Relationship between smoking and ALS: Mendelian randomization interrogation of causality

Sarah Opie-Martin, Robyn E Wootton, Ashley Budu-Aggrey, Aleksey Shatunov, Ashley Jones, Alfredo Lacoangeli, Ahmad Al Khleifat, George Davey Smith, A Al-Chalabi*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

Objective: Smoking has been widely studied as a susceptibility factor for 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 bi-directional 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 odds ratio 0.94 (95% confidence intervals 0.74,1.19), p-value 0.59; ever smoking odds ratio 1.10 (95% CI 1,1.23), 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

Original languageEnglish
JournalJournal of Neurology, Neurosurgery, and Psychiatry
DOIs
Publication statusPublished - 26 Aug 2020

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