Genetic Association of Diagnostic Traits of Metabolic Syndrome with Lysosomal Pathways: Insights from Target Gene Enrichment Analysis

Abstract

Genome-wide association studies (GWAS) identified many association signals for metabolic syndrome (MetS). However, the understanding of its pathophysiology may be limited because of the complexity of the intertwined genetic factors that underlie diagnostic condition traits. We conducted an enrichment analysis of spatial expression genes (eGenes) associated with GWAS signals for MetS and its diagnostic condition traits. Consequently, eGenes associated with MetS were significantly enriched in 14 biological pathways (PBH < 0.05, where PBH is the p-value adjusted for Benjamini–Hochberg multiple testing). Moreover, 38 biological pathways were additionally identified in the enrichment analysis of the individual diagnostic traits (PBH < 0.05). In particular, the lysosomal pathway was revealed for waist-to-hip ratio, glucose measurement, and high-density lipoprotein cholesterol (PBH < 0.05), but not for MetS (PBH > 0.05). It was inferred that lysosomal pathway-based control of cellular lipid metabolism and insulin secretion/resistance could result in eGene enrichment for these diagnostic traits. In conclusion, this target gene enrichment analysis of diagnostic traits of MetS uncovered a lysosomal pathway that may dilute its effects on the MetS. We propose that lysosomal dysfunction should be a priority for research on the underlying pathogenic mechanisms of MetS and its diagnostic traits. Experimental studies are needed to elucidate causal relationships of ribosomal pathways with metabolic syndrome and its diagnostic traits.