Nature Communications (Mar 2025)

Missense variants in FRS3 affect body mass index in populations of diverse ancestries

  • Andrea B. Jonsdottir,
  • Gardar Sveinbjornsson,
  • Rosa B. Thorolfsdottir,
  • Max Tamlander,
  • Vinicius Tragante,
  • Thorhildur Olafsdottir,
  • Solvi Rognvaldsson,
  • Asgeir Sigurdsson,
  • Hannes P. Eggertsson,
  • Hildur M. Aegisdottir,
  • David O. Arnar,
  • Karina Banasik,
  • Doruk Beyter,
  • Ragnar G. Bjarnason,
  • Gyda Bjornsdottir,
  • Søren Brunak,
  • Mie Topholm Bruun,
  • Joseph Dowsett,
  • Eythor Einarsson,
  • Gudmundur Einarsson,
  • Christian Erikstrup,
  • Run Fridriksdottir,
  • Jonas Ghouse,
  • Solveig Gretarsdottir,
  • Gisli H. Halldorsson,
  • Torben Hansen,
  • Anna Helgadottir,
  • Peter C. Holm,
  • Erna V. Ivarsdottir,
  • Kasper Karmark Iversen,
  • Bitten Aagaard Jensen,
  • Ingileif Jonsdottir,
  • Stacey Knight,
  • Kirk U. Knowlton,
  • Snaedis Kristmundsdottir,
  • Adalheidur E. Larusdottir,
  • Olafur Th. Magnusson,
  • Gisli Masson,
  • Pall Melsted,
  • Christina Mikkelsen,
  • Kristjan H. S. Moore,
  • Asmundur Oddsson,
  • Pall I. Olason,
  • Frosti Palsson,
  • Ole Birger Pedersen,
  • Michael Schwinn,
  • Emil L. Sigurdsson,
  • Aron Skaftason,
  • Lilja Stefansdottir,
  • Hreinn Stefansson,
  • Thora Steingrimsdottir,
  • Arni Sturluson,
  • Unnur Styrkarsdottir,
  • Erik Sørensen,
  • Unnur D. Teitsdottir,
  • Thorgeir E. Thorgeirsson,
  • Gudmundur A. Thorisson,
  • Unnur Thorsteinsdottir,
  • Magnus O. Ulfarsson,
  • Henrik Ullum,
  • Arnor Vikingsson,
  • G. Bragi Walters,
  • DBDS Genomic Consortium,
  • Lincoln D. Nadauld,
  • Henning Bundgaard,
  • Sisse Rye Ostrowski,
  • Agnar Helgason,
  • Bjarni V. Halldorsson,
  • Gudmundur L. Norddahl,
  • Samuli Ripatti,
  • Daniel F. Gudbjartsson,
  • Gudmar Thorleifsson,
  • Valgerdur Steinthorsdottir,
  • Hilma Holm,
  • Patrick Sulem,
  • Kari Stefansson

DOI
https://doi.org/10.1038/s41467-025-57753-2
Journal volume & issue
Vol. 16, no. 1
pp. 1 – 16

Abstract

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Abstract Obesity is associated with adverse effects on health and quality of life. Improved understanding of its underlying pathophysiology is essential for developing counteractive measures. To search for sequence variants with large effects on BMI, we perform a multi-ancestry meta-analysis of 13 genome-wide association studies on BMI, including data derived from 1,534,555 individuals of European ancestry, 339,657 of Asian ancestry, and 130,968 of African ancestry. We identify an intergenic 262,760 base pair deletion at the MC4R locus that associates with 4.11 kg/m2 higher BMI per allele, likely through downregulation of MC4R. Moreover, a rare FRS3 missense variant, p.Glu115Lys, only found in individuals from Finland, associates with 1.09 kg/m2 lower BMI per allele. We also detect three other low-frequency FRS3 missense variants that associate with BMI with smaller effects and are enriched in different ancestries. We characterize FRS3 as a BMI-associated gene, encoding an adaptor protein known to act downstream of BDNF and TrkB, which regulate appetite, food intake, and energy expenditure through unknown signaling pathways. The work presented here contributes to the biological foundation of obesity by providing a convincing downstream component of the BDNF-TrkB pathway, which could potentially be targeted for obesity treatment.