title: Genetically decreased vitamin D and risk of Alzheimer disease.
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 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.
authors.affiliation: From the Department of Epidemiology, Biostatistics and Occupational Health (L.E.M., J.B.R.), Centre for Clinical Epidemiology (L.E.M., S.R., J.A.M., D.M., V.F., J.B.R.), Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Human Genetics (J.A.M., J.B.R.), and Department of Medicine (D.M., J.B.R.), McGill University, Montreal, Quebec, Canada; and Department of Twin Research and Genetic Epidemiology (J.B.R.), King's College London, UK.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Mokry
authors.affiliation: From the Department of Epidemiology, Biostatistics and Occupational Health (L.E.M., J.B.R.), Centre for Clinical Epidemiology (L.E.M., S.R., J.A.M., D.M., V.F., J.B.R.), Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Human Genetics (J.A.M., J.B.R.), and Department of Medicine (D.M., J.B.R.), McGill University, Montreal, Quebec, Canada; and Department of Twin Research and Genetic Epidemiology (J.B.R.), King's College London, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ross
authors.affiliation: From the Department of Epidemiology, Biostatistics and Occupational Health (L.E.M., J.B.R.), Centre for Clinical Epidemiology (L.E.M., S.R., J.A.M., D.M., V.F., J.B.R.), Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Human Genetics (J.A.M., J.B.R.), and Department of Medicine (D.M., J.B.R.), McGill University, Montreal, Quebec, Canada; and Department of Twin Research and Genetic Epidemiology (J.B.R.), King's College London, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Morris
authors.affiliation: From the Department of Epidemiology, Biostatistics and Occupational Health (L.E.M., J.B.R.), Centre for Clinical Epidemiology (L.E.M., S.R., J.A.M., D.M., V.F., J.B.R.), Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Human Genetics (J.A.M., J.B.R.), and Department of Medicine (D.M., J.B.R.), McGill University, Montreal, Quebec, Canada; and Department of Twin Research and Genetic Epidemiology (J.B.R.), King's College London, UK.
authors.forename: Despoina
authors.initials: D
authors.lastname: Manousaki
authors.affiliation: From the Department of Epidemiology, Biostatistics and Occupational Health (L.E.M., J.B.R.), Centre for Clinical Epidemiology (L.E.M., S.R., J.A.M., D.M., V.F., J.B.R.), Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Human Genetics (J.A.M., J.B.R.), and Department of Medicine (D.M., J.B.R.), McGill University, Montreal, Quebec, Canada; and Department of Twin Research and Genetic Epidemiology (J.B.R.), King's College London, UK.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Forgetta
authors.affiliation: From the Department of Epidemiology, Biostatistics and Occupational Health (L.E.M., J.B.R.), Centre for Clinical Epidemiology (L.E.M., S.R., J.A.M., D.M., V.F., J.B.R.), Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Human Genetics (J.A.M., J.B.R.), and Department of Medicine (D.M., J.B.R.), McGill University, Montreal, Quebec, Canada; and Department of Twin Research and Genetic Epidemiology (J.B.R.), King's College London, UK. brent.richards@mcgill.ca.
authors.forename: J Brent
authors.initials: JB
authors.lastname: Richards
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics*; D002170:Canada; D019587:Dietary Supplements; D006801:Humans; D057182:Mendelian Randomization Analysis / Q000379:methods; D010024:Osteoporosis / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D014807:Vitamin D / Q000097:blood*
chemical_list: D014807:Vitamin D