Association of smoking with brain gray and white matter volume: a Mendelian randomization study

Observational studies have found a significant association between smoking and smaller gray matter volume, but this finding was limited by the reverse causality bias and possible confounding factors. Therefore, we conducted a Mendelian randomization (MR) study to explore the causal association of smoking with brain gray and white matter volume from a genetic perspective, and to investigate the possible mediators influencing the association.

Smoking initiation (ever being a regular smoker) was used as the primary exposure from the GWAS & Sequencing Consortium of Alcohol and Nicotine use in up to 1,232,091 individuals of European descent. Their associations with brain volume were acquired from a recent genome-wide association study of brain imaging phenotypes conducted among 34,298 individuals of the UK Biobank. The random-effects inverse-variance weighted method was applied as the main analysis. Multivariable MR analysis was performed to assess the potential interference of confounding factors on causal effect.

Genetic liability to smoking initiation was significantly associated with lower gray matter volume (beta, -0.100; 95% CI, -0.156 to -0.043; P=5.23×10^-4) but not with white matter volume. Multivariable MR results suggested that the association with lower gray matter volume might be mediated by alcohol drinking. Regarding localized gray matter volume, genetic liability to smoking initiation was associated with lower gray matter volume in left superior temporal gyrus, anterior division and right superior temporal gyrus, posterior division.

This MR study supports the association between smoking and lower gray matter volume, and highlights the importance of never smoking.