Causal relationship and shared genetic pathways between diabetic kidney disease and cognitive impairment: a Mendelian...

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 p < .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.