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Genome-Wide Association Studies of Fatty Liver Index and Kidney Stone Disease: Insights into Shared and Ancestry-Specific Genetic Risk Across Populations
Other Title
Genome-Wide Association Studies of Fatty Liver Index and Kidney Stone Disease: Insights into Shared and Ancestry-Specific Genetic Risk Across Populations
Type
thesis
Date Issued
2025-12-22
Author(s)
LAU PEI PEI
Advisor
張偉嶠
Subjects
系所名稱：藥學系博士班
Publisher
藥學系博士班
Description
學位別：博士
語文別：英文
口試委員：邱彥霖; 許書睿; 張君照; 張偉嶠; 高治圻
語文別：英文
口試委員：邱彥霖; 許書睿; 張君照; 張偉嶠; 高治圻
Abstract
Rationale
The global burden of fatty liver disease continues to rise, yet the underlying genetic determinants are not fully characterized. Using the fatty liver index (FLI) as a non-invasive proxy phenotype, this study sought to identify genetic variants associated with fatty liver disease in both Taiwanese and European populations.
Results
In this study, individuals with higher FLI values showed a markedly increased likelihood of fatty liver, which was supported by imaging-based confirmation (OR = 4.43; 95% CI: 3.88–5.06). Our GWAS identified six previously reported fatty liver–associated variants, reinforcing known genetic contributions to disease susceptibility. Further conditional analysis based on 423 genome-wide significant variants refined these signals into 16 independent variants across 14 genes, including TRIB1AL and LPL, both of which have been implicated in NAFLD in prior studies. For cross-ancestry validation, 50 risk variants were assessed in a European GWAS dataset, with replicated associations mapping to the ZPR1 and FTO loci. In addition, pathway enrichment results indicated significant involvement of lipid metabolism and the PPAR signaling pathway, highlighting biological mechanisms that may contribute to hepatic lipid accumulation and fatty liver development.
Conclusion
We identified six independent NAFLD-related variants in GCKR, LPL, TRIB1AL, and FTO, and confirmed ZPR1 and FTO as shared risk genes for FLI-defined fatty liver across Taiwanese and European cohorts. These findings support the use of FLI as a non-invasive predictor of fatty liver and highlight genetic pathways that may be common across populations. This work provides a strong basis for future personalized risk assessment and therapeutic development.
The global burden of fatty liver disease continues to rise, yet the underlying genetic determinants are not fully characterized. Using the fatty liver index (FLI) as a non-invasive proxy phenotype, this study sought to identify genetic variants associated with fatty liver disease in both Taiwanese and European populations.
Results
In this study, individuals with higher FLI values showed a markedly increased likelihood of fatty liver, which was supported by imaging-based confirmation (OR = 4.43; 95% CI: 3.88–5.06). Our GWAS identified six previously reported fatty liver–associated variants, reinforcing known genetic contributions to disease susceptibility. Further conditional analysis based on 423 genome-wide significant variants refined these signals into 16 independent variants across 14 genes, including TRIB1AL and LPL, both of which have been implicated in NAFLD in prior studies. For cross-ancestry validation, 50 risk variants were assessed in a European GWAS dataset, with replicated associations mapping to the ZPR1 and FTO loci. In addition, pathway enrichment results indicated significant involvement of lipid metabolism and the PPAR signaling pathway, highlighting biological mechanisms that may contribute to hepatic lipid accumulation and fatty liver development.
Conclusion
We identified six independent NAFLD-related variants in GCKR, LPL, TRIB1AL, and FTO, and confirmed ZPR1 and FTO as shared risk genes for FLI-defined fatty liver across Taiwanese and European cohorts. These findings support the use of FLI as a non-invasive predictor of fatty liver and highlight genetic pathways that may be common across populations. This work provides a strong basis for future personalized risk assessment and therapeutic development.