An atlas of genetic determinants of forearm fracture
Nethander, Maria; Movérare-Skrtic, Sofia; Kämpe, Anders; Coward, Eivind; Reimann, Ene; Grahnemo, Louise; Borbély, Éva; Helyes, Zsuzsanna; Funck-Brentano, Thomas; Cohen-Solal, Martine; Tuukkanen, Juha; Koskela, Antti; Wu, Jianyao; Li, Lei; Lu, Tianyuan; Gabrielsen, Maiken E.; Estonian Biobank Research Team; Mägi, Reedik; Hoff, Mari; Lerner, Ulf H.; Henning, Petra; Ullum, Henrik; Erikstrup, Christian; Brunak, Søren; DBDS Genomic Consortium; Langhammer, Arnulf; Tuomi, Tiinamaija; Oddsson, Asmundur; Stefansson, Kari; Pettersson-Kymmer, Ulrika; Ostrowski, Sisse Rye; Pedersen, Ole Birger Vesterager; Styrkarsdottir, Unnur; Mäkitie, Outi; Hveem, Kristian; Richards, J. Brent; Ohlsson, Claes (2023-11-02)
Springer
02.11.2023
Nethander, M., Movérare-Skrtic, S., Kämpe, A. et al. An atlas of genetic determinants of forearm fracture. Nat Genet 55, 1820–1830 (2023). https://doi.org/10.1038/s41588-023-01527-3.
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© The Author(s) 2023.. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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© The Author(s) 2023.. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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https://urn.fi/URN:NBN:fi:oulu-202312153833
https://urn.fi/URN:NBN:fi:oulu-202312153833
Tiivistelmä
Abstract
Osteoporotic fracture is among the most common and costly of diseases. While reasonably heritable, its genetic determinants have remained elusive. Forearm fractures are the most common clinically recognized osteoporotic fractures with a relatively high heritability. To establish an atlas of the genetic determinants of forearm fractures, we performed genome-wide association analyses including 100,026 forearm fracture cases. We identified 43 loci, including 26 new fracture loci. Although most fracture loci associated with bone mineral density, we also identified loci that primarily regulate bone quality parameters. Functional studies of one such locus, at TAC4, revealed that Tac4–/– mice have reduced mechanical bone strength. The strongest forearm fracture signal, at WNT16, displayed remarkable bone-site-specificity with no association with hip fractures. Tall stature and low body mass index were identified as new causal risk factors for fractures. The insights from this atlas may improve fracture prediction and enable therapeutic development to prevent fractures.
Osteoporotic fracture is among the most common and costly of diseases. While reasonably heritable, its genetic determinants have remained elusive. Forearm fractures are the most common clinically recognized osteoporotic fractures with a relatively high heritability. To establish an atlas of the genetic determinants of forearm fractures, we performed genome-wide association analyses including 100,026 forearm fracture cases. We identified 43 loci, including 26 new fracture loci. Although most fracture loci associated with bone mineral density, we also identified loci that primarily regulate bone quality parameters. Functional studies of one such locus, at TAC4, revealed that Tac4–/– mice have reduced mechanical bone strength. The strongest forearm fracture signal, at WNT16, displayed remarkable bone-site-specificity with no association with hip fractures. Tall stature and low body mass index were identified as new causal risk factors for fractures. The insights from this atlas may improve fracture prediction and enable therapeutic development to prevent fractures.
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