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Meta-analysis identifies mitochondrial DNA sequence variants associated with walking speed

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Abstract

Declines in walking speed are associated with a variety of poor health outcomes including disability, comorbidity, and mortality. While genetic factors are putative contributors to variability in walking, few genetic loci have been identified for this trait. We examined the role of mitochondrial genomic variation on walking speed by sequencing the entire mitochondrial DNA (mtDNA). Data were meta-analyzed from 1758 Lifestyle Interventions and Independence for Elders (LIFE) Study and replication data from 730 Health, Aging, and Body Composition (HABC) Study participants with baseline walking speed information. Participants were 69+ years old of diverse racial backgrounds (African, European, and other race/ethnic groups) and had a wide range of mean walking speeds [4–6 m (0.78–1.09 m/s) and 400 m (0.83–1.24 m/s)]. Meta-analysis across studies and racial groups showed that m.12705C>T, ND5 variant was significantly associated (p < 0.0001) with walking speed at both short and long distances. Replication and meta-analysis also identified statistically significant walking speed associations (p < 0.0001) between the m.5460.G>A, ND2 and m.309C>CT, HV2 variants at short and long distances, respectively. All results remained statistically significant after multiple comparisons adjustment for 499 mtDNA variants. The m.12705C>T variant can be traced to the beginnings of human global migration and that cells carrying this variant display altered tRNA expression. Significant pooled effects related to stopping during the long-distance walk test were observed across OXPHOS complexes I (p = 0.0017) and III (p = 0.0048). These results suggest that mtDNA-encoded variants are associated with differences in walking speed among older adults, potentially identifying those at risk of developing mobility impairments.

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Funding

This work is primarily supported by R01HL121023. The Lifestyle Interventions and Independence for Elders Study was funded by a National Institutes of Health/National Institute on Aging Cooperative Agreement #UO1 AG22376 and a supplement from the National Heart, Lung, and Blood Institute 3U01AG022376- 05A2S and sponsored in part by the Intramural Research Program, National Institute on Aging, NIH. The research is partially supported by the Claude D. Pepper Older Americans Independence Centers at the University of Florida (1 P30 AG028740), Wake Forest University (1 P30 AG21332), Tufts University (1P30AG031679), University of Pittsburgh (P30 AG024827), and the NIH/NCRR CTSA at Stanford University (UL1 RR025744); Tufts University is also supported by the Boston Rehabilitation Outcomes Center (1R24HD065688-01A1). LIFE investigators are also partially supported by the following: Dr. Carlos Fragoso (Spirometry Reading Center, Yale University) is the recipient of a Career Development Award from the Department of Veterans Affairs. Dr. Roger Fielding (Tufts University) is partially supported by the U.S. Department of Agriculture, under agreement No. 58-1950-0-014. Any opinions, findings, conclusion, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the U.S. Dept of Agriculture. This Health, Aging, and Body Composition Study was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, Contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; National Institutes of Health grants R01-AG028050, R03-AG032498, R01-NR012459, Z01A6000932, and R01-HL121023; and grants from the Research and Education Leadership Committee of the CPMC Foundation and the L. K. Whittier Foundation.

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Authors and Affiliations

  1. Department of Aging and Geriatric Research, University of Florida, 2004 Mowry Rd., Gainesville, FL, 32611, USA

    Todd M. Manini & Marco Pahor

  2. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Thomas W. Buford

  3. Department of Biostatistics, University of Florida, Gainesville, FL, USA

    John A. Kairalla

  4. General Internal Medicine and Geriatrics and Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Mary M. McDermott

  5. Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA

    Carlos A. Vaz Fragoso

  6. Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA

    Roger A. Fielding

  7. The Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Fang-Chi Hsu

  8. Preventive Medicine Department, Pennington Biomedical Research Center, Baton Rouge, LA, USA

    Neil Johannsen

  9. Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Stephen Kritchevsky

  10. Intramural Research Program, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD, USA

    Tamara B. Harris

  11. Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA

    Anne B. Newman & Adam J. Santanasto

  12. California Pacific Medical Center Research Institute, San Francisco, CA, 94107, USA

    Steven R. Cummings & Gregory J. Tranah

  13. Department of Health Research and Policy – Epidemiology, Stanford University School of Medicine, Stanford, CA, USA

    Abby C. King

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  1. Todd M. Manini
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Contributions

TMM and GJT were responsible for the study concept, obtained funding, and created initial draft of manuscript and results; GJT and JAK: statistical analyses; MP: PI of the LIFE study and obtained funding for the LIFE study. Authors MMM, CAF, RAF, FH, NJ, SK, TBH, ABN, SRC, ACK, MP, and AJS were responsible for data collection, critical revisions of content, and approval of final version for publication; GJT and JAK had full access to all of the data (including statistical reports and tables) and can take responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding authors

Correspondence to Todd M. Manini or Gregory J. Tranah.

Ethics declarations

The institutional review board at all field sites approved each study protocol, and written informed consent was obtained from all study participants.

Conflict of interest

The authors declare that they have no conflict of interest.

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Manini, T.M., Buford, T.W., Kairalla, J.A. et al. Meta-analysis identifies mitochondrial DNA sequence variants associated with walking speed. GeroScience 40, 497–511 (2018). https://doi.org/10.1007/s11357-018-0043-x

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