title: The complex genetics of gait speed: genome-wide meta-analysis approach.
abstract: Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging.
authors.affiliation: Department of Medicine and Genetics Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Ben-Avraham
authors.affiliation: Institute for Aging Research, Hebrew SeniorLife, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02131, USA.|Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Karasik
authors.affiliation: Integrated Divisions of Cognitive & Motor Aging (Neurology) and Geriatrics (Medicine), Montefiore-Einstein Center for the Aging Brain, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Verghese
authors.affiliation: The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA 01702, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lunetta
authors.affiliation: Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Smith
authors.affiliation: The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA 01702, USA.|Population Sciences Branch, National Heart Lung and Blood Institute, Framingham, MA 01702, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Eicher
authors.affiliation: Psychology Department, University of Haifa, Haifa, Israel.
authors.forename: Rotem
authors.initials: R
authors.lastname: Vered
authors.affiliation: Molecular Epidemiology, Leiden University Medical Center, Leiden, Netherlands.|Max Planck Institute for Biology of Ageing, Köln, Germany.
authors.forename: Joris
authors.initials: J
authors.lastname: Deelen
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98115, USA.
authors.forename: Alice M
authors.initials: AM
authors.lastname: Arnold
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60614, USA.
authors.forename: Aron S
authors.initials: AS
authors.lastname: Buchman
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, Baltimore MD 21224, USA.
authors.forename: Toshiko
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI 48104, USA.
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Faul
authors.affiliation: Bioinformatics Core Facility, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Nethander
authors.affiliation: The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Myriam
authors.initials: M
authors.lastname: Fornage
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, Netherlands.|Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, Netherlands.
authors.forename: Hieab H
authors.initials: HH
authors.lastname: Adams
authors.affiliation: Division of Geriatric Medicine, Johns Hopkins Medical Institutes, Baltimore, MD 21224, USA.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Matteini
authors.affiliation: Medicine, Peninsula Health, Peninsula Clinical School, Central Clinical School, Frankston, Melbourne, Victoria, Australia.|Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: Michele L
authors.initials: ML
authors.lastname: Callisaya
authors.affiliation: Icelandic Heart Association, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
authors.forename: Albert V
authors.initials: AV
authors.lastname: Smith
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60614, USA.
authors.forename: Lei
authors.initials: L
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authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Harvard Medical School, Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.affiliation: Rush Institute for Healthy Aging and Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Denis A
authors.initials: DA
authors.lastname: Evans
authors.affiliation: Icelandic Heart Association, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, Netherlands.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Pattie
authors.affiliation: Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors.forename: Janie
authors.initials: J
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authors.affiliation: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lenore J
authors.initials: LJ
authors.lastname: Launer
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authors.forename: Davis S
authors.initials: DS
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authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, CA 94107, USA.
authors.forename: Neeta
authors.initials: N
authors.lastname: Parimi
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Turner
authors.affiliation: Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bandinelli
authors.affiliation: Molecular Epidemiology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Marian
authors.initials: M
authors.lastname: Beekman
authors.affiliation: Department of Human Biology, Faculty of Natural Science, University of Haifa, Haifa, Israel.
authors.forename: Danielle
authors.initials: D
authors.lastname: Gutman
authors.affiliation: Department of Human Biology, Faculty of Natural Science, University of Haifa, Haifa, Israel.
authors.forename: Lital
authors.initials: L
authors.lastname: Sharvit
authors.affiliation: Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherland.
authors.forename: Simon P
authors.initials: SP
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authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Liewald
authors.affiliation: Genetical Statistics, Leiden University Medical Center, Leiden, Netherland. Department of Statistics, University of Leeds, Leeds, UK.
authors.forename: Jeanine J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.affiliation: Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska, Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
authors.affiliation: Molecular Epidemiology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Matthijs
authors.initials: M
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authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, Netherlands.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Verlinden
authors.affiliation: Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska, Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Dan
authors.initials: D
authors.lastname: Mellström
authors.affiliation: Department of Neuroscience, Erasmus MC, Rotterdam, Netherlands.
authors.forename: Jos N
authors.initials: JN
authors.lastname: van der Geest
authors.affiliation: Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Karlsson
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.
authors.forename: Dena
authors.initials: D
authors.lastname: Hernandez
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: Rebekah
authors.initials: R
authors.lastname: McWhirter
authors.affiliation: Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, NC 27109, USA.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.|School of Computing, Engineering and Mathematics, University of Western Sydney, Sydney, Australia.
authors.forename: Russell
authors.initials: R
authors.lastname: Thomson
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, CA 94107, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tranah
authors.affiliation: Department of Internal Medicine, Erasmus MC, and Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, The Netherlands.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI 48104, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Weir
authors.affiliation: Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
authors.forename: John M
authors.initials: JM
authors.lastname: Starr
authors.affiliation: The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA 01702, USA.|Population Sciences Branch, National Heart Lung and Blood Institute, Framingham, MA 01702, USA.
authors.forename: Andrew D
authors.initials: AD
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authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, Netherlands.|Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, Netherlands.
authors.forename: M Arfan
authors.initials: MA
authors.lastname: Ikram
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60614, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, CA 94107, USA.
authors.forename: Steven R
authors.initials: SR
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authors.affiliation: Department of Psychology, University of Edinburgh, Edinburgh, UK.|Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
authors.affiliation: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USA.
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authors.initials: TB
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authors.affiliation: Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Sharon L R
authors.initials: SL
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authors.affiliation: University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Mosley
authors.affiliation: Medicine, Peninsula Health, Peninsula Clinical School, Central Clinical School, Frankston, Melbourne, Victoria, Australia.|Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: Velandai K
authors.initials: VK
authors.lastname: Srikanth
authors.affiliation: University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Beverly G
authors.initials: BG
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authors.affiliation: Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Ann B
authors.initials: AB
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authors.affiliation: Division of Geriatric Medicine, Johns Hopkins Medical Institutes, Baltimore, MD 21224, USA.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Walston
authors.affiliation: Department of Psychology, University of Edinburgh, Edinburgh, UK.|Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
authors.forename: Gail
authors.initials: G
authors.lastname: Davies
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, CA 94107, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Evans
authors.affiliation: Molecular Epidemiology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Eline P
authors.initials: EP
authors.lastname: Slagboom
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, Baltimore MD 21224, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.affiliation: Institute for Aging Research, Hebrew SeniorLife, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02131, USA.|Broad Institute of Harvard and MIT, Boston, MA 02131, USA.|Co senior authors.
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Kiel
authors.affiliation: The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA 01702, USA.|Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.|Co senior authors.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Murabito
authors.affiliation: Department of Medicine and Genetics Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Department of Human Biology, Faculty of Natural Science, University of Haifa, Haifa, Israel.|Co senior authors.
authors.forename: Gil
authors.initials: G
authors.lastname: Atzmon
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D005260:Female; D005684:Gait / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D000072797:Walking Speed / Q000235:genetics*
chemical_list: C516865:PTPRT protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; C472502:PRSS16 protein, human; D012697:Serine Endopeptidases
keywords: GWAS; aging; gait speed; meta-analysis