Higher Coffee Consumption Is Associated With Reduced Cerebral Gray Matter Volume: A Mendelian Randomization Study

BACKGROUND: Recently published two-sample Mendelian randomization (MR) studies showed that genetically predicted coffee consumption may be associated with increased risk of Alzheimer’s disease and intracerebral hemorrhage but associated with a decreased risk of small vessel ischemic stroke. We aimed to investigate the effects of genetically predicted coffee consumption on magnetic resonance imaging (MRI) markers of cerebral small vessel disease and brain volume using the two-sample MR method. METHODS: Twelve single nucleotide polymorphisms (SNPs) in up to 375,833 individuals were used as genetic instruments for cups consumed per day of coffee. Another four SNPs from an independent sample were used to perform the replication analysis. Three SNPs in up to 45,821 individuals were used as genetic instruments for high coffee consumption vs. low/no coffee consumption. RESULTS: Mendelian randomization analysis showed that coffee consumption (cups/day) was inversely associated with gray matter volume (beta = −0.371, 95% CI = −0.596 to −0.147, p = 0.001). Replication analysis and multivariable analyses after adjusting for other risk factors confirmed the effect. High coffee consumption was also suggestively associated with decreased gray matter volume (beta = −0.061, 95% CI = −0.109 to −0.013, p = 0.013) compared with low/no coffee consumption. All analyses did not find an effect of coffee consumption on other outcomes including white matter hyperintensity volume, mean diffusivity, fractional anisotropy, brain microbleed, total brain volume, white matter volume, and hippocampus volume. CONCLUSION: This two-sample MR study showed that genetically predicted higher coffee consumption is causally associated with reduced gray matter volume of the brain.