Associations between polygenic risk scores and accelerated brain ageing in smokers.

BACKGROUND: Smoking contributes to a variety of neurodegenerative diseases and neurobiological abnormalities, suggesting that smoking is associated with accelerated brain aging. However, the neurobiological mechanisms affected by smoking, and whether they are genetically influenced, remain to be investigated. METHODS: Using structural magnetic resonance imaging data from the UK Biobank (n = 33 293), a brain age predictor was trained on non-smoking healthy groups and tested on smokers to obtain the BrainAge Gap (BAG). The cumulative effect of multiple common genetic variants associated with smoking was then calculated to acquire a polygenic risk score (PRS). The relationship between PRS, BAG, total gray matter volume (tGMV), and smoking parameters was explored and further genes included in the PRS were annotated to identify potential molecular mechanisms affected by smoking. RESULTS: The BrainAge in smokers was predicted with very high accuracy (r = 0.725, MAE = 4.16). Smokers had a greater BAG (Cohen's d = 0.074, p < 0.0001) and higher PRS (Cohen's d = 0.63, p < 0.0001) than non-smokers. A higher PRS was associated with increased amount of smoking, mediated by BAG and tGMV. Several neurotransmitters and ion channel pathways were enriched in the group of smoking-related genes involved in addiction, brain synaptic plasticity, and some neurological disorders. CONCLUSION: By using a simplified single indicator of the entire brain (BAG) in combination with the PRS, this study highlights the greater BAG in smokers and its linkage with genes and smoking behavior, providing insight into the neurobiological underpinnings and potential features of smoking-related aging.

Smoking is associated with lower brain volume and cognitive differences: A large population analysis based on the UK Biobank.

The evidence about the association of smoking with both brain structure and cognitive functions remains inconsistent. Using structural magnetic resonance imaging from the UK Biobank (n = 33,293), we examined the relationships between smoking status, dosage, and abstinence with total and 166 regional brain gray matter volumes (GMV). The relationships between the smoking parameters with cognitive function, and whether this relationship was mediated by brain structure, were then investigated. Smoking was associated with lower total and regional GMV, with the extent depending on the frequency of smoking and on whether smoking had ceased: active regular smokers had the lowest GMV (Cohen's d = -0.362), and former light smokers had a slightly smaller GMV (Cohen's d = -0.060). The smaller GMV in smokers was most evident in the thalamus. Higher lifetime exposure (i.e., pack-years) was associated with lower total GMV (ß = -311.84, p = 8.35 × 10-36). In those who ceased smoking, the duration of abstinence was associated with a larger total GMV (ß = 139.57, p = 2.36 × 10-08). It was further found that reduced cognitive function was associated with smoker parameters and that the associations were partially mediated by brain structure. This is the largest scale investigation we know of smoking and brain structure, and these results are likely to be robust. The findings are of associations between brain structure and smoking, and in the future, it will be important to assess whether brain structure influences smoking status, or whether smoking influences brain structure, or both.

Associations between smoking and accelerated brain ageing.

Smoking accelerates the ageing of multiple organs. However, few studies have quantified the association between smoking, especially smoking cessation, and brain ageing. Using structural magnetic resonance imaging data from the UK Biobank (n = 33,293), a brain age predictor was trained using a machine learning technique in the non-smoker group (n = 14,667) and then tested in the smoker group (n = 18,626) to determine the relationships between BrainAge Gap (predicted age - true age) and smoking parameters. Further, we examined whether smoking was associated with poorer cognition and whether this relationship was mediated by brain age. The predictor achieved an appreciable performance in training data (r = 0.712, mean-absolute-error [MAE] = 4.220) and test data (r = 0.725, MAE = 4.160). On average, smokers showed a larger BrainAge Gap (+0.304 years, Cohens'd = 0.083) than controls, more explicitly, the extents vary depending on their smoking characteristic that active regular smokers had the largest BrainAge Gap (+1.190 years, Cohens'd = 0.321), and light smokers had a moderate BrainAge Gap (+0.478, Cohens'd = 0.129). The increased smoking amount was associated with a larger BrainAge Gap (ß = 0.035, p = 1.72 × 10-20) while a longer duration of quitting smoking in ex-smokers was associated with a smaller BrainAge Gap (ß = -0.015, p = 2.14 × 10-05). Furthermore, smoking was associated with poorer cognition, and this relationship was partially mediated by BrainAge Gap. The study provides insight into the association between smoking, brain ageing, and cognition, which provide more publicly acceptable propaganda against smoking.