Genetically decreased vitamin D and risk of Alzheimer disease

Neurology
Q1
Dec 2016
Citations:101
Influential Citations:4
Observational Studies (Human)
83
S2 IconPDF Icon

Enhanced Details

Methods
Two-sample Mendelian randomization using four SNPs for 25OHD from SUNLIGHT (N=33,996). SNP effects on 25OHD derived in CaMos (N=2,347). AD risk effects obtained from IGAP (17,008 cases; 37,154 controls). Population: individuals of European ancestry in CaMos and IGAP. Design: fixed-effects meta-analysis; sensitivity analyses to assess pleiotropy and population stratification; stratified analyses separating metabolism- and synthesis-related SNPs.
Results
A 1-SD decrease in genetically determined natural log-transformed 25OHD increased Alzheimer's disease odds by 25% (OR 1.25, 95% CI 1.03–1.51, p=0.021). Sensitivity analyses excluding potentially pleiotropic SNPs left results largely unchanged. Stratified analyses suggested stronger effects for metabolism-related SNPs (OR 1.46, 95% CI 1.03–2.07, p=0.032) than synthesis-related SNPs (OR 1.17, 95% CI 0.93–1.46, p=0.17). Conclusion: Vitamin D insufficiency likely causally increases AD risk; findings support investigating whether vitamin D supplementation could reduce AD risk in randomized controlled trials and highlight the need to understand vitamin D’s role in cognition and AD.
Limitations
Potential residual pleiotropy and population stratification despite sensitivity analyses; IGAP’s case-control design; European ancestry limits generalizability; genetic instruments explain 2.44% of 25OHD variance; cannot define a precise protective 25OHD threshold; removal of GC or DHCR7 loci in sensitivity analyses altered significance, suggesting possible mediation by DBP or cholesterol.

Abstract

Objective: To test whether genetically decreased vitamin D levels are associated with Alzheimer disease (AD) using mendelian randomization (MR), a method that minimizes bias due to confounding or reverse causation. Methods: We selected single nucleot...