Mokry Lauren E, Ross Stephanie, Morris John A, Manousaki Despoina, Forgetta Vincenzo, Richards J Brent
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.
Neurology. 2016 Dec 13;87(24):2567-2574. doi: 10.1212/WNL.0000000000003430. Epub 2016 Nov 16.
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.
We selected single nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels (p < 5 × 10) 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.
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.
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.
采用孟德尔随机化（MR）方法检验遗传性维生素D水平降低是否与阿尔茨海默病（AD）相关，该方法可将混杂因素或反向因果关系导致的偏倚降至最低。
我们从维生素D及高度相关性状的潜在遗传决定因素研究（SUNLIGHT）联盟（N = 33,996）中选择了与25-羟基维生素D（25OHD）水平密切相关的单核苷酸多态性（SNP）（p < 5×10），作为MR研究的工具变量。我们在加拿大多中心骨质疏松研究（CaMos；N = 2,347）中测量了每个SNP对25OHD水平的影响，并从国际阿尔茨海默病基因组计划（N = 17,008例AD病例和37,154例对照）中获得了每个SNP对AD风险的相应效应估计值。为了得出MR估计值，我们根据每个SNP对25OHD的影响对其对AD的影响进行加权，并使用固定效应模型对这些估计值进行荟萃分析，以提供汇总效应估计值。
SUNLIGHT联盟确定了4个SNP在全基因组范围内对25OHD具有显著意义，它们解释了CaMos中25OHD变异的2.44%。所有4个SNP均映射到维生素D代谢途径中的基因。MR分析表明，自然对数转换后的25OHD每降低1个标准差，AD风险增加25%（优势比1.25，95%置信区间1.03 - 1.51，p = 0.021）。在去除可能受多效性和群体分层影响的SNP的敏感性分析后，结果基本未变。
我们的结果提供了证据支持25OHD作为AD的因果风险因素。这些发现为理解维生素D补充剂在随机对照试验中对认知和AD风险的影响提供了进一步的理论依据。
