Distinct genetic signals at the FGF21 locus complicate studies of FGF21's role in diet regulation using human cohort data

Stina Ramne; Mario García-Ureña; Matthew P Gillum; Lars Ängquist; Torben Hansen; Jordi Merino; Niels Grarup

doi:10.1016/j.molmet.2024.102049

Distinct genetic signals at the FGF21 locus complicate studies of FGF21's role in diet regulation using human cohort data

Mol Metab. 2024 Oct 18:90:102049. doi: 10.1016/j.molmet.2024.102049. Online ahead of print.

Authors

Stina Ramne¹, Mario García-Ureña¹, Matthew P Gillum², Lars Ängquist¹, Torben Hansen¹, Jordi Merino³, Niels Grarup⁴

Affiliations

¹ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
² Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk A/S, Early Innovation, Outreach, and Alliances, Måløv, Denmark.
³ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Diabetes Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁴ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: niels.grarup@sund.ku.dk.

Abstract

Objectives: Experimental and genetic studies suggest that fibroblast growth factor 21 (FGF21) modulates macronutrient and alcohol preferences, but evidence of such regulation in humans remains scarce. To address this gap in translation, we aimed to map the relationships between plasma FGF21 levels, FGF21 genetic variation and habitual macronutrient intake in a large human population.

Methods: We fine-mapped and performed colocalization of the FGF21 genetic region in GWAS summary statistics of plasma FGF21 levels and macronutrient intake. UK Biobank data were used to investigate the associations between FGF21 genetic variants, plasma FGF21 protein levels, and macronutrient intake (including alcohol) assessed with repeated 24-hour recalls. One- and two-sample mendelian randomization were performed to estimate the effects of plasma FGF21 on macronutrient intake.

Results: We show that the main macronutrient-associated variant rs838133 and the FGF21 cis-pQTL rs838131, both in the FGF21 gene, are distinct genetic signals. Effect directions also suggest that the influence of FGF21 variation on macronutrient intake appear more complex than by direct mediation through plasma FGF21. Only when considering this complexity at FGF21, is plasma FGF21 estimated to reduce alcohol and increase protein and fat intake using mendelian randomization. Importantly, plasma FGF21 levels also appear markedly elevated by primarily high alcohol and low protein intake.

Conclusions: These findings support the feedback diet-regulatory mechanism of FGF21 in humans, but highlights the need for mechanistic characterization of the complex FGF21 genetic region.

Keywords: Alcohol; Diet preference; Fibroblast growth factor 21; Macronutrients; Mendelian randomization; Nutrigenetics.