Genetics
Taiwan Biobank GWAS of 40,773 people finds a three-way APOA5-LPL-CETP gene interaction behind metabolic syndrome susceptibility (Genome Biol 2026)
Original title: Genome-wide association and MaODR-based multi-locus interaction analyses reveal a susceptibility gene network for newly identified metabolic syndrome
A genome-wide association study applied a many-objective multifactor dimensionality reduction method to detect gene-gene interactions in 40,773 Taiwan Biobank participants (5,723 newly identified metabolic syndrome cases, 35,050 controls). Genome-wide analysis identified 35 significant SNPs and a two-locus interaction between APOA5 and LPL (rs331-GG with rs651821-CC, bootstrap odds ratio 1.76, highly statistically significant). The method also revealed a three-way interaction among APOA5, LPL and CETP, with LPL, APOA5, BUD13, ZPR1, APOC3, CETP and APOE genes collectively contributing to metabolic syndrome susceptibility, enriched in cholesterol metabolism and PPAR signalling pathways. CETP appears here as one node in a broader lipid-gene interaction network rather than as the primary target of the study.
Original abstract
Background: Metabolic syndrome involves several lipid-related genes, including apolipoprotein A5 (APOA5), lipoprotein lipase (LPL), and cholesteryl ester transfer protein (CETP). Although individual SNP susceptibility has been reported, gene-gene interactions remain underexplored. To address this gap, we apply many-objective multifactor dimensionality reduction (MaODR)-previously developed by our group-to detect gene‒gene interactions in unbalanced newly identified MetS and non-MetS subjects.
Results: Among 40,773 Taiwan Biobank participants (5,723 newly identified metabolic syndrome cases and 35,050 controls) after excluding smokers and individuals with chronic diseases, genome-wide association analysis identifies 35 significant SNPs. We detect a two-locus SNP-SNP interaction between APOA5 and LPL; the most significant genotype combination is rs331-GG with rs651821-CC (bootstrap odds ratio = 1.76; p = 9.61 × 10⁻2⁰). MaODR also reveals a three-way interaction among APOA5, LPL, and CETP. Furthermore, we find that the LPL, APOA5, BUD13, zinc finger protein 1 (ZPR1), APOC3, CETP, and APOE genes collectively contributed to MetS susceptibility, with SNPs of LPL showing a significant metabolic syndrome-associated effect and interacting with SNPs of the APOA5 and CETP genes. Genes linked to metabolic syndrome are enriched in cholesterol metabolism and the peroxisome proliferator-activated receptor signaling pathway.
Conclusions: MaODR detects epistasis networks through SNP-SNP interactions in newly identified metabolic syndrome, highlighting APOA5-LPL and APOA5-LPL-CETP interaction models.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.