Gene transcripts associated with muscle strength: a CHARGE meta-analysis of 7,781 persons.
Lower muscle strength in midlife predicts disability and mortality in later life. Blood-borne factors, including growth differentiation factor 11 (GDF11), have been linked to muscle regeneration in animal models. We aimed to identify gene transcripts associated with muscle strength in adults. Meta-analysis of whole blood gene expression (overall 17,534 unique genes measured by microarray) and hand-grip strength in four independent cohorts (n = 7,781, ages: 20-104 yr, weighted mean = 56), adjusted for age, sex, height, weight, and leukocyte subtypes. Separate analyses were performed in subsets (older/younger than 60, men/women). Expression levels of 221 genes were associated with strength after adjustment for cofactors and for multiple statistical testing, including ALAS2 (rate-limiting enzyme in heme synthesis), PRF1 (perforin, a cytotoxic protein associated with inflammation), IGF1R, and IGF2BP2 (both insulin like growth factor related). We identified statistical enrichment for hemoglobin biosynthesis, innate immune activation, and the stress response. Ten genes were associated only in younger individuals, four in men only and one in women only. For example, PIK3R2 (a negative regulator of PI3K/AKT growth pathway) was negatively associated with muscle strength in younger (<60 yr) individuals but not older (≥ 60 yr). We also show that 115 genes (52%) have not previously been linked to muscle in NCBI PubMed abstracts. This first large-scale transcriptome study of muscle strength in human adults confirmed associations with known pathways and provides new evidence for over half of the genes identified. There may be age- and sex-specific gene expression signatures in blood for muscle strength.
Epidemiology and Public Health Group, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom;
L C
http://orcid.org/0000-0002-3332-8454
LC
Pilling
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; Population Studies Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland;
R
R
Joehanes
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany;
T
T
Kacprowski
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, the Netherlands;
M
M
Peters
Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands;
R
R
Jansen
Hebrew SeniorLife Institute for Aging Research, Boston, Massachusetts;
D
D
Karasik
Hebrew SeniorLife Institute for Aging Research, Boston, Massachusetts;
D P
DP
Kiel
RNA mechanisms of complex diseases group, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom;
L W
LW
Harries
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany;
A
A
Teumer
Centre for Neurogenetics and Statistical Genomics, Queensland Brain Institute, University of Queensland, St. Lucia, Brisbane, Australia;
J
J
Powell
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; Population Studies Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland;
D
D
Levy
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts;
H
H
Lin
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts;
K
K
Lunetta
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; The Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, Maryland;
P
P
Munson
Geriatric Unit, Azienda Sanitaria di Firenze, Florence, Italy;
S
S
Bandinelli
Institute for Health Services Research, University of Exeter Medical School, Exeter, United Kingdom;
W
W
Henley
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland;
D
D
Hernandez
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland;
A
A
Singleton
Clinical Research Branch, National Institute on Aging, Baltimore, Maryland;
T
T
Tanaka
Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands;
G
G
van Grootheest
The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, the Netherlands; Department of Epidemiology, Erasmus Medical Center Rotterdam, the Netherlands;
A
A
Hofman
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, the Netherlands; Department of Epidemiology, Erasmus Medical Center Rotterdam, the Netherlands;
A G
AG
Uitterlinden
Department of Prosthetic Dentistry, Gerostomatology and Dental Materials, University Medicine Greifswald, Greifswald, Germany;
R
R
Biffar
Department of Internal Medicine B - Cardiology, Intensive Care, Pulmonary Medicine and Infectious Diseases, University of Greifswald, Greifswald, Germany;
S
S
Gläser
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany;
G
G
Homuth
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany;
C
C
Malsch
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany;
U
U
Völker
Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands;
B
B
Penninx
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, the Netherlands;
J B J
JB
van Meurs
Clinical Research Branch, National Institute on Aging, Baltimore, Maryland;
L
L
Ferrucci
Unit of Periodontology, Department of Restorative Dentistry, Periodontology and Endodontology, University Medicine Greifswald, Greifswald, Germany; and.
T
T
Kocher
The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts; General Internal Medicine Section, Boston University, Boston, Massachusetts.
J
J
Murabito
Epidemiology and Public Health Group, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom; D.Melzer@exeter.ac.uk.
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D
Melzer
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology*; D015331:Cohort Studies; D005260:Female; D063990:Gene Ontology; D006321:Heart / Q000502:physiology*; D006801:Humans; D007717:Knee / Q000502:physiology; D008297:Male; D008875:Middle Aged; D053580:Muscle Strength / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D012727:Sex Characteristics; D055815:Young Adult
D012333:RNA, Messenger
blood; gene-expression; human; leukocyte; muscle; strength