Uncovering polygenic and local genetic overlap between sarcopenia and Alzheimer's disease

BackgroundSarcopenia and Alzheimer's disease (AD) are prevalent comorbidities in older adults. Their common genetic basis remains unclear.ObjectiveUtilizing Genomic Structural Equation Modeling, we used European-ancestry genome-wide association study (GWAS) summary statistics to model sarcopenia-related traits. Multiple AD GWAS datasets and the sarcopenia GWAS dataset were used to conduct cross-trait analyses.MethodsGenome-wide and local genetic correlations were assessed using LDSC and LAVA. MiXeR was applied to evaluate shared versus trait-specific variants. Shared loci were identified using conjFDR. Candidate genes were further explored via tissue-specific expression (MetaXcan) and Mendelian randomization (MR).ResultsLDSC analysis revealed no significant genome-wide genetic correlation between AD and sarcopenia (rg = 0.020, p = 0.178). Bivariate LAVA analysis identified significant local genetic correlations at three specific genomic regions (chr3:183.2-184.5 Mb, chr8:144.9-146.3 Mb, and chr8:27.4-28.3 Mb; p < 0.05/90). MiXeR indicated moderate polygenic overlap (228 shared variants). ConjFDR identified 20 shared loci, and MetaXcan highlighted ETHE1, FEZ2, PHLDB3, and PINLYP. MR analysis indicated a positive causal effect of FEZ2 in excitatory neurons on AD and sarcopenia risk (FDR < 0.05).ConclusionsThis study indicates no significant genome-wide genetic correlation between sarcopenia and AD, while suggesting the presence of localized shared genetic signals at specific genomic regions. Dysregulation of the cytoskeleton and autophagy pathways may contribute to both sarcopenia and AD. FEZ2, ETHE1, PHLDB3, and PINLYP expression in muscle and brain may contribute to the comorbidity between sarcopenia and AD. Overall, these findings provide exploratory evidence for local shared genetic architecture between sarcopenia and AD.