Robust human genetic evidence supporting causal effects of FGF21 on reducing alcohol consuming behaviours

IntroductionAlcohol use disorder (AUD) represents a tremendous societal burden, yet few efficacious therapies are available and widely used. Pre-clinical and human observational data support fibroblast growth factor 21 (FGF21) as a promising therapeutic target for the treatment of AUD. Here, we identify a robust genetic instrument for FGF21 agonism and leverage it in the Mendelian randomization paradigm to explore the effects of FGF21 agonism on AUD and related traits, as well as metabolic outcomes more widely. MethodsWe first compared associations with the positive control outcomes of liver fat and liver cirrhosis risk for the FGF21 cis-protein quantitative trait Iocus (cis-pQTL) (rs838131) to those for the common allele FGF21 L174P missense variant (rs739320). Having identified the L174P missense variant as a clinically validated genetic instrument, we subsequently performed unweighted Mendelian randomization investigating effects on AUD, related traits, and metabolic outcomes more widely. Finally, we performed colocalization analyses to test whether observed association results reflect a causal mechanism that overlaps with the clinical effects of FGF21 on liver fat and liver cirrhosis. ResultsConsistent Mendelian randomization and colocalization evidence support a protective association between genetically predicted FGF21 agonism and alcohol consumption (Mendelian randomization p=1x10-18, colocalization posterior probability=0.90), problematic alcohol use (Mendelian randomization p=0.02, posterior probability=0.64), and AUD (Mendelian randomization p=9x10-8, posterior probability=0.97). Similar evidence was also observed for favourable effects of FGF21 on improving kidney function, lowering triglyceride levels, lowering proportional energy intake from carbohydrates, increasing proportional energy intake from protein and fat, increasing body weight and lowering waist-to-hip ratio. ConclusionThis study identifies a clinically validated genetic instrument for FGF21 effects to provide robust causal human evidence supporting favourable effects of FGF21 analogues for the treatment of AUD and related traits, as well as on metabolic outcomes more broadly. Further clinical study is duly warranted.