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

G Jones; Katerina Trajanoska; AJ Santanasto; Najada Stringa; CL Kuo; JL Atkins; JR Lewis; TV Duong; S Hong; ML Biggs; J Luan; C Sarnowski; KL Lunetta; T Tanaka; MK Wojczynski; R Cvejkus; M Nethander; S Ghasemi; J Yang; M.C. Zillikens; S Walter; K Sicinski; E Kague; CL Ackert-Bicknell; DE Arking; BG Windham; E Boerwinkle; ML Grove; M Graff; D Spira; I Demuth; N Velde; LCPCM de Groot; BM Psaty; MC Odden; AE Fohner; C Langenberg; NJ Wareham; S Bandinelli; NM Schoor; M Huisman; Q Tan; J Zmuda; D Mellström; M Karlsson; DA Bennett; AS Buchman; PL De Jager; André Uitterlinden; U Völker; T Kocher; A Teumer; L Rodriguéz-Mañas; FJ García; JA Carnicero; P Herd; L Bertram; C Ohlsson; JM Murabito; D Melzer; GA Kuchel; L Ferrucci; D Karasik; Fernando Rivadeneira; DP Kiel; LC Pilling

doi:10.1038/s41467-021-20918-w

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

G Jones, Katerina Trajanoska, AJ Santanasto, Najada Stringa, CL Kuo, JL Atkins, JR Lewis, TV Duong, S Hong, ML Biggs, J Luan, C Sarnowski, KL Lunetta, T Tanaka, MK Wojczynski, R Cvejkus, M Nethander, S Ghasemi, J Yang, M.C. ZillikensS Walter, K Sicinski, E Kague, CL Ackert-Bicknell, DE Arking, BG Windham, E Boerwinkle, ML Grove, M Graff, D Spira, I Demuth, N Velde, LCPCM de Groot, BM Psaty, MC Odden, AE Fohner, C Langenberg, NJ Wareham, S Bandinelli, NM Schoor, M Huisman, Q Tan, J Zmuda, D Mellström, M Karlsson, DA Bennett, AS Buchman, PL De Jager, André Uitterlinden, U Völker, T Kocher, A Teumer, L Rodriguéz-Mañas, FJ García, JA Carnicero, P Herd, L Bertram, C Ohlsson, JM Murabito, D Melzer, GA Kuchel, L Ferrucci, D Karasik, Fernando Rivadeneira, DP Kiel, LC 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 - 28 Jan 2021

Bibliographical 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:
© 2021, The Author(s).

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Jones, G., Trajanoska, K., Santanasto, AJ., Stringa, N., Kuo, CL., Atkins, JL., Lewis, JR., Duong, TV., Hong, S., Biggs, ML., Luan, J., Sarnowski, C., Lunetta, KL., Tanaka, T., Wojczynski, MK., Cvejkus, R., Nethander, M., Ghasemi, S., Yang, J., ... Pilling, LC. (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 = "G Jones and Katerina Trajanoska and AJ Santanasto and Najada Stringa and CL Kuo and JL Atkins and JR Lewis and TV Duong and S Hong and ML Biggs and J Luan and C Sarnowski and KL Lunetta and T Tanaka and MK Wojczynski and R Cvejkus and M Nethander and S Ghasemi and J Yang and M.C. Zillikens and S Walter and K Sicinski and E Kague and CL Ackert-Bicknell and DE Arking and BG Windham and E Boerwinkle and ML Grove and M Graff and D Spira and I Demuth and N Velde and {de Groot}, LCPCM and BM Psaty and MC Odden and AE Fohner and C Langenberg and NJ Wareham and S Bandinelli and NM Schoor and M Huisman and Q Tan and J Zmuda and D Mellstr{\"o}m and M Karlsson and DA Bennett and AS Buchman and {De Jager}, PL and Andr{\'e} Uitterlinden and U V{\"o}lker and T Kocher and A Teumer and L Rodrigu{\'e}z-Ma{\~n}as and FJ Garc{\'i}a and JA Carnicero and P Herd and L Bertram and C Ohlsson and JM Murabito and D Melzer and GA Kuchel and L Ferrucci and D Karasik and Fernando Rivadeneira and DP Kiel and LC Pilling",

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).",

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Jones, G, Trajanoska, K, Santanasto, AJ, Stringa, N, Kuo, CL, Atkins, JL, Lewis, JR, Duong, TV, 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, Velde, N, de Groot, LCPCM, Psaty, BM, Odden, MC, Fohner, AE, Langenberg, C, Wareham, NJ, Bandinelli, S, Schoor, NM, Huisman, M, Tan, Q, Zmuda, J, Mellström, D, Karlsson, M, Bennett, DA, Buchman, AS, De Jager, PL, Uitterlinden, A, 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, G

AU - Trajanoska, Katerina

AU - Santanasto, AJ

AU - Stringa, Najada

AU - Kuo, CL

AU - Atkins, JL

AU - Lewis, JR

AU - Duong, TV

AU - Hong, S

AU - Biggs, ML

AU - Luan, J

AU - Sarnowski, C

AU - Lunetta, KL

AU - Tanaka, T

AU - Wojczynski, MK

AU - Cvejkus, R

AU - Nethander, M

AU - Ghasemi, S

AU - Yang, J

AU - Zillikens, M.C.

AU - Walter, S

AU - Sicinski, K

AU - Kague, E

AU - Ackert-Bicknell, CL

AU - Arking, DE

AU - Windham, BG

AU - Boerwinkle, E

AU - Grove, ML

AU - Graff, M

AU - Spira, D

AU - Demuth, I

AU - Velde, N

AU - de Groot, LCPCM

AU - Psaty, BM

AU - Odden, MC

AU - Fohner, AE

AU - Langenberg, C

AU - Wareham, NJ

AU - Bandinelli, S

AU - Schoor, NM

AU - Huisman, M

AU - Tan, Q

AU - Zmuda, J

AU - Mellström, D

AU - Karlsson, M

AU - Bennett, DA

AU - Buchman, AS

AU - De Jager, PL

AU - Uitterlinden, André

AU - Völker, U

AU - Kocher, T

AU - Teumer, A

AU - Rodriguéz-Mañas, L

AU - García, FJ

AU - Carnicero, JA

AU - Herd, P

AU - Bertram, L

AU - Ohlsson, C

AU - Murabito, JM

AU - Melzer, D

AU - Kuchel, GA

AU - Ferrucci, L

AU - Karasik, D

AU - Rivadeneira, Fernando

AU - Kiel, DP

AU - Pilling, LC

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).

PY - 2021/1/28

Y1 - 2021/1/28

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.

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

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Bibliographical note

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UN SDGs

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