Investigating Causal Relations Between Circulating Metabolites and Alzheimer's Diseases: a Mendelian Randomization Study [post]

Shu-Yi Huang, Yu-Xiang Yang, Ya-Ru Zhang, Kevin Kuo, Hong-Qi Li, Xue-Ning Shen, Shi-Dong Chen, Ke-Liang Chen, Qiang Dong, Lan Tan, Jin-Tai Yu
2021 unpublished
BackgroundMetabolomics is a promising approach that can be used to understand pathophysiological pathways of Alzheimer disease (AD). However, the relationships between metabolism and AD are poorly understood. The aim of this study is to investigate the causal association between circulating metabolites and risk of AD by combining metabolomics with genomics through two-sample Mendelian randomization (MR) approach. MethodGenetic associations with 123 circulating metabolic traits were utilized as
more » ... xposures. A large summary statistics data from International Genomics of Alzheimer's Project was used in primary analysis, including 21,982 AD cases and 41,944 controls. Validation was further performed using family history of AD data from UK Biobank (27,696 cases of maternal AD, 14,338 cases of paternal AD and 272,244 controls). We utilized the inverse-variance weighted method as primary analysis and four additional MR methods (MR-Egger, weighted median, weighted mode, and MR pleiotropy residual sum and outlier) for sensitivity analyses. ResultsWe found one-fold increased risk of developing AD per standard deviation increase in the levels of circulating ApoB (odd ratio (OR)=3.18; 95% confidence interval (CI): 1.52–6.66, P=0.0022) and glycoprotein acetyls (OR=1.21; 95% CI: 1.05–1.39, P=0.0093), serum total cholesterol (OR=2.73; 95% CI: 1.41-5.30, P=0.0030), and low-density lipoprotein (LDL) cholesterol (OR=2.34; 95% CI: 1.53-3.57, P=0.0001). Whereas glutamine (OR=0.81; 95% CI: 0.71-0.92, P=0.0011) were significantly associated with lower risk of AD. We also detected causal effects of several different composition of LDL fractions on increased AD risk, which has been verified in validation. However, we found no association between circulating high-density lipoprotein cholesterol and AD. ConclusionsOur findings provided robust evidence supporting causal effects of circulating glycoprotein acetyls, ApoB, LDL cholesterol, and serum total cholesterol on higher risk of AD, whereas glutamine showed the protective effect. Further research is required to decipher the biological pathways underpinning associations.
doi:10.21203/ fatcat:4neibu6jmva3xeen4y2ximgtoa