GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium.
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.
Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Amy M
AM
Matteini
Longitudinal Studies Section, Translational Gerontology Branch, Gerontology Research Center, National Institute on Aging, Baltimore, MD, USA.
Toshiko
T
Tanaka
Institute for Aging Research, Hebrew SeniorLife, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.|Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, 13010, Israel.
David
D
Karasik
Institute for Aging Research Departments of Medicine and Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, USA.|Department of Human Biology, University of Haifa, Haifa, Israel.
Gil
G
Atzmon
Institute for Aging Research, Hebrew SeniorLife, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
Wen-Chi
WC
Chou
National Heart, Lung and Blood Institute, Population Sciences Branch, Bethesda, MD, USA.|National Heart, Lung and Blood Institute's The Framingham Heart Study, Framingham, MA, USA.
John D
JD
Eicher
National Heart, Lung and Blood Institute, Population Sciences Branch, Bethesda, MD, USA.|National Heart, Lung and Blood Institute's The Framingham Heart Study, Framingham, MA, USA.
Andrew D
AD
Johnson
Department of Biostatistics, University of Washington, Seattle, WA, USA.
Alice M
AM
Arnold
Stroke and Ageing Research Group, Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Vic., Australia.|Menzies Institute for Medical Research, University of Tasmania, Hobart, Tas., Australia.
Michele L
ML
Callisaya
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Department of Psychology, University of Edinburgh, Edinburgh, UK.
Gail
G
Davies
California Pacific Medical Center Research Institute, San Francisco, CA, USA.
Daniel S
DS
Evans
Unit of Periodontology, Department of Restorative Dentistry, Periodontology and Endodontology, Centre of Oral Health, University Medicine Greifswald, Greifswald, Germany.
Birte
B
Holtfreter
Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Kurt
K
Lohman
National Heart, Lung and Blood Institute's The Framingham Heart Study, Framingham, MA, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Kathryn L
KL
Lunetta
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.|NIHR Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust, London, UK.
Massimo
M
Mangino
Icelandic Heart Association, Kopavogur, Iceland.
Albert V
AV
Smith
Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
Jennifer A
JA
Smith
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
Alexander
A
Teumer
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
Lei
L
Yu
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Dan E
DE
Arking
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.|Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
Aron S
AS
Buchman
Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
Lori B
LB
Chibinik
Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
Philip L
PL
De Jager
Institute of Healthy Aging and Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA.
Denis A
DA
Evans
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
Jessica D
JD
Faul
Laboratory of Epidemiology and Population Science, National Institute on Aging, Bethesda, MD, USA.
Melissa E
ME
Garcia
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
Irina
I
Gillham-Nasenya
Icelandic Heart Association, Kopavogur, Iceland.|University of Iceland, Reykjavik, Iceland.
Vilmundur
V
Gudnason
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
Albert
A
Hofman
Institute for Aging Research, Hebrew SeniorLife, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.|Department of Medicine, Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, MA, USA.
Yi-Hsiang
YH
Hsu
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
Till
T
Ittermann
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.|Department of Respiratory Medicine, Ghent University and Ghent University Hospital, Ghent, Belgium.
Lies
L
Lahousse
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
David C
DC
Liewald
Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Yongmei
Y
Liu
Department of Psychology, University of Edinburgh, Edinburgh, UK.
Lorna
L
Lopez
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.|Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.|Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands.
Fernando
F
Rivadeneira
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.
Jerome I
JI
Rotter
Icelandic Heart Association, Kopavogur, Iceland.
Kristin
K
Siggeirsdottir
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
John M
JM
Starr
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tas., Australia.
Russell
R
Thomson
California Pacific Medical Center Research Institute, San Francisco, CA, USA.
Gregory J
GJ
Tranah
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.|Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.|Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands.
André G
AG
Uitterlinden
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Uwe
U
Völker
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.|German Center for Cardiovascular Research (DZHK), Greifswald, Germany.|German Center for Diabetes Research (DZD), Greifswald, Germany.
Henry
H
Völzke
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
David R
DR
Weir
Departments of Neurology, Psychiatry and Epidemiology & Biostatistics, University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.
Kristine
K
Yaffe
Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
Wei
W
Zhao
Public Health Program, Center for Health Policy and Ethics, Creighton University School of Medicine, Omaha, NE, USA.
Wei Vivian
WV
Zhuang
Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA.
Joseph M
JM
Zmuda
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
David A
DA
Bennett
California Pacific Medical Center Research Institute, San Francisco, CA, USA.
Steven R
SR
Cummings
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Department of Psychology, University of Edinburgh, Edinburgh, UK.
Ian J
IJ
Deary
Longitudinal Studies Section, Translational Gerontology Branch, Gerontology Research Center, National Institute on Aging, Baltimore, MD, USA.
Luigi
L
Ferrucci
Laboratory of Epidemiology and Population Science, NIA, Bethesda, MD, USA.
Tamara B
TB
Harris
Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
Sharon L R
SL
Kardia
Unit of Periodontology, Department of Restorative Dentistry, Periodontology and Endodontology, Centre of Oral Health, University Medicine Greifswald, Greifswald, Germany.
Thomas
T
Kocher
Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Stephen B
SB
Kritchevsky
Cardiovascular Health Research Unit and Department of Medicine, University of Washington and Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
Bruce M
BM
Psaty
National Heart, Lung and Blood Institute's The Framingham Heart Study, Framingham, MA, USA.|Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
Sudha
S
Seshadri
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
Timothy D
TD
Spector
Stroke and Ageing Research Group, Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Vic., Australia.|Menzies Institute for Medical Research, University of Tasmania, Hobart, Tas., Australia.
Velandai K
VK
Srikanth
Department of Medicine/Division of Geriatrics, University of Mississippi Medical Center, Jackson, MS, USA.
B Gwen
BG
Windham
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
M Carola
MC
Zillikens
Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA.
Anne B
AB
Newman
Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Jeremy D
JD
Walston
Institute for Aging Research, Hebrew SeniorLife, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
Douglas P
DP
Kiel
National Heart, Lung and Blood Institute's The Framingham Heart Study, Framingham, MA, USA.|Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Joanne M
JM
Murabito
D000328:Adult; D000368:Aged; D047369:Chromatin Immunoprecipitation; D015331:Cohort Studies; D044127:Epigenesis, Genetic; D055106:Genome-Wide Association Study; D018737:Hand Strength / Q000502:physiology*; D006801:Humans; D058977:Molecular Sequence Annotation; D053580:Muscle Strength / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D015203:Reproducibility of Results
SNP; aging; genomewide association; meta-analysis; muscle strength; older adults