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

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57753-2

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