Using a 2-sample Mendelian randomization (MR) approach, we evaluated MR evidence for genetically proxied effects of 10 pre-specified gut bacterial classes on type 2 diabetes mellitus (T2DM) and Alzheimer disease (AD), and assessed MR evidence for a direct genetically proxied effect of T2DM on AD. Mediation by T2DM was explored where feasible. We performed 2-sample MR using MiBioGen gut microbiota GWAS summary statistics as exposure, and DIAMANTE (T2DM) and European AD GWAS data as outcomes. Inverse-variance weighted (IVW) MR was the primary analysis, with MR-Egger, weighted median, and weighted mode as sensitivity analyses. Heterogeneity and directional pleiotropy were assessed, and IVW results were false discovery rate (FDR) corrected using Benjamini–Hochberg. MR analysis using 184 independent SNPs provided no robust evidence for a direct genetically proxied effect of T2DM on AD risk (IVW odds ratio OR = 0.98, 95% confidence interval CI: 0.94–1.02, P = .28). After FDR correction, higher genetically predicted Clostridia abundance was associated with lower AD risk (IVW OR = 0.86, 95% CI: 0.77–0.96, FDR < 0.05), and higher genetically predicted Deltaproteobacteria abundance was associated with higher T2DM risk (IVW OR = 1.11, 95% CI: 1.04–1.20, FDR < 0.05). Other classes were not significant after FDR correction. Reverse MR and multivariable MR were not testable due to insufficient SNP overlap after harmonization (effective SNPs < 3). These findings provide MR evidence consistent with genetically proxied effects of Clostridia on AD and Deltaproteobacteria on T2DM and do not support robust MR evidence for a direct genetically proxied effect of T2DM on AD. Results are hypothesis-generating and require replication in diverse ancestries and follow-up mechanistic/experimental studies, given that included GWAS sources are predominantly of European ancestry.
Gao et al. (Fri,) studied this question.