Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women
Garan Jones, Katerina Trajanoska, Adam J. Santanasto, Najada Stringa, Chia‐Ling Kuo, Janice L. Atkins, Joshua R. Lewis, ThuyVy Duong, Shengjun Hong, Mary L. Biggs, Jian’an Luan, Chloé Sarnowski, Kathryn L. Lunetta, Toshiko Tanaka, Mary K. Wojczynski, Ryan Cvejkus, Maria Nethander, Sahar Ghasemi, Jingyun Yang, M. Carola Zillikens, Stefan Walter, Kamil Sicinski, Érika Kague, Cheryl L. Ackert‐Bicknell, Dan E. Arking, B. Gwen Windham, Eric Boerwinkle, Megan L. Grove, Misa Graff, Dominik Spira, Ilja Demuth, Nathalie van der Velde, C.P.G.M. de Groot, Bruce M. Psaty, Michelle C. Odden, Alison E. Fohner, Claudia Langenberg, Nicholas J. Wareham, Stefania Bandinelli, Natasja M. van Schoor, Martijn Huisman, Qihua Tan, Joseph M. Zmuda, Dan Mellström, Magnus K. Karlsson, David A. Bennett, Aron S. Buchman, Philip L. De Jager, André G. Uitterlinden, Uwe Völker, Thomas Kocher, Alexander Teumer, Leocadio Rodríguez‐Mañas, Francisco J. García‐García, José Antonio Carranza Carnicero, Pamela Herd, Lars Bertram, Claes Ohlsson, Joanne M. Murabito, David Melzer, George A. Kuchel, Luigi Ferrucci, David Karasik, Fernando Rivadeneira, Douglas P. Kiel, Luke C. Pilling
Abstract
Abstract Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease ( HLA-DQA1 p = 4 × 10 −17 ), arthritis ( GDF5 p = 4 × 10 −13 ), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.