Missense variants in FRS3 affect body mass index in populations of diverse ancestries
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 g...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-03-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57753-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850208494847787008 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Andrea B. Jonsdottir |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b24ecf182e4c47349175bacfde780179 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b24ecf182e4c47349175bacfde7801792025-08-20T02:10:14ZengNature PortfolioNature Communications2041-17232025-03-0116111610.1038/s41467-025-57753-2Missense variants in FRS3 affect body mass index in populations of diverse ancestriesAndrea B. Jonsdottir0Gardar Sveinbjornsson1Rosa B. Thorolfsdottir2Max Tamlander3Vinicius Tragante4Thorhildur Olafsdottir5Solvi Rognvaldsson6Asgeir Sigurdsson7Hannes P. Eggertsson8Hildur M. Aegisdottir9David O. Arnar10Karina Banasik11Doruk Beyter12Ragnar G. Bjarnason13Gyda Bjornsdottir14Søren Brunak15Mie Topholm Bruun16Joseph Dowsett17Eythor Einarsson18Gudmundur Einarsson19Christian Erikstrup20Run Fridriksdottir21Jonas Ghouse22Solveig Gretarsdottir23Gisli H. Halldorsson24Torben Hansen25Anna Helgadottir26Peter C. Holm27Erna V. Ivarsdottir28Kasper Karmark Iversen29Bitten Aagaard Jensen30Ingileif Jonsdottir31Stacey Knight32Kirk U. Knowlton33Snaedis Kristmundsdottir34Adalheidur E. Larusdottir35Olafur Th. Magnusson36Gisli Masson37Pall Melsted38Christina Mikkelsen39Kristjan H. S. Moore40Asmundur Oddsson41Pall I. Olason42Frosti Palsson43Ole Birger Pedersen44Michael Schwinn45Emil L. Sigurdsson46Aron Skaftason47Lilja Stefansdottir48Hreinn Stefansson49Thora Steingrimsdottir50Arni Sturluson51Unnur Styrkarsdottir52Erik Sørensen53Unnur D. Teitsdottir54Thorgeir E. Thorgeirsson55Gudmundur A. Thorisson56Unnur Thorsteinsdottir57Magnus O. Ulfarsson58Henrik Ullum59Arnor Vikingsson60G. Bragi Walters61DBDS Genomic ConsortiumLincoln D. Nadauld62Henning Bundgaard63Sisse Rye Ostrowski64Agnar Helgason65Bjarni V. Halldorsson66Gudmundur L. Norddahl67Samuli Ripatti68Daniel F. Gudbjartsson69Gudmar Thorleifsson70Valgerdur Steinthorsdottir71Hilma Holm72Patrick Sulem73Kari Stefansson74deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of HelsinkideCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of CopenhagendeCODE genetics/Amgen Inc.Faculty of Medicine, School of Health Sciences, University of IcelanddeCODE genetics/Amgen Inc.The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Clinical Immunology, Odense University HospitalDepartment of Clinical Immunology, Copenhagen University Hospital, RigshospitaletdeCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.Department of Clinical Immunology, Aarhus University HospitaldeCODE genetics/Amgen Inc.Department of Cardiology, Copenhagen University Hospital, RigshospitaletdeCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of CopenhagendeCODE genetics/Amgen Inc.The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of CopenhagendeCODE genetics/Amgen Inc.Department of Cardiology, Copenhagen University Hospital, Herlev and Gentofte HospitalDepartment of Clinical Immunology, Aalborg University HospitaldeCODE genetics/Amgen Inc.Intermountain Medical Center, Intermountain Heart InstituteIntermountain Medical Center, Intermountain Heart InstitutedeCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.Department of Clinical Immunology, Copenhagen University Hospital, RigshospitaletdeCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Clinical Immunology, Copenhagen University Hospital, RigshospitaletFaculty of Medicine, School of Health Sciences, University of IcelanddeCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.Faculty of Medicine, School of Health Sciences, University of IcelanddeCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.Department of Clinical Immunology, Copenhagen University Hospital, RigshospitaletdeCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.Statens Serum InstitutDepartment of Medicine, Landspitali - The National University Hospital of IcelanddeCODE genetics/Amgen Inc.Precision Genomics, Intermountain HealthcareDepartment of Cardiology, Copenhagen University Hospital, RigshospitaletDepartment of Clinical Immunology, Copenhagen University Hospital, RigshospitaletdeCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of HelsinkideCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.deCODE genetics/Amgen Inc.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.https://doi.org/10.1038/s41467-025-57753-2 |
| spellingShingle | 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 Missense variants in FRS3 affect body mass index in populations of diverse ancestries Nature Communications |
| title | Missense variants in FRS3 affect body mass index in populations of diverse ancestries |
| title_full | Missense variants in FRS3 affect body mass index in populations of diverse ancestries |
| title_fullStr | Missense variants in FRS3 affect body mass index in populations of diverse ancestries |
| title_full_unstemmed | Missense variants in FRS3 affect body mass index in populations of diverse ancestries |
| title_short | Missense variants in FRS3 affect body mass index in populations of diverse ancestries |
| title_sort | missense variants in frs3 affect body mass index in populations of diverse ancestries |
| url | https://doi.org/10.1038/s41467-025-57753-2 |
| work_keys_str_mv | AT andreabjonsdottir missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT gardarsveinbjornsson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT rosabthorolfsdottir missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT maxtamlander missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT viniciustragante missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT thorhildurolafsdottir missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT solvirognvaldsson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT asgeirsigurdsson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT hannespeggertsson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT hildurmaegisdottir missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT davidoarnar missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT karinabanasik missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT dorukbeyter missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT ragnargbjarnason missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT gydabjornsdottir missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT sørenbrunak missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT mietopholmbruun missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT josephdowsett missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT eythoreinarsson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT gudmundureinarsson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT christianerikstrup missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT runfridriksdottir missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT jonasghouse missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT solveiggretarsdottir missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT gislihhalldorsson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT torbenhansen missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT annahelgadottir missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT petercholm missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT ernavivarsdottir missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT kasperkarmarkiversen missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT bittenaagaardjensen missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT ingileifjonsdottir missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT staceyknight missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT kirkuknowlton missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT snaediskristmundsdottir missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT adalheidurelarusdottir missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT olafurthmagnusson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT gislimasson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT pallmelsted missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT christinamikkelsen missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT kristjanhsmoore missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT asmunduroddsson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT palliolason missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT frostipalsson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT olebirgerpedersen missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT michaelschwinn missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT emillsigurdsson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT aronskaftason missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT liljastefansdottir missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT hreinnstefansson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT thorasteingrimsdottir missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT arnisturluson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT unnurstyrkarsdottir missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT eriksørensen missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT unnurdteitsdottir missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT thorgeirethorgeirsson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT gudmundurathorisson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT unnurthorsteinsdottir missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT magnusoulfarsson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT henrikullum missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT arnorvikingsson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT gbragiwalters missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT dbdsgenomicconsortium missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT lincolndnadauld missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT henningbundgaard missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT sisseryeostrowski missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT agnarhelgason missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT bjarnivhalldorsson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT gudmundurlnorddahl missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT samuliripatti missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT danielfgudbjartsson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT gudmarthorleifsson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT valgerdursteinthorsdottir missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT hilmaholm missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT patricksulem missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries AT karistefansson missensevariantsinfrs3affectbodymassindexinpopulationsofdiverseancestries |