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 van der Velde; Lisette 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 Zmuda; Dan Mellström; Magnus Karlsson; David A. Bennett; Aron S. Buchman; Philip L. de 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; Luke C. Pilling

doi:https://doi.org/10.1038/s41467-021-20918-w

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 ZillikensStefan 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 van der Velde, Lisette 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 Zmuda, Dan Mellström, Magnus Karlsson, David A. Bennett, Aron S. Buchman, Philip L. de 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, Luke C. Pilling

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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-DQA1p = 4 × 10−17), arthritis (GDF5p = 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.

Original language	English
Article number	654
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-20918-w
Publication status	Published - 1 Dec 2021

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Jones, G., Trajanoska, K., Santanasto, A. J., Stringa, N., Kuo, C.-L., Atkins, J. L., Lewis, J. R., Duong, T., Hong, S., Biggs, M. L., Luan, J., Sarnowski, C., Lunetta, K. L., Tanaka, T., Wojczynski, M. K., Cvejkus, R., Nethander, M., Ghasemi, S., Yang, J., ... Pilling, L. C. (2021). Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women. Nature communications, 12(1), Article 654. https://doi.org/10.1038/s41467-021-20918-w

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title = "Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women",

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-DQA1p = 4 × 10−17), arthritis (GDF5p = 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.",

author = "Garan Jones and Katerina Trajanoska and Santanasto, {Adam J.} and Najada Stringa and Chia-Ling Kuo and Atkins, {Janice L.} and Lewis, {Joshua R.} and ThuyVy Duong and Shengjun Hong and Biggs, {Mary L.} and Jian{\textquoteright}an Luan and Chloe Sarnowski and Lunetta, {Kathryn L.} and Toshiko Tanaka and Wojczynski, {Mary K.} and Ryan Cvejkus and Maria Nethander and Sahar Ghasemi and Jingyun Yang and Zillikens, {M. Carola} and Stefan Walter and Kamil Sicinski and Erika Kague and Ackert-Bicknell, {Cheryl L.} and Arking, {Dan E.} and Windham, {B. Gwen} and Eric Boerwinkle and Grove, {Megan L.} and Misa Graff and Dominik Spira and Ilja Demuth and {van der Velde}, Nathalie and {de Groot}, {Lisette C. P. G. M.} and Psaty, {Bruce M.} and Odden, {Michelle C.} and Fohner, {Alison E.} and Claudia Langenberg and Wareham, {Nicholas J.} and Stefania Bandinelli and {van Schoor}, {Natasja M.} and Martijn Huisman and Qihua Tan and Joseph Zmuda and Dan Mellstr{\"o}m and Magnus Karlsson and Bennett, {David A.} and Buchman, {Aron S.} and {de Jager}, {Philip L.} and Uitterlinden, {Andre G.} and Uwe V{\"o}lker and Thomas Kocher and Alexander Teumer and Leocadio Rodrigu{\'e}z-Ma{\~n}as and Garc{\'i}a, {Francisco J.} and Carnicero, {Jos{\'e} A.} and Pamela Herd and Lars Bertram and Claes Ohlsson and Murabito, {Joanne M.} and David Melzer and Kuchel, {George A.} and Luigi Ferrucci and David Karasik and Fernando Rivadeneira and Kiel, {Douglas P.} and Pilling, {Luke C.}",

note = "Funding Information: This study was part funded by an award to DM by the UK Medical Research Council (MR/M023095/1). A full list of acknowledgements and grant support can be found in Supplementary Note 1 (in the Supplementary Information). We would like to acknowledge the use of the University of Exeter High-Performance Computing (HPC) facility in carrying out this work. Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = dec,

day = "1",

doi = "https://doi.org/10.1038/s41467-021-20918-w",

language = "English",

volume = "12",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

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Jones, G, Trajanoska, K, Santanasto, AJ, Stringa, N, Kuo, C-L, Atkins, JL, Lewis, JR, Duong, T, Hong, S, Biggs, ML, Luan, J, Sarnowski, C, Lunetta, KL, Tanaka, T, Wojczynski, MK, Cvejkus, R, Nethander, M, Ghasemi, S, Yang, J, Zillikens, MC, Walter, S, Sicinski, K, Kague, E, Ackert-Bicknell, CL, Arking, DE, Windham, BG, Boerwinkle, E, Grove, ML, Graff, M, Spira, D, Demuth, I, van der Velde, N, de Groot, LCPGM, Psaty, BM, Odden, MC, Fohner, AE, Langenberg, C, Wareham, NJ, Bandinelli, S, van Schoor, NM , Huisman, M, Tan, Q, Zmuda, J, Mellström, D, Karlsson, M, Bennett, DA, Buchman, AS, de Jager, PL, Uitterlinden, AG, Völker, U, Kocher, T, Teumer, A, Rodriguéz-Mañas, L, García, FJ, Carnicero, JA, Herd, P, Bertram, L, Ohlsson, C, Murabito, JM, Melzer, D, Kuchel, GA, Ferrucci, L, Karasik, D, Rivadeneira, F, Kiel, DP & Pilling, LC 2021, 'Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women', Nature communications, vol. 12, no. 1, 654. https://doi.org/10.1038/s41467-021-20918-w

TY - JOUR

T1 - Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women

AU - Jones, Garan

AU - Trajanoska, Katerina

AU - Santanasto, Adam J.

AU - Stringa, Najada

AU - Kuo, Chia-Ling

AU - Atkins, Janice L.

AU - Lewis, Joshua R.

AU - Duong, ThuyVy

AU - Hong, Shengjun

AU - Biggs, Mary L.

AU - Luan, Jian’an

AU - Sarnowski, Chloe

AU - Lunetta, Kathryn L.

AU - Tanaka, Toshiko

AU - Wojczynski, Mary K.

AU - Cvejkus, Ryan

AU - Nethander, Maria

AU - Ghasemi, Sahar

AU - Yang, Jingyun

AU - Zillikens, M. Carola

AU - Walter, Stefan

AU - Sicinski, Kamil

AU - Kague, Erika

AU - Ackert-Bicknell, Cheryl L.

AU - Arking, Dan E.

AU - Windham, B. Gwen

AU - Boerwinkle, Eric

AU - Grove, Megan L.

AU - Graff, Misa

AU - Spira, Dominik

AU - Demuth, Ilja

AU - van der Velde, Nathalie

AU - de Groot, Lisette C. P. G. M.

AU - Psaty, Bruce M.

AU - Odden, Michelle C.

AU - Fohner, Alison E.

AU - Langenberg, Claudia

AU - Wareham, Nicholas J.

AU - Bandinelli, Stefania

AU - van Schoor, Natasja M.

AU - Huisman, Martijn

AU - Tan, Qihua

AU - Zmuda, Joseph

AU - Mellström, Dan

AU - Karlsson, Magnus

AU - Bennett, David A.

AU - Buchman, Aron S.

AU - de Jager, Philip L.

AU - Uitterlinden, Andre G.

AU - Völker, Uwe

AU - Kocher, Thomas

AU - Teumer, Alexander

AU - Rodriguéz-Mañas, Leocadio

AU - García, Francisco J.

AU - Carnicero, José A.

AU - Herd, Pamela

AU - Bertram, Lars

AU - Ohlsson, Claes

AU - Murabito, Joanne M.

AU - Melzer, David

AU - Kuchel, George A.

AU - Ferrucci, Luigi

AU - Karasik, David

AU - Rivadeneira, Fernando

AU - Kiel, Douglas P.

AU - Pilling, Luke C.

N1 - Funding Information: This study was part funded by an award to DM by the UK Medical Research Council (MR/M023095/1). A full list of acknowledgements and grant support can be found in Supplementary Note 1 (in the Supplementary Information). We would like to acknowledge the use of the University of Exeter High-Performance Computing (HPC) facility in carrying out this work. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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-DQA1p = 4 × 10−17), arthritis (GDF5p = 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.

AB - 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-DQA1p = 4 × 10−17), arthritis (GDF5p = 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.

UR - http://www.scopus.com/inward/record.url?scp=85100042471&partnerID=8YFLogxK

U2 - https://doi.org/10.1038/s41467-021-20918-w

DO - https://doi.org/10.1038/s41467-021-20918-w

M3 - Article

C2 - 33510174

SN - 2041-1723

VL - 12

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 654

ER -

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women

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