PT - JOURNAL ARTICLE AU - Mokry, Lauren E. AU - Ross, Stephanie AU - Morris, John A. AU - Manousaki, Despoina AU - Forgetta, Vincenzo AU - Richards, J. Brent TI - Genetically decreased vitamin D and risk of Alzheimer disease AID - 10.1212/WNL.0000000000003430 DP - 2016 Dec 13 TA - Neurology PG - 2567--2574 VI - 87 IP - 24 4099 - http://n.neurology.org/content/87/24/2567.short 4100 - http://n.neurology.org/content/87/24/2567.full SO - Neurology2016 Dec 13; 87 AB - 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 nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels (p < 5 × 10−8) from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) Consortium (N = 33,996) to act as instrumental variables for the MR study. We measured the effect of each of these SNPs on 25OHD levels in the Canadian Multicentre Osteoporosis Study (CaMos; N = 2,347) and obtained the corresponding effect estimates for each SNP on AD risk from the International Genomics of Alzheimer's Project (N = 17,008 AD cases and 37,154 controls). To produce MR estimates, we weighted the effect of each SNP on AD by its effect on 25OHD and meta-analyzed these estimates using a fixed-effects model to provide a summary effect estimate.Results: The SUNLIGHT Consortium identified 4 SNPs to be genome-wide significant for 25OHD, which described 2.44% of the variance in 25OHD in CaMos. All 4 SNPs map to genes within the vitamin D metabolic pathway. MR analyses demonstrated that a 1-SD decrease in natural log–transformed 25OHD increased AD risk by 25% (odds ratio 1.25, 95% confidence interval 1.03–1.51, p = 0.021). After sensitivity analysis in which we removed SNPs possibly influenced by pleiotropy and population stratification, the results were largely unchanged.Conclusions: Our results provide evidence supporting 25OHD as a causal risk factor for AD. These findings provide further rationale to understand the effect of vitamin D supplementation on cognition and AD risk in randomized controlled trials.AD=Alzheimer disease; CAD=coronary artery disease; CaMos=Canadian Multicentre Osteoporosis Study; CI=confidence interval; DBP=vitamin D–binding protein; DSM-IV=Diagnostic and Statistical Manual of Mental Disorders, 4th edition; GWAS=genome-wide association study; IGAP=International Genomics of Alzheimer's Project; LD=linkage disequilibrium; LDL-C=low-density lipoprotein cholesterol; MR=mendelian randomization; MS=multiple sclerosis; OR=odds ratio; RCT=randomized controlled trial; SBP=systolic blood pressure; SNP=single nucleotide polymorphism; 25OHD=25-hydroxyvitamin D