【摘要】 目的 采用双向两样本孟德尔随机化（MR）方法来探究酮体与认知表现之间的因果关系。方法 采用欧洲全基因组关联研究汇总数据中的单核苷酸多态性（SNPs）作为工具变量。将逆方差加权法作为主要方法来评估酮体工具变量与认知表现的因果关系，并进行通路和功能富集分析预测潜在的机制。使用Bonferroni法校正显著性阈值确定显著性（P=0.017）。结果 两样本孟德尔随机化分析显示，乙酰乙酸（β=0.075, 95%CI:0.002～0.148,P=0.045）和β-羟基丁酸(β=0.082, 95%CI:0.039～0.126,P=2.36×10^-4)与认知表现有因果关系，但经Bonferroni法校正后，乙酰乙酸与认知表现的因果关系不再显著。此外，发现丙酮与认知表现之间不存在因果关系（β=0.041, 95%CI:-0.018～0.099,P=0.175）。通路和功能富集分析表明，β-羟基丁酸对认知表现的影响机制可能通过多种方式，如胆固醇代谢和胰岛素抵抗。在反向孟德尔随机化分析中，我们没有发现认知表现对酮体方向上的因果关系。结论 β-羟基丁酸水平与更好的认知表现之间存在因果关系。更多还原

【Abstract】 Objective To explore whether there is any causal association between ketone bodies and cognitive performance employing the bidirectional and two-sample Mendelian randomization（MR） method. Methods Single nucleotide polymorphisms（SNPs） from the genome-wide association studies summary data from Europe were used as instrumental variables. The inverse-variance weighted method was used as the primary method to estimate the causal effect of ketone bodies instrumental variables with cognitive performance, and pathway and functional enrichment analyses were performed to predict potential mechanisms. Significance was ascertained with the use of Bonferroni-corrected significance thresholds（P=0.017）. Results Two-sample MR analysis showed that acetoacetate（β=0.075, 95%CI: 0.002-0.148, P=0.045） and β-hydroxybutyrate(β=0.082, 95%CI: 0.039-0.126, P=2.36×10^-4) were causally associated with cognitive performance. However, the association of acetoacetate was no longer significant after Bonferroni-corrected. In addition, no link between acetone（β=0.041, 95%CI:-0.018-0.099, P=0.175） and cognitive performance was discovered. Pathway and functional enrichment analyses suggest that the mechanism of β-hydroxybutyrate effect on cognitive performance may be through a variety of ways, such as cholesterol metabolism and insulin resistance. In reverse MR Analysis, we found no causal effects of cognitive performance on ketone bodies. Conclusion Our findings support a causal relationship between β-hydroxybutyrate levels and better cognitive performance.更多还原