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, Chloe Sarnowski, Kathryn L. Lunetta, Toshiko Tanaka, Mary K. Wojczynski, Ryan Cvejkus, Maria Nethander, Sahar Ghasemi, Jingyun Yang, M. Carola Zillikens, Stefan Walter, Kamil Sicinski, Erika Kague, Cheryl L. Ackert-Bicknell, Dan E. Arking, B. Gwen Windham, Eric Boerwinkle, Megan L. Grove, Misa Graff, Dominik Spira, Ilja Demuth, Nathalie Velde, Lisette C. P. G. M. Groot, Bruce M. Psaty, Michelle C. Odden, Alison E. Fohner, Claudia Langenberg, Nicholas J. Wareham, Stefania Bandinelli, Natasja M. Schoor, Martijn Huisman, Qihua Tan, Joseph Zmuda, Dan Mellström, Magnus Karlsson, David A. Bennett, Aron S. Buchman, Philip L. Jager, Andre G. Uitterlinden, Uwe Völker, Thomas Kocher, Alexander Teumer, Leocadio Rodriguéz-Mañas, Francisco J. García, José A. Carnicero, Pamela Herd, Lars Bertram, Claes Ohlsson, Joanne M. Murabito, David Melzer, George A. Kuchel, Luigi Ferrucci, David Karasik, Fernando Rivadeneira, Douglas P. Kiel and Luke C. Pilling ()
Additional contact information
Garan Jones: University of Exeter Medical School
Katerina Trajanoska: Erasmus Medical Center
Adam J. Santanasto: University of Pittsburgh, Department of Epidemiology
Najada Stringa: Amsterdam UMC- Vrije Universiteit, Amsterdam Public Health Research Institute
Chia-Ling Kuo: Biostatistics Center, Connecticut Convergence Institute for Translation in Regenerative Engineering, UConn Health
Janice L. Atkins: University of Exeter Medical School
Joshua R. Lewis: Edith Cowan University
ThuyVy Duong: Johns Hopkins University School of Medicine
Shengjun Hong: University of Lübeck
Mary L. Biggs: University of Washington
Jian’an Luan: University of Cambridge School of Clinical Medicine
Chloe Sarnowski: Boston University School of Public Health
Kathryn L. Lunetta: Boston University School of Public Health
Toshiko Tanaka: National Institute on Aging
Mary K. Wojczynski: Washington University School of Medicine
Ryan Cvejkus: University of Pittsburgh, Department of Epidemiology
Maria Nethander: Institute of Medicine, Sahlgrenska Academy, University of Gothenburg
Sahar Ghasemi: University Medicine Greifswald
Jingyun Yang: Rush University Medical Center
M. Carola Zillikens: Erasmus Medical Center
Stefan Walter: Rey Juan Carlos University
Kamil Sicinski: University of Wisconsin-Madison
Erika Kague: University of Bristol
Cheryl L. Ackert-Bicknell: University of Colorado
Dan E. Arking: Johns Hopkins University School of Medicine
B. Gwen Windham: University of Mississippi School of Medicine
Eric Boerwinkle: The University of Texas Health Science Center at Houston
Megan L. Grove: The University of Texas Health Science Center at Houston
Misa Graff: University of North Carolina
Dominik Spira: Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Ilja Demuth: Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Nathalie Velde: University of Amsterdam
Lisette C. P. G. M. Groot: Wageningen University, Division of Human Nutrition
Bruce M. Psaty: Epidemiology, and Health services, University of Washington
Michelle C. Odden: Stanford University
Alison E. Fohner: University of Washington
Claudia Langenberg: University of Cambridge School of Clinical Medicine
Nicholas J. Wareham: University of Cambridge School of Clinical Medicine
Stefania Bandinelli: Geriatric Unit, Azienda Sanitaria Firenze (ASF)
Natasja M. Schoor: Amsterdam UMC- Vrije Universiteit, Amsterdam Public Health Research Institute
Martijn Huisman: Amsterdam UMC- Vrije Universiteit, Amsterdam Public Health Research Institute
Qihua Tan: University of Southern Denmark
Joseph Zmuda: University of Pittsburgh, Department of Epidemiology
Dan Mellström: Institute of Medicine, Sahlgrenska Academy, University of Gothenburg
Magnus Karlsson: Lund University, Skåne University Hospital
David A. Bennett: Rush University Medical Center
Aron S. Buchman: Rush University Medical Center
Philip L. Jager: Columbia University Medical Center
Andre G. Uitterlinden: Erasmus Medical Center
Uwe Völker: University Medicine Greifswald
Thomas Kocher: University Medicine Greifswald
Alexander Teumer: University Medicine Greifswald
Leocadio Rodriguéz-Mañas: CIBER of Frailty and Healthy Aging (CIBERFES)
Francisco J. García: CIBER of Frailty and Healthy Aging (CIBERFES)
José A. Carnicero: CIBER of Frailty and Healthy Aging (CIBERFES)
Pamela Herd: Georgetown University
Lars Bertram: University of Lübeck
Claes Ohlsson: Institute of Medicine, Sahlgrenska Academy, University of Gothenburg
Joanne M. Murabito: Boston University School of Medicine
David Melzer: University of Exeter Medical School
George A. Kuchel: Center on Aging, University of Connecticut Health
Luigi Ferrucci: National Institute on Aging
David Karasik: Marcus Institute for Aging Research, Hebrew SeniorLife
Fernando Rivadeneira: Erasmus Medical Center
Douglas P. Kiel: Beth Israel Deaconess Medical Center and Harvard Medical School, Broad Institute of MIT & Harvard
Luke C. Pilling: University of Exeter Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-11

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.

Date: 2021
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DOI: 10.1038/s41467-021-20918-w

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