An atlas of genetic determinants of forearm fracture
Maria Nethander, Sofia Movérare‐Skrtic, Anders Kämpe, Eivind Coward, Ene Reimann, Louise Grahnemo, Éva Borbély, Zsuzsanna Helyes, Thomas Funck‐Brentano, Martine Cohen‐Solal, Juha Tuukkanen, Antti Koskela, Jianyao Wu, Lei Li, Tianyuan Lu, Maiken E. Gabrielsen, Reedik Mägi, Mari Hoff, Ulf H. Lerner, Petra Henning, Henrik Ullum, Christian Erikstrup, Søren Brunak, Arnulf Langhammer, Tiinamaija Tuomi, Ásmundur Oddsson, Kāri Stefánsson, U. Pettersson, Sisse Rye Ostrowski, Ole Birger Pedersen, Unnur Styrkársdóttir, Outi Mäkitie, Kristian Hveem, J. Brent Richards, Claes Ohlsson
Abstract
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.