Yu Ke, Chi Yanqing, Wang Qian, Chen Yongzhe, Han Ning, Li Ying
Department of Nephrology, Hebei Medical University Third Hospital, Shijiazhuang City, China.
Hebei Key Laboratory of Diabetic Kidney Disease, Shijiazhuang City, China.
Ren Fail. 2025 Dec;47(1):2525471. doi: 10.1080/0886022X.2025.2525471. Epub 2025 Jul 1.
Diabetic kidney disease (DKD) may increase cognitive impairment (CI) risk, but causal evidence remains limited. We aimed to investigate this causality and elucidate underlying genetic mechanisms.
Bidirectional two-sample Mendelian randomization (MR) was performed using summary statistics from four DKD genome-wide association studies (GWAS) and a large-scale cognitive function GWAS. Sensitivity analyses (heterogeneity, pleiotropy, leave-one-out, and Steiger directionality tests) confirmed the robustness of the results. Multivariable MR was used to adjust for potential confounders. Genetic correlation was assessed via linkage disequilibrium score regression (LDSC). Shared loci and pathways were identified through colocalization and functional enrichment analyses.
DKD significantly increased cognitive decline risk (inverse-variance weighted (IVW) OR range: 0.55-0.88; all < .05), with consistent results across sensitivity analyses. Multivariable MR confirmed that the association was independent of confounders. Significant genetic correlations were observed (LDSC rg = 0.072-0.201). Colocalization identified six shared risk loci (posterior probability for H4 (PP.H4) > 0.90). Enriched pathways included ribosomal function, mitochondrial oxidative phosphorylation, and neurodegeneration.
This study provides evidence supporting a causal relationship and genetic correlation between DKD and CI, while also identifying shared genetic features and biological pathways that may contribute to their association.
糖尿病肾病（DKD）可能会增加认知障碍（CI）风险，但因果证据仍然有限。我们旨在研究这种因果关系，并阐明潜在的遗传机制。
使用来自四项DKD全基因组关联研究（GWAS）和一项大规模认知功能GWAS的汇总统计数据进行双向两样本孟德尔随机化（MR）。敏感性分析（异质性、多效性、留一法和Steiger方向性检验）证实了结果的稳健性。使用多变量MR来调整潜在的混杂因素。通过连锁不平衡评分回归（LDSC）评估遗传相关性。通过共定位和功能富集分析确定共享位点和途径。
DKD显著增加认知衰退风险（逆方差加权（IVW）OR范围：0.55 - 0.88；所有P <.05），敏感性分析结果一致。多变量MR证实该关联独立于混杂因素。观察到显著的遗传相关性（LDSC rg = 0.072 - 0.201）。共定位确定了六个共享风险位点（H4的后验概率（PP.H4）> 0.90）。富集途径包括核糖体功能、线粒体氧化磷酸化和神经退行性变。
本研究提供了支持DKD与CI之间因果关系和遗传相关性的证据，同时还确定了可能导致它们关联的共享遗传特征和生物学途径。
