Relationship between smoking and ALS: Mendelian randomisation interrogation of causality

TY - JOUR

T1 - Relationship between smoking and ALS

T2 - Mendelian randomisation interrogation of causality

AU - Opie-Martin, Sarah

AU - Wootton, Robyn E.

AU - Budu-Aggrey, Ashley

AU - Shatunov, Aleksey

AU - Jones, Ashley R.

AU - Iacoangeli, Alfredo

AU - Al Khleifat, Ahmad

AU - Davey-Smith, George

AU - Al-Chalabi, Ammar

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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

AB - 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

UR - http://www.scopus.com/inward/record.url?scp=85090972121&partnerID=8YFLogxK

U2 - 10.1136/jnnp-2020-323316

DO - 10.1136/jnnp-2020-323316

M3 - Article

C2 - 32848012

AN - SCOPUS:85090972121

SN - 0022-3050

VL - 91

SP - 1312

EP - 1315

JO - Journal of Neurology, Neurosurgery and Psychiatry

JF - Journal of Neurology, Neurosurgery and Psychiatry

IS - 12

ER -