Left caudal middle frontal surface area and cigarette per day were found to have unidirectional causality: Genetic correlation and Mendelian randomization study (Preprint)

BACKGROUND Previous researches are controversial about smoking is associated with changes in cortical thickness and surface area. However, observational studies cannot avoid confounding factors. OBJECTIVE The aim of this study was to examine the causal association of cortical thickness and surface area with smoking phenotype, using Mendelian randomization (MR) analysis to avoid confounding factors as much as possible. METHODS To obtain the summary statistics of GWAS on cortical thickness and surface area and four smoking phenotypes (1) Age of Initiation of Regular Smoking (AgeSmk); (2) Smoking Initiation (SmkInit); (3) Smoking Cessation (SmkCes); (4) Cigarettes Per Day (CigDay). Genetic association analysis was investigated by linkage disequilibrium score regression (LDSC). And MR analyses were performed for traits with normal significant genetic associations. RESULTS We found significant genetic correlations between AgeSmk with right precentral surface area (rg = -0.25, p= 8.3×10-3), left caudal anterior cingulate surface area (rg = -0.22, p = 0.025) , left cuneus surface area (rg = -0.26, p = 0.013), left inferior parietal surface area (rg = 0.25, p = 0.035), right caudal anterior cingulate thickness (rg = 0.29, p = 0.028); CigDay with left caudal middle frontal surface area (rg = 0.21, p = 0.040); SmkCes with left entorhinal thickness (rg = -0.36, p = 0.019); SmkInit with left rostral anterior cingulate surface area (rg = -0.20, p = 0.015), right rostral anterior cingulate thickness (rg = -0.24, p = 0.011), right superior frontal thickness (rg = -0.17, p = 0.045). MR indicated a unidirectional causal relationship between left caudal middle frontal surface area and CigDay (βIVW = 0.056, p =1×10-5). CONCLUSIONS We found genetic associations between four phenotypes of smoking (AgeSmk, CigDay, SmkInit and SmkCes) and cortical thickness and surface area. And found that the left caudal middle frontal surface area has a one-way causal relationship with cigarettes per day. In the future, this brain imaging indicator may become an important indicator to predict future smoking behavior.