Meta-Analysis

. 2021 Jan 28;12(1):654.

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

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

Garan Jones^#¹, Katerina Trajanoska^#^{2

3}, Adam J Santanasto^#⁴, Najada Stringa^#⁵, Chia-Ling Kuo^#⁶, Janice L Atkins^#¹, Joshua R Lewis^{7

8

9}, ThuyVy Duong¹⁰, Shengjun Hong¹¹, Mary L Biggs¹², Jian'an Luan¹³, Chloe Sarnowski¹⁴, Kathryn L Lunetta¹⁴, Toshiko Tanaka¹⁵, Mary K Wojczynski¹⁶, Ryan Cvejkus⁴, Maria Nethander^{17

18}, Sahar Ghasemi^{19

20}, Jingyun Yang²¹, M Carola Zillikens², Stefan Walter^{22

23}, Kamil Sicinski²⁴, Erika Kague²⁵, Cheryl L Ackert-Bicknell²⁶, Dan E Arking¹⁰, B Gwen Windham²⁷, Eric Boerwinkle^{28

29}, Megan L Grove²⁸, Misa Graff³⁰, Dominik Spira^{31

32}, Ilja Demuth^{31

32

33}, Nathalie van der Velde³⁴, Lisette C P G M de Groot³⁵, Bruce M Psaty^{36

37}, Michelle C Odden³⁸, Alison E Fohner³⁹, Claudia Langenberg¹³, Nicholas J Wareham¹³, Stefania Bandinelli⁴⁰, Natasja M van Schoor⁵, Martijn Huisman⁵, Qihua Tan⁴¹, Joseph Zmuda⁴, Dan Mellström^{17

42}, Magnus Karlsson⁴³, David A Bennett²¹, Aron S Buchman²¹, Philip L De Jager^{44

45}, Andre G Uitterlinden², Uwe Völker⁴⁶, Thomas Kocher⁴⁷, Alexander Teumer²⁰, Leocadio Rodriguéz-Mañas^{23

48}, Francisco J García^{23

49}, José A Carnicero²³, Pamela Herd⁵⁰, Lars Bertram¹¹, Claes Ohlsson^{17

51}, Joanne M Murabito⁵², David Melzer¹, George A Kuchel⁵³, Luigi Ferrucci⁵⁴, David Karasik^{55

56}, Fernando Rivadeneira^{2

3}, Douglas P Kiel⁵⁷, Luke C Pilling⁵⁸

Affiliations

¹ Epidemiology and Public Health Group, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
² Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
³ Department of Epidemiology Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
⁴ University of Pittsburgh, Department of Epidemiology, Pittsburgh, PA, USA.
⁵ Department of Epidemiology and Biostatistics, Amsterdam UMC- Vrije Universiteit, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.
⁶ Biostatistics Center, Connecticut Convergence Institute for Translation in Regenerative Engineering, UConn Health, Farmington, CT, USA.
⁷ School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.
⁸ School fo Public Health University of Sydney, Sydney, NSW, Australia.
⁹ Medical School, University of Western Australia, Crawley, WA, Australia.
¹⁰ McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Lübeck Interdisciplinary Plattform for Genome Analytics, Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Lübeck, Germany.
¹² Cardiovascular Health Research Unit, Department of Medicine, and Department of Biostatistics, University of Washington, Seattle, WA, USA.
¹³ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, UK.
¹⁴ Biostatistics Department, Boston University School of Public Health, Boston, MA, USA.
¹⁵ Longitudinal Study Section, Translational Gerontology branch, National Institute on Aging, Baltimore, MD, USA.
¹⁶ Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
¹⁷ Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁸ Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁹ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
²⁰ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
²¹ Rush Alzheimer's Disease Center & Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
²² Department of Medicine and Public Health, Rey Juan Carlos University, Madrid, Spain.
²³ CIBER of Frailty and Healthy Aging (CIBERFES), Madrid, Spain.
²⁴ Center for Demography of Health and Aging, University of Wisconsin-Madison, Madison, WI, USA.
²⁵ School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK.
²⁶ Department of Orthopedics, University of Colorado, Aurora, CO, USA.
²⁷ Department of Medicine/Geriatrics, University of Mississippi School of Medicine, Jackson, MS, USA.
²⁸ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
²⁹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
³⁰ Department of Epidemiology, University of North Carolina, Chapel Hill, NC, 27516, USA.
³¹ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
³² Berlin Institute of Health, Department of Endocrinology and Metabolism, Berlin, Germany.
³³ Charité - Universitätsmedizin Berlin, BCRT - Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany.
³⁴ Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
³⁵ Wageningen University, Division of Human Nutrition, PO-box 17, 6700 AA, Wageningen, The Netherlands.
³⁶ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health services, University of Washington, Seattle, WA, USA.
³⁷ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
³⁸ Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA.
³⁹ Department of Epidemiology and Institute of Public Genetics, University of Washington, Seattle, WA, USA.
⁴⁰ Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy.
⁴¹ Epidemiology and Biostatistics, Department of Public Health, Faculty of Health Science, University of Southern Denmark, Odense, Denmark.
⁴² Geriatric Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁴³ Clinical and Molecular Osteoporosis Research Unit, Department of Orthopedics and Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
⁴⁴ Center for Translational and Systems Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA.
⁴⁵ Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
⁴⁶ Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
⁴⁷ Department of Restorative Dentistry, Periodontology, Endodontology, and Preventive and Pediatric Dentistry, University Medicine Greifswald, Greifswald, Germany.
⁴⁸ Department of Geriatrics, Getafe University Hospital, Getafe, Spain.
⁴⁹ Department of Geriatrics, Hospital Virgen del Valle, Complejo Hospitalario de Toledo, Toledo, Spain.
⁵⁰ Professor of Public Policy, Georgetown University, Washington, DC, USA.
⁵¹ Sahlgrenska University Hospital, Department of Drug Treatment, Gothenburg, Sweden.
⁵² Section of General Internal Medicine, Boston University School of Medicine, Boston, MA, USA.
⁵³ Center on Aging, University of Connecticut Health, 263 Farmington Avenue, Farmington, CT, 06030, USA.
⁵⁴ National Institute on Aging, Baltimore, MD, USA.
⁵⁵ Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA.
⁵⁶ Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel.
⁵⁷ Marcus Institute for Aging Research, Hebrew SeniorLife and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Broad Institute of MIT & Harvard, Boston, MA, USA.
⁵⁸ Epidemiology and Public Health Group, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK. L.Pilling@exeter.ac.uk.

^# Contributed equally.

PMID: 33510174
PMCID: PMC7844411
DOI: 10.1038/s41467-021-20918-w

Meta-Analysis

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

Garan Jones et al. Nat Commun. 2021.

. 2021 Jan 28;12(1):654.

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

Authors

Affiliations

¹ Epidemiology and Public Health Group, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
² Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
³ Department of Epidemiology Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
⁴ University of Pittsburgh, Department of Epidemiology, Pittsburgh, PA, USA.
⁵ Department of Epidemiology and Biostatistics, Amsterdam UMC- Vrije Universiteit, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.
⁶ Biostatistics Center, Connecticut Convergence Institute for Translation in Regenerative Engineering, UConn Health, Farmington, CT, USA.
⁷ School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.
⁸ School fo Public Health University of Sydney, Sydney, NSW, Australia.
⁹ Medical School, University of Western Australia, Crawley, WA, Australia.
¹⁰ McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Lübeck Interdisciplinary Plattform for Genome Analytics, Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Lübeck, Germany.
¹² Cardiovascular Health Research Unit, Department of Medicine, and Department of Biostatistics, University of Washington, Seattle, WA, USA.
¹³ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, UK.
¹⁴ Biostatistics Department, Boston University School of Public Health, Boston, MA, USA.
¹⁵ Longitudinal Study Section, Translational Gerontology branch, National Institute on Aging, Baltimore, MD, USA.
¹⁶ Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
¹⁷ Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁸ Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁹ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
²⁰ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
²¹ Rush Alzheimer's Disease Center & Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
²² Department of Medicine and Public Health, Rey Juan Carlos University, Madrid, Spain.
²³ CIBER of Frailty and Healthy Aging (CIBERFES), Madrid, Spain.
²⁴ Center for Demography of Health and Aging, University of Wisconsin-Madison, Madison, WI, USA.
²⁵ School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK.
²⁶ Department of Orthopedics, University of Colorado, Aurora, CO, USA.
²⁷ Department of Medicine/Geriatrics, University of Mississippi School of Medicine, Jackson, MS, USA.
²⁸ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
²⁹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
³⁰ Department of Epidemiology, University of North Carolina, Chapel Hill, NC, 27516, USA.
³¹ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
³² Berlin Institute of Health, Department of Endocrinology and Metabolism, Berlin, Germany.
³³ Charité - Universitätsmedizin Berlin, BCRT - Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany.
³⁴ Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
³⁵ Wageningen University, Division of Human Nutrition, PO-box 17, 6700 AA, Wageningen, The Netherlands.
³⁶ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health services, University of Washington, Seattle, WA, USA.
³⁷ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
³⁸ Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA.
³⁹ Department of Epidemiology and Institute of Public Genetics, University of Washington, Seattle, WA, USA.
⁴⁰ Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy.
⁴¹ Epidemiology and Biostatistics, Department of Public Health, Faculty of Health Science, University of Southern Denmark, Odense, Denmark.
⁴² Geriatric Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁴³ Clinical and Molecular Osteoporosis Research Unit, Department of Orthopedics and Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
⁴⁴ Center for Translational and Systems Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA.
⁴⁵ Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
⁴⁶ Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
⁴⁷ Department of Restorative Dentistry, Periodontology, Endodontology, and Preventive and Pediatric Dentistry, University Medicine Greifswald, Greifswald, Germany.
⁴⁸ Department of Geriatrics, Getafe University Hospital, Getafe, Spain.
⁴⁹ Department of Geriatrics, Hospital Virgen del Valle, Complejo Hospitalario de Toledo, Toledo, Spain.
⁵⁰ Professor of Public Policy, Georgetown University, Washington, DC, USA.
⁵¹ Sahlgrenska University Hospital, Department of Drug Treatment, Gothenburg, Sweden.
⁵² Section of General Internal Medicine, Boston University School of Medicine, Boston, MA, USA.
⁵³ Center on Aging, University of Connecticut Health, 263 Farmington Avenue, Farmington, CT, 06030, USA.
⁵⁴ National Institute on Aging, Baltimore, MD, USA.
⁵⁵ Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA.
⁵⁶ Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel.
⁵⁷ Marcus Institute for Aging Research, Hebrew SeniorLife and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Broad Institute of MIT & Harvard, Boston, MA, USA.
⁵⁸ Epidemiology and Public Health Group, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK. L.Pilling@exeter.ac.uk.

^# Contributed equally.

PMID: 33510174
PMCID: PMC7844411
DOI: 10.1038/s41467-021-20918-w

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.

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Conflict of interest statement

D.P.K. is a consultant for Solarea Bio, received institutional grants from Amgen and Radius Health, and received royalties for publication Wolters Kluwer. M.C.O. serves as a consultant for Cricket Health, a kidney care company. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. All other authors declare no competing interests.

Figures

**Fig. 1. Manhattan plot of low grip strength genome-wide association study -log10 p values.**
The p values are from a fixed-effects meta-analysis of 256,523 Europeans aged 60 or older from 22 cohorts. The outcome was low hand grip strength grip strength cutoff (males <30 Kg, females <20 Kg). The x-axis is the chromosomal location, and the y-axis is the –log₁₀ p value for each genetic variant. The horizontal red line is the threshold for genome-wide significance (p < 5 × 10⁻⁸). Fifteen genomic loci cross the threshold, and the lead variant (most significantly associated with low strength) is described in Table 1. The nearest gene is displayed for each locus.

**Fig. 2. Low grip strength genetic correlations with ten common diseases and five anthropometric traits.**
Genome-wide genetic correlations between low muscle strength and published summary statistics for common age-related diseases and low muscle strength risk factors. N = meta-analysis of 256,523 Europeans (biologically independent samples) aged 60 or older from 22 cohorts. Data presented are genetic correlation (rG) ± 95% Confidence Intervals from LD-Score Regression analysis of 1.2 million SNPs. Full results available in Supplementary Table 5.

**Fig. 3. Traits sharing causal pathways with low grip strength at older ages identified in Mendelian Randomization analysis.**
In Mendelian randomization analyses we estimated whether 83 exposures may share causal pathways with low grip strength in people aged 60 and older. Those identified as significant (multiple testing-adjusted p < 0.05) in at least one analysis (all participants, or males or females separately) are included in the figure. *WHR (adj. BMI in Women) = Waist-Hip Ratio SNPs identified in GWAS analysis of females only, adjusted for Body Mass Index. N = meta-analysis of 256,523 Europeans (biologically independent samples) aged 60 or older from 22 cohorts. Data presented as Odds Ratios + /− 95% Confidence Intervals. Unadjusted p value (two-sided) from IVW regression analysis of exposure SNPs effect on low grip strength (EWGSOP definition). Full results of Mendelian randomization available in Supplementary Data 11, 12 and 13.

See this image and copyright information in PMC

References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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