amyotrophic lateral sclerosis (ALS), but results are conflicting and at risk of confounding bias. We used the results of recently published large genome-wide association studies and Mendelian randomisation methods to reduce confounding to assess the relationship between smoking and ALS.
Methods Two genome-wide association studies investigating lifetime smoking (n=463 003) and ever smoking (n=1 232 091) were identified and used to define instrumental variables for smoking. A genome-wide association study of ALS (20 806 cases; 59 804 controls) was used as the outcome for inverse variance weighted Mendelian randomisation, and four other Mendelian randomisation methods, to test whether smoking is causal for ALS. Analyses were bidirectional to assess reverse causality.
Results There was no strong evidence for a causal or reverse causal relationship between smoking and ALS. The results of Mendelian randomisation using the inverse variance weighted method were: lifetime smoking OR 0.94 (95% CI 0.74 to 1.19), p value 0.59; ever smoking OR 1.10 (95% CI 1 to 1.23), p value 0.05.
Conclusions Using multiple methods, large sample sizes and sensitivity analyses, we find no evidence with Mendelian randomisation techniques that smoking causes ALS. Other smoking phenotypes, such as current smoking, may be suitable for future Mendelian randomisation studies
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Contributors AA-C and SO-M conceived and planned the study. AB-A conducted genetic risk score (GRS) analysis, S-OM conducted all other statistical analysis supported by REW. AA-C, GD-S, AB-A and REW provided intellectual input for data interpretation. AA-C and SO-M wrote the first draft of the manuscript. All authors reviewed and approved the final manuscript.
Funding The project is supported through the following funding organisations under the egis of JPND—www.jpnd.eu (UK, Medical Research Council (MR/L501529/1; MR/R024804/1) and Economic and Social Research Council (ES/ L008238/1)). The work leading up to this publication was funded by the European Community’s Health Seventh Framework Program (FP7/2007–2013; grant agreement number 259 867), Horizon 2020 Framework Programme (H2020-PHC-2014-two-stage; grant agreement number 633 413) and Programme Grants for Applied Research. This project is also supported by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London Maudsley Foundation Trust and King's College London. This research has been conducted using data from the UK Biobank Resource (application number 19278). We have also received funding from the Motor Neurone Disease Association, ALS Association, Patients Like Me and the Psychiatry Research Trust. This research was also supported by the NIHR Bristol Biomedical Research Centre at University Hospitals Bristol National Health Service (NHS) Foundation Trust and the University of Bristol.
Disclaimer The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval This research involves analysing publicly available data, with no collection of new data. Ethical approval had been obtained by the original study authors.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement This study used publicly available summary statistics from genome-wide association studies to define instruments for Mendelian Randomisation:
Lifetime smoking index: https://www.cambridge.org/core/journals/psychological-medicine/article/evidence-for-causal-effects-of-lifetime-smoking-on-risk-for-depression-and-schizophrenia-a-mendelian-randomisation-study/AA82945360EC59FEC4331A7A567309C9%23fndtn-supplementary-materials
Ever smoking (GSCAN): https://conservancy.umn.edu/handle/11299/201564
The single nucleotide polymorphisms that passed QC and were used in the MR analysis are in supplementary file 2.
Genetic risk score analysis used data from the UK Biobank (application number 19278)
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