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Research Paper|Volume 9, Issue 1|pp 209—246

The complex genetics of gait speed: genome-wide meta-analysis approach

Dan Ben-Avraham1, David Karasik2,3, Joe Verghese4, Kathryn L. Lunetta5,6, Jennifer A. Smith7, John D. Eicher5,8, Rotem Vered9, Joris Deelen10,11, Alice M. Arnold12, Aron S. Buchman13, Toshiko Tanaka14, Jessica D. Faul15, Maria Nethander16, Myriam Fornage17, Hieab H. Adams18,19, Amy M. Matteini20, Michele L. Callisaya21,22, Albert V. Smith23, Lei Yu13, Philip L. De Jager24, Denis A. Evans25, Vilmundur Gudnason23, Albert Hofman18,26, Alison Pattie27, Janie Corley27, Lenore J. Launer28, Davis S. Knopman29, Neeta Parimi30, Stephen T. Turner31, Stefania Bandinelli32, Marian Beekman10, Danielle Gutman48, Lital Sharvit48, Simon P. Mooijaart33, David C. Liewald34, Jeanine J. Houwing-Duistermaat35, Claes Ohlsson36, Matthijs Moed10, Vincent J. Verlinden18, Dan Mellström36, Jos N. van der Geest37, Magnus Karlsson38, Dena Hernandez39, Rebekah McWhirter22, Yongmei Liu40, Russell Thomson22,41, Gregory J. Tranah30, Andre G. Uitterlinden42, David R. Weir15, Wei Zhao7, John M. Starr34,43, Andrew D. Johnson5,8, M. Arfan Ikram18,19, David A. Bennett13, Steven R. Cummings30, Ian J. Deary27,34, Tamara B. Harris28, Sharon L. R. Kardia7, Thomas H. Mosley44, Velandai K. Srikanth21,22, Beverly G. Windham44, Ann B. Newman45, Jeremy D. Walston20, Gail Davies27,34, Daniel S. Evans30, Eline P. Slagboom10, Luigi Ferrucci14, Douglas P. Kiel2,46, Joanne M. Murabito5,47, Gil Atzmon1,48
  • 1Department of Medicine and Genetics Albert Einstein College of Medicine, Bronx, NY 10461, USA
  • 2Institute for Aging Research, Hebrew SeniorLife, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02131, USA
  • 3Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel
  • 4Integrated 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
  • 5The National Heart Lung and Blood Institute’s Framingham Heart Study, Framingham, MA 01702, USA
  • 6Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA
  • 7Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109,, USA
  • 8Population Sciences Branch, National Heart Lung and Blood Institute, Framingham, MA 01702, USA
  • 9Psychology Department, University of Haifa, Haifa, Israel
  • 10Molecular Epidemiology, Leiden University Medical Center, Leiden, Netherlands
  • 11Max Planck Institute for Biology of Ageing, Köln, Germany
  • 12Department of Biostatistics, University of Washington, Seattle, WA 98115, USA
  • 13Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60614, USA
  • 14Translational Gerontology Branch, National Institute on Aging, Baltimore MD 21224, USA
  • 15Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI 48104, USA
  • 16Bioinformatics Core Facility, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  • 17The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
  • 18Department of Epidemiology, Erasmus MC, Rotterdam, Netherlands
  • 19Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, Netherlands
  • 20Division of Geriatric Medicine, Johns Hopkins Medical Institutes, Baltimore, MD 21224, USA
  • 21Medicine, Peninsula Health, Peninsula Clinical School, Central Clinical School, Frankston, Melbourne, Victoria, Australia
  • 22Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
  • 23Icelandic Heart Association, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
  • 24Broad Institute of Harvard and MIT, Cambridge, Harvard Medical School, Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA
  • 25Rush Institute for Healthy Aging and Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612, USA
  • 26Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
  • 27Department of Psychology, University of Edinburgh, Edinburgh, UK
  • 28Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USA
  • 29Mayo Clinic, Rochester, MN 55905, USA
  • 30California Pacific Medical Center Research Institute, San Francisco, CA 94107, USA
  • 31Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA
  • 32Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy
  • 33Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherland
  • 34Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
  • 35Genetical Statistics, Leiden University Medical Center, Leiden, Netherland. Department of Statistics, University of Leeds, Leeds, UK
  • 36Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska, Academy, University of Gothenburg, Gothenburg, Sweden
  • 37Department of Neuroscience, Erasmus MC, Rotterdam, Netherlands
  • 38Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden
  • 39Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA
  • 40Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, NC 27109, USA
  • 41School of Computing, Engineering and Mathematics, University of Western Sydney, Sydney, Australia
  • 42Department of Internal Medicine, Erasmus MC, and Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, The Netherlands
  • 43Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK
  • 44University of Mississippi Medical Center, Jackson, MS 39216, USA
  • 45Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15261, USA
  • 46Broad Institute of Harvard and MIT, Boston, MA 02131, USA
  • 47Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
  • 48Department of Human Biology, Faculty of Natural Science, University of Haifa, Haifa, Israel

* * Equal contribution

Received: July 25, 2016Accepted: December 26, 2015Published: January 10, 2017

Copyright: © 2017 Ben-Avraham et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.