Genetically decreased vitamin D and risk of Alzheimer disease
Autor: | John A. Morris, Stephanie Ross, Lauren E. Mokry, Despoina Manousaki, Vincenzo Forgetta, J. Brent Richards |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Oncology Canada medicine.medical_specialty Single-nucleotide polymorphism Population stratification Polymorphism Single Nucleotide Article 03 medical and health sciences 0302 clinical medicine Alzheimer Disease Risk Factors Internal medicine Mendelian randomization medicine Vitamin D and neurology Humans SNP Vitamin D Risk factor business.industry Confounding Odds ratio Mendelian Randomization Analysis Phenotype 030104 developmental biology Dietary Supplements Osteoporosis Neurology (clinical) business 030217 neurology & neurosurgery |
Zdroj: | Neurology. 87:2567-2574 |
ISSN: | 1526-632X 0028-3878 |
DOI: | 10.1212/wnl.0000000000003430 |
Popis: | 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 −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 Alzheimer9s 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. |
Databáze: | OpenAIRE |
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