GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium

Amy M Matteini¹, Toshiko Tanaka², David Karasik^{3

4}, Gil Atzmon^{5

6}, Wen-Chi Chou³, John D Eicher^{7

8}, Andrew D Johnson^{7

8}, Alice M Arnold⁹, Michele L Callisaya^{10

11}, Gail Davies^{12

13}, Daniel S Evans¹⁴, Birte Holtfreter¹⁵, Kurt Lohman¹⁶, Kathryn L Lunetta^{8

17}, Massimo Mangino^{18

19}, Albert V Smith²⁰, Jennifer A Smith²¹, Alexander Teumer²², Lei Yu²³, Dan E Arking²⁴, Aron S Buchman^{23

25}, Lori B Chibinik^{26

27}, Philip L De Jager^{26

27}, Denis A Evans²⁸, Jessica D Faul²⁹, Melissa E Garcia³⁰, Irina Gillham-Nasenya¹⁸, Vilmundur Gudnason^{20

31}, Albert Hofman³², Yi-Hsiang Hsu^{3

33}, Till Ittermann²², Lies Lahousse^{32

34}, David C Liewald¹², Yongmei Liu¹⁶, Lorna Lopez¹³, Fernando Rivadeneira^{32

35

36}, Jerome I Rotter³⁷, Kristin Siggeirsdottir²⁰, John M Starr^{12

38}, Russell Thomson¹¹, Gregory J Tranah¹⁴, André G Uitterlinden^{32

35

36}, Uwe Völker³⁹, Henry Völzke^{22

40

41}, David R Weir²⁹, Kristine Yaffe⁴², Wei Zhao²¹, Wei Vivian Zhuang⁴³, Joseph M Zmuda⁴⁴, David A Bennett²³, Steven R Cummings¹⁴, Ian J Deary^{12

13}, Luigi Ferrucci², Tamara B Harris⁴⁵, Sharon L R Kardia²¹, Thomas Kocher¹⁵, Stephen B Kritchevsky⁴⁶, Bruce M Psaty⁴⁷, Sudha Seshadri^{8

48}, Timothy D Spector¹⁸, Velandai K Srikanth^{10

11}, B Gwen Windham⁴⁹, M Carola Zillikens³⁵, Anne B Newman⁴⁴, Jeremy D Walston¹, Douglas P Kiel³, Joanne M Murabito^{8

50}

Affiliations

¹ Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Longitudinal Studies Section, Translational Gerontology Branch, Gerontology Research Center, National Institute on Aging, Baltimore, MD, USA.
³ Institute for Aging Research, Hebrew SeniorLife, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
⁴ Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, 13010, Israel.
⁵ Institute for Aging Research Departments of Medicine and Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, USA.
⁶ Department of Human Biology, University of Haifa, Haifa, Israel.
⁷ National Heart, Lung and Blood Institute, Population Sciences Branch, Bethesda, MD, USA.
⁸ National Heart, Lung and Blood Institute's The Framingham Heart Study, Framingham, MA, USA.
⁹ Department of Biostatistics, University of Washington, Seattle, WA, USA.
¹⁰ Stroke and Ageing Research Group, Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Vic., Australia.
¹¹ Menzies Institute for Medical Research, University of Tasmania, Hobart, Tas., Australia.
¹² Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
¹³ Department of Psychology, University of Edinburgh, Edinburgh, UK.
¹⁴ California Pacific Medical Center Research Institute, San Francisco, CA, USA.
¹⁵ Unit of Periodontology, Department of Restorative Dentistry, Periodontology and Endodontology, Centre of Oral Health, University Medicine Greifswald, Greifswald, Germany.
¹⁶ Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹⁷ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁸ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
¹⁹ NIHR Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust, London, UK.
²⁰ Icelandic Heart Association, Kopavogur, Iceland.
²¹ Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
²² Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
²³ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
²⁴ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁵ Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
²⁶ Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
²⁷ Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
²⁸ Institute of Healthy Aging and Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA.
²⁹ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
³⁰ Laboratory of Epidemiology and Population Science, National Institute on Aging, Bethesda, MD, USA.
³¹ University of Iceland, Reykjavik, Iceland.
³² Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
³³ Department of Medicine, Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, MA, USA.
³⁴ Department of Respiratory Medicine, Ghent University and Ghent University Hospital, Ghent, Belgium.
³⁵ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
³⁶ Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands.
³⁷ Division of Genomic Outcome, Departments of Pediatrics and Medicine, Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, University of California Los Angeles, Los Angeles, CA, USA.
³⁸ Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
³⁹ Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
⁴⁰ German Center for Cardiovascular Research (DZHK), Greifswald, Germany.
⁴¹ German Center for Diabetes Research (DZD), Greifswald, Germany.
⁴² Departments of Neurology, Psychiatry and Epidemiology & Biostatistics, University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.
⁴³ Public Health Program, Center for Health Policy and Ethics, Creighton University School of Medicine, Omaha, NE, USA.
⁴⁴ Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA.
⁴⁵ Laboratory of Epidemiology and Population Science, NIA, Bethesda, MD, USA.
⁴⁶ Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁴⁷ Cardiovascular Health Research Unit and Department of Medicine, University of Washington and Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
⁴⁸ Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
⁴⁹ Department of Medicine/Division of Geriatrics, University of Mississippi Medical Center, Jackson, MS, USA.
⁵⁰ Department of Medicine, Boston University School of Medicine, Boston, MA, USA.

PMID: 27325353
PMCID: PMC5013019
DOI: 10.1111/acel.12468

GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium

Amy M Matteini et al. Aging Cell. 2016 Oct.

. 2016 Oct;15(5):792-800.

doi: 10.1111/acel.12468. Epub 2016 Jun 21.

Authors

Affiliations

¹ Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Longitudinal Studies Section, Translational Gerontology Branch, Gerontology Research Center, National Institute on Aging, Baltimore, MD, USA.
³ Institute for Aging Research, Hebrew SeniorLife, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
⁴ Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, 13010, Israel.
⁵ Institute for Aging Research Departments of Medicine and Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, USA.
⁶ Department of Human Biology, University of Haifa, Haifa, Israel.
⁷ National Heart, Lung and Blood Institute, Population Sciences Branch, Bethesda, MD, USA.
⁸ National Heart, Lung and Blood Institute's The Framingham Heart Study, Framingham, MA, USA.
⁹ Department of Biostatistics, University of Washington, Seattle, WA, USA.
¹⁰ Stroke and Ageing Research Group, Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Vic., Australia.
¹¹ Menzies Institute for Medical Research, University of Tasmania, Hobart, Tas., Australia.
¹² Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
¹³ Department of Psychology, University of Edinburgh, Edinburgh, UK.
¹⁴ California Pacific Medical Center Research Institute, San Francisco, CA, USA.
¹⁵ Unit of Periodontology, Department of Restorative Dentistry, Periodontology and Endodontology, Centre of Oral Health, University Medicine Greifswald, Greifswald, Germany.
¹⁶ Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹⁷ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁸ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
¹⁹ NIHR Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust, London, UK.
²⁰ Icelandic Heart Association, Kopavogur, Iceland.
²¹ Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
²² Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
²³ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
²⁴ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁵ Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
²⁶ Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
²⁷ Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
²⁸ Institute of Healthy Aging and Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA.
²⁹ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
³⁰ Laboratory of Epidemiology and Population Science, National Institute on Aging, Bethesda, MD, USA.
³¹ University of Iceland, Reykjavik, Iceland.
³² Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
³³ Department of Medicine, Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, MA, USA.
³⁴ Department of Respiratory Medicine, Ghent University and Ghent University Hospital, Ghent, Belgium.
³⁵ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
³⁶ Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands.
³⁷ Division of Genomic Outcome, Departments of Pediatrics and Medicine, Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, University of California Los Angeles, Los Angeles, CA, USA.
³⁸ Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
³⁹ Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
⁴⁰ German Center for Cardiovascular Research (DZHK), Greifswald, Germany.
⁴¹ German Center for Diabetes Research (DZD), Greifswald, Germany.
⁴² Departments of Neurology, Psychiatry and Epidemiology & Biostatistics, University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.
⁴³ Public Health Program, Center for Health Policy and Ethics, Creighton University School of Medicine, Omaha, NE, USA.
⁴⁴ Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA.
⁴⁵ Laboratory of Epidemiology and Population Science, NIA, Bethesda, MD, USA.
⁴⁶ Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁴⁷ Cardiovascular Health Research Unit and Department of Medicine, University of Washington and Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
⁴⁸ Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
⁴⁹ Department of Medicine/Division of Geriatrics, University of Mississippi Medical Center, Jackson, MS, USA.
⁵⁰ Department of Medicine, Boston University School of Medicine, Boston, MA, USA.

PMID: 27325353
PMCID: PMC5013019
DOI: 10.1111/acel.12468

Abstract

Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.

Keywords: SNP; aging; genomewide association; meta-analysis; muscle strength; older adults.

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Figures

**Figure 1**
Regional association plots for the most significant associations from the meta‐analysis of handgrip strength in the discovery set. The figures display –log10 P‐values for SNPs that passed quality control for the analysis of handgrip strength for locus on (A) chromosome 7, (B) chromosome 8p23, (C) chromosome 8q12, (D) chromosome 10, and (E) chromosome 11. The degree of linkage disequilibrium (r ²) is displayed in the following categories: r ² ≥ 0.8, ≥ 0.6, ≥0.4, ≥0.2, and ≥0.

See this image and copyright information in PMC

References

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GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium

Affiliations

GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

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