Data_Sheet_1_No genetic causal association between Alzheimer’s disease and osteoporosis: A bidirectional two-sample Mendelian randomization study.docx

ObjectiveMany observational studies have found an association between Alzheimer’s disease (AD) and osteoporosis. However, it is unclear whether there is causal genetic between osteoporosis and AD.
MethodsA two-sample Mendelian randomization (MR) study was used to investigate whether there is a causal relationship between osteoporosis and AD. Genes for osteoporosis and AD were obtained from published the genome-wide association studies (GWAS). Single nucleotide polymorphisms (SNPs) with significant genome-wide differences (p < 5 × 10−8) and independent (r2 < 0.001) were selected, and SNPs with F ≥ 10 were further analyzed. Inverse variance weighted (IVW) was used to assess causality, and the results were reported as odds ratios (ORs). Subsequently, heterogeneity was tested using Cochran’s Q test, pleiotropy was tested using the MR–Egger intercept, and leave-one-out sensitivity analysis was performed to assess the robustness of the results.
ResultsUsing the IVW method, MR Egger method, and median-weighted method, we found that the results showed no significant causal effect of osteoporosis at different sites and at different ages on AD, regardless of the removal of potentially pleiotropic SNPs. The results were similar for the opposite direction of causality. These results were confirmed to be reliable and stable by sensitivity analysis.
ConclusionThis study found that there is no bidirectional causal relationship between osteoporosis and AD. However, they share similar pathogenesis and pathways.

研究目的：多项观察性研究已证实阿尔茨海默病（Alzheimer’s disease, AD）与骨质疏松症之间存在关联，但目前尚不明确二者之间是否存在因果遗传联系。
研究方法：本研究采用两样本孟德尔随机化（two-sample Mendelian randomization, MR）方法，探究骨质疏松症与阿尔茨海默病之间的因果关系。骨质疏松症与阿尔茨海默病的基因数据来源于已发表的全基因组关联研究（genome-wide association studies, GWAS）。筛选全基因组水平差异显著（p < 5 × 10⁻⁸）且相互独立（r² < 0.001）的单核苷酸多态性（single nucleotide polymorphisms, SNPs），并进一步对F值≥10的SNPs开展分析。采用逆方差加权（inverse variance weighted, IVW）法评估因果关联，结果以比值比（odds ratios, ORs）报告。随后通过科克伦Q检验（Cochran’s Q test）检验异质性，利用MR-Egger截距项（MR–Egger intercept）检测多效性，并实施留一法敏感性分析（leave-one-out sensitivity analysis）以评估研究结果的稳健性。
研究结果：通过逆方差加权法、MR Egger法以及加权中位数法（median-weighted method）分析发现，无论是否剔除潜在多效性SNPs，不同部位、不同年龄段的骨质疏松症对阿尔茨海默病均无显著因果效应；反向因果分析亦得到相似结果。敏感性分析证实上述结果可靠且稳定。
研究结论：本研究表明，骨质疏松症与阿尔茨海默病之间不存在双向因果关系，但二者具有相似的发病机制与通路。