Genetic evidence that FGF21 signaling reduces problematic alcohol use and alcohol-related liver disease.

BACKGROUND & AIMS: Fibroblast growth factor 21 (FGF21) analogs are in development for metabolic dysfunction-associated steatotic liver disease (MASLD), but their impact on problematic alcohol use (PAU), alcohol use disorder, binge drinking, and alcohol-related liver disease (ALD) is unknown.

METHODS

We leveraged genome-wide association study data from the UK Biobank, FinnGen, Million Veterans Program, and GenomALC for PAU, alcohol use disorder, binge drinking, weekly drinks, and ALD. Our four-tier evaluation included: (1) multivariable Mendelian randomization (MR) and mediation with circulating FGF21 levels; (2) comparative MR of MASLD and ALD targets (PNPLA3, TM6SF2, HSD17B13) using liver fat and expression instruments; (3) receptor-focused MR of β-Klotho (KLB) and FGFR1/2/3 incorporating brain-region expression; and (4) a phenome-wide MR across 1,022 traits to assess safety.

RESULTS

Genetically higher FGF21 protein levels were associated with lower PAU (β = -0.097, 95% CI -0.135 to -0.059, p = 6.13 × 10-7), fewer binge episodes, reduced drinking, and lower ALD risk (odds ratio [OR] = 0.79, 95% CI 0.638-0.987, p = 0.038). Multivariable MR and mediation attributed these effects entirely to behavioral pathways (reduced drinking, improved diet) and increased basal metabolic rate. In comparative MR, FGF21 - unlike PNPLA3, or HSD17B13 - reduced alcohol outcomes: a 1-SD rise in hepatic FGF21 expression reduced PAU (β = -0.245, 95% CI -0.409 to -0.082, p = 0.003) and ALD (OR = 0.54, 95% CI 0.417-0.697, p = 2.44×10-6) risk. Receptor analyses implicated hippocampal FGFR3 (OR = 0.909, 95% CI 0.876-0.943, p = 4.28 × 10-7) and basal ganglia KLB expression, supporting a liver-brain axis. Phenome-wide MR uncovered 28 Bonferroni-significant protective associations with higher FGF21 (e.g. gout). Hepatic FGF21 expression showed fewer on-target liabilities than HSD17B13 or PNPLA3.

CONCLUSIONS

Human genetic evidence indicates that FGF21 analogs mitigate hazardous drinking and ALD via both behavioral and metabolic pathways. These findings distinguish FGF21 from other MASLD targets and highlight its potential for precision treatment of alcohol-related disorders.

IMPACT AND IMPLICATIONS: This study leverages human genetic evidence to validate FGF21 - a liver-derived hormone currently in clinical trials for fatty liver disease - as a dual-action therapeutic that both curbs harmful drinking behaviors and protects against alcohol-related liver injury, addressing a critical therapeutic gap with limited existing pharmacotherapies. The results are important for clinicians and researchers seeking precision medicine strategies for alcohol use disorder and liver disease, as well as for patients who currently face limited treatment options. By pinpointing FGF21's behavioral and metabolic pathways and demonstrating a favorable safety profile, our findings support the repurposing of FGF21 analogs in clinical trials of alcohol use disorder and alcohol-related liver disease and suggest that genetic stratification could optimize patient selection for therapy. While these conclusions rely on European-ancestry genetic data and Mendelian randomization assumptions, they help inform future clinical studies, biomarker development, and policy efforts aimed at expanding treatment options for alcohol-related conditions.