An atlas of genetic determinants of forearm fracture

• Published in: Nature genetics Vol. 55; no. 11; pp. 1820 - 1830
• Main Authors: 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., Mägi, Reedik, Hoff, Mari, Lerner, Ulf H., Henning, Petra, Ullum, Henrik, Erikstrup, Christian, Brunak, Søren, 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 2023; Nature Publishing Group
• Subjects: 14/32; 38/43; 38/90; 64/110; 64/60; 692/308/2056; 692/308/575; Agriculture; Animal Genetics and Genomics; Animals; Biomedical and Life Sciences; Biomedicine; Body mass index; Body size; Bone; Bone Density; Bone Density - genetics; Bone mineral density; Bone strength; Cancer Research; Clinical Medicine; Endocrinology and Diabetes; Endokrinologi och diabetes; Forearm; Fractures; Fractures, Bone - genetics; Gene Function; genetics; Genome-Wide Association Study; Genomes; Heritability; Hip joint; Human Genetics; Influence; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Mice; Orthopedics; Ortopedi; Osteoporosis; Parameter identification; Risk Factors; Statistical significance
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-023-01527-3

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. Genome-wide analyses identify 43 loci associated with forearm fracture, including some influencing bone quality parameters. Follow-up work shows that Tac4 knockout mice exhibit reduced mechanical bone strength with no effect on bone mineral density.