Genes & Nutrition

, 9:415

Heritability and genetic etiology of habitual physical activity: a twin study with objective measures

  • M. Gielen
  • M. S. Westerterp-Plantenga
  • F. G. Bouwman
  • A. M. C. P. Joosen
  • R. Vlietinck
  • C. Derom
  • M. P. Zeegers
  • E. C. M. Mariman
  • K. R. Westerterp
Research Paper

Abstract

Twin studies with objective measurements suggest habitual physical activity (HPA) are modestly to highly heritable, depending on age. We aimed to confirm or refute this finding and identify relevant genetic variants using a candidate gene approach. HPA was measured for 14 days with a validated triaxial accelerometer (Tracmor) in two populations: (1) 28 monozygotic and 24 dizygotic same-sex twin pairs (aged 22 ± 5 years, BMI 21.8 ± 3.4 kg/m2, 21 male, 31 female pairs); (2) 52 and 65 unrelated men and women (aged 21 ± 2 years, BMI 22.0 ± 2.5 kg/m2). Single nucleotide polymorphisms (SNPs) in PPARD, PPARGC1A, NRF1 and MTOR were considered candidates. Association analyses were performed for both groups separately followed by meta-analysis. Structural equation modeling shows significant familiality for HPA, consistent with a role for additive genetic factors (heritability 57 %, 95 % CI 32–74 %, AE model) or common environmental factors (47 %, 95 % CI 23–65 %, CE model). A moderate heritability was observed for the time spent on low- and high-intensity physical activity (P ≤ 0.05), but could not be confirmed for the time spent on moderate-intensity physical activity. For PPARD, each additional effect allele was inversely associated with HPA (P ≤ 0.01; rs2076168 allele C) or tended to be associated with HPA (P ≤ 0.05; rs2267668 allele G). Linkage disequilibrium existed between those two SNPs (alleles A/G and A/C, respectively) and meta-analysis showed that carriers of the AAGC haplotype were less physically active than carriers of the AAAA and AA AC haplotypes combined (P = 0.017). For PPARGC1A, carriers of AA in rs8192678 spent more time on high-intensity physical activity than GG carriers (P = 0.001). No associations were observed with SNPs in NRF1 and MTOR. In conclusion, HPA may be modestly heritable, which is confirmed by an association with variants in PPARD.

Keywords

Physical activity Mitochondrial biogenesis PPARD PGC1A Triaxial accelerometry 

References

  1. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265PubMedCrossRefGoogle Scholar
  2. Barroso I, Luan J, Sandhu MS, Franks PW, Crowley V, Schafer AJ, O’Rahilly S, Wareham NJ (2006) Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes. Diabetologia 49(3):501–505PubMedCrossRefGoogle Scholar
  3. Bouchard C, Simoneau JA, Lortie G, Boulay MR, Marcotte M, Thibault MC (1986) Genetic effects in human skeletal muscle fiber type distribution and enzyme activities. Can J Physiol Pharmacol 64(9):1245–1251PubMedCrossRefGoogle Scholar
  4. Cai G, Cole SA, Butte N, Bacino C, Diego V, Tan K, Goring HH, O’Rahilly S, Farooqi IS, Comuzzie AG (2006) A quantitative trait locus on chromosome 18q for physical activity and dietary intake in Hispanic children. Obesity 14(9):1596–1604PubMedCrossRefGoogle Scholar
  5. Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P (2007) mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 450(7170):736–740PubMedCrossRefGoogle Scholar
  6. den Hoed M, Westerterp KR (2008) Body composition is associated with physical activity in daily life as measured using a triaxial accelerometer in both men and women. Int J Obes (Lond) 32(8):1264–1270CrossRefGoogle Scholar
  7. den Hoed M, Hesselink MK, van Kranenburg GP, Westerterp KR (2008) Habitual physical activity in daily life correlates positively with markers for mitochondrial capacity. J Appl Physiol 105(2):561–568CrossRefGoogle Scholar
  8. den Hoed M, Brage S, Zhao JH, Westgate K, Nessa A, Ekelund U, Spector TD, Wareham NJ, Loos RJ (2013) Heritability of objectively assessed daily physical activity and sedentary behavior. Am J Clin Nutr 98(5):1317–1325. doi:10.3945/ajcn.113.069849 CrossRefGoogle Scholar
  9. Derom CA, Vlietinck RF, Thiery EW, Leroy FO, Fryns JP, Derom RM (2006) The east flanders prospective twin survey (EFPTS). Twin Res Hum Genet 9(6):733–738PubMedCrossRefGoogle Scholar
  10. Ekelund U, Aman J, Yngve A, Renman C, Westerterp K, Sjostrom M (2002) Physical activity but not energy expenditure is reduced in obese adolescents: a case–control study. Am J Clin Nutr 76(5):935–941PubMedGoogle Scholar
  11. Fang J, Wylie-Rosett J, Cohen HW, Kaplan RC, Alderman MH (2003) Exercise, body mass index, caloric intake, and cardiovascular mortality. Am J Prev Med 25(4):283–289PubMedCrossRefGoogle Scholar
  12. Fisher A, van Jaarsveld CH, Llewellyn CH, Wardle J (2010) Environmental influences on children’s physical activity: quantitative estimates using a twin design. PLoS One 5(4):e10110Google Scholar
  13. Franks PW, Loos RJ (2006) PGC-1alpha gene and physical activity in type 2 diabetes mellitus. Exerc Sport Sci Rev 34(4):171–175PubMedCrossRefGoogle Scholar
  14. Franks PW, Barroso I, Luan J, Ekelund U, Crowley VE, Brage S, Sandhu MS, Jakes RW, Middelberg RP, Harding AH, Schafer AJ, O’Rahilly S, Wareham NJ (2003) PGC-1alpha genotype modifies the association of volitional energy expenditure with [OV0312]O2max. Med Sci Sports Exerc 35(12):1998–2004PubMedCrossRefGoogle Scholar
  15. Gavin TP, Ruster RS, Carrithers JA, Zwetsloot KA, Kraus RM, Evans CA, Knapp DJ, Drew JL, McCartney JS, Garry JP, Hickner RC (2007) No difference in the skeletal muscle angiogenic response to aerobic exercise training between young and aged men. J Physiol 585(Pt 1):231–239PubMedCentralPubMedCrossRefGoogle Scholar
  16. Goyenochea E, Crujeiras AB, Abete I, Parra D, Martinez JA (2008) Enhanced short-term improvement of insulin response to a low-caloric diet in obese carriers of the Gly482Ser variant of the PGC-1alpha gene. Diabetes Res Clin Pract 82(2):190–196Google Scholar
  17. Hu G, Qiao Q, Silventoinen K, Eriksson JG, Jousilahti P, Lindstrom J, Valle TT, Nissinen A, Tuomilehto J (2003) Occupational, commuting, and leisure-time physical activity in relation to risk for Type 2 diabetes in middle-aged Finnish men and women. Diabetologia 46(3):322–329PubMedGoogle Scholar
  18. Hu FB, Willett WC, Li T, Stampfer MJ, Colditz GA, Manson JE (2004) Adiposity as compared with physical activity in predicting mortality among women. N Engl J Med 351(26):2694–2703. doi:10.1056/NEJMoa042135 PubMedCrossRefGoogle Scholar
  19. Joosen AM, Gielen M, Vlietinck R, Westerterp KR (2005) Genetic analysis of physical activity in twins. Am J Clin Nutr 82(6):1253–1259PubMedGoogle Scholar
  20. Lee YC, Lai CQ, Ordovas JM, Parnell LD (2011) A database of gene-environment interactions pertaining to blood lipid traits, cardiovascular disease and type 2 diabetes. J Data Mining Genomics Proteomics 2(1):106Google Scholar
  21. Ling C, Poulsen P, Carlsson E, Ridderstrale M, Almgren P, Wojtaszewski J, Beck-Nielsen H, Groop L, Vaag A (2004) Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins. J Clin Invest 114(10):1518–1526PubMedCentralPubMedCrossRefGoogle Scholar
  22. Liu Y, Niu N, Zhu X, Du T, Wang X, Chen D, Wu X, Gu HF, Liu Y (2008) Genetic variation and association analyses of the nuclear respiratory factor 1 (nRF1) gene in Chinese patients with type 2 diabetes. Diabetes 57(3):777–782PubMedCrossRefGoogle Scholar
  23. McCarty MF (2005) Up-regulation of PPARgamma coactivator-1alpha as a strategy for preventing and reversing insulin resistance and obesity. Med Hypotheses 64(2):399–407PubMedCrossRefGoogle Scholar
  24. Meijer EP, Goris AH, Wouters L, Westerterp KR (2001) Physical inactivity as a determinant of the physical activity level in the elderly. Int J Obes Relat Metab Disord 25(7):935–939PubMedCrossRefGoogle Scholar
  25. Melanson EL Jr, Freedson PS (1996) Physical activity assessment: a review of methods. Crit Rev Food Sci Nutr 36(5):385–396. doi:10.1080/10408399609527732 PubMedCrossRefGoogle Scholar
  26. Mustelin L, Silventoinen K, Pietilainen K, Rissanen A, Kaprio J (2009) Physical activity reduces the influence of genetic effects on BMI and waist circumference: a study in young adult twins. Int J Obes (Lond) 33(1):29–36. doi:10.1038/ijo.2008.258 CrossRefGoogle Scholar
  27. Neale M, Cardon L (1992) Methodology for genetic studies of twins and families. Kluwer Academic, DordrechtCrossRefGoogle Scholar
  28. Neale MC, Broker SM, Xie G, Maes HH (2006) Mx: statistical modeling, 7th edn. Department of Psychiatry, Virginia Commonwealth University, RichmondGoogle Scholar
  29. Neville CE, Murray LJ, Boreham CA, Gallagher AM, Twisk J, Robson PJ, Savage JM, Kemper HC, Ralston SH, Davey Smith G (2002) Relationship between physical activity and bone mineral status in young adults: the Northern Ireland Young Hearts Project. Bone 30(5):792–798PubMedCrossRefGoogle Scholar
  30. Nilsson E, Poulsen P, Sjogren M, Ling C, Ridderstrale M, Groop L, Vaag A (2007) Regulation of skeletal muscle PPAR{delta} mRNA expression in twins. J Physiol 584(Pt 3):1011–1017PubMedCentralPubMedCrossRefGoogle Scholar
  31. Pilegaard H, Saltin B, Neufer PD (2003) Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. J Physiol 546(Pt 3):851–858PubMedCentralPubMedCrossRefGoogle Scholar
  32. Plasqui G, Westerterp KR (2007) Physical activity assessment with accelerometers: an evaluation against doubly labeled water. Obesity 15(10):2371–2379. doi:10.1038/oby.2007.281 PubMedCrossRefGoogle Scholar
  33. Plasqui G, Joosen AM, Kester AD, Goris AH, Westerterp KR (2005) Measuring free-living energy expenditure and physical activity with triaxial accelerometry. Obes Res 13(8):1363–1369PubMedCrossRefGoogle Scholar
  34. Ravussin E, Swinburn BA (1992) Pathophysiology of obesity. Lancet 340(8816):404–408PubMedCrossRefGoogle Scholar
  35. Ridderstrale M, Johansson LE, Rastam L, Lindblad U (2006) Increased risk of obesity association with the variant allel of the PPARGC1A Gly482Ser polymorphism in physically inactive elderly men. Diabetologia 49(3):496–500Google Scholar
  36. Schieke SM, Phillips D, McCoy JP Jr, Aponte AM, Shen RF, Balaban RS, Finkel T (2006) The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem 281(37):27643–27652PubMedCrossRefGoogle Scholar
  37. Schoeller DA, Shay K, Kushner RF (1997) How much physical activity is needed to minimize weight gain in previously obese women? Am J Clin Nutr 66(3):551–556PubMedGoogle Scholar
  38. Scholtysek C, Katzenbeisser J, Fu H, Uderhardt S, Ipseiz N, Stoll C, Zaiss MM, Stock M, Donhauser L, Bohm C, Kleyer A, Hess A, Engelke K, David JP, Djouad F, Tuckermann JP, Desvergne B, Schett G, Kronke G (2013) PPARbeta/delta governs Wnt signaling and bone turnover. Nat Med 19(5):608–613. doi:10.1038/nm.3146 PubMedCrossRefGoogle Scholar
  39. Siri WE (1993) Body composition from fluid spaces and density: analysis of methods. Nutrition 9(5):480–491Google Scholar
  40. Stefan N, Thamer C, Staiger H, Machicao F, Machann J, Schick F, Venter C, Niess A, Laakso M, Fritsche A, Haring HU (2007) Genetic variations in PPARD and PPARGC1A determine mitochondrial function and change in aerobic physical fitness and insulin sensitivity during lifestyle intervention. J Clin Endocrinol Metab 92(5):1827–1833PubMedCrossRefGoogle Scholar
  41. Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68(4):978–989PubMedCentralPubMedCrossRefGoogle Scholar
  42. Tanaka T, Yamamoto J, Iwasaki S, Asaba H, Hamura H, Ikeda Y, Watanabe M, Magoori K, Ioka RX, Tachibana K, Watanabe Y, Uchiyama Y, Sumi K, Iguchi H, Ito S, Doi T, Hamakubo T, Naito M, Auwerx J, Yanagisawa M, Kodama T, Sakai J (2003) Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc Natl Acad Sci USA 100(26):15924–15929PubMedCentralPubMedCrossRefGoogle Scholar
  43. Tarnopolsky MA, Rennie CD, Robertshaw HA, Fedak-Tarnopolsky SN, Devries MC, Hamadeh MJ (2007) Influence of endurance exercise training and sex on intramyocellular lipid and mitochondrial ultrastructure, substrate use, and mitochondrial enzyme activity. Am J Physiol Regul Integr Comp Physiol 292(3):R1271–R1278PubMedCrossRefGoogle Scholar
  44. Tonkonogi M, Sahlin K (2002) Physical exercise and mitochondrial function in human skeletal muscle. Exerc Sport Sci Rev 30(3):129–137PubMedCrossRefGoogle Scholar
  45. Tudor-Locke C, Brashear MM, Johnson WD, Katzmarzyk PT (2010) Accelerometer profiles of physical activity and inactivity in normal weight, overweight and obese U.S. men and women. Int J Behav Nutr Phys Act 7:60. doi:10.1186/1479-5868-7-60 PubMedCentralPubMedCrossRefGoogle Scholar
  46. Visscher PM, Gordon S, Neale MC (2008) Power of the classical twin design revisited: II detection of common environmental variance. Twin Res Hum Genet 11(1):48–54PubMedCentralPubMedCrossRefGoogle Scholar
  47. Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H, Evans RM (2003) Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 113(2):159–170PubMedCrossRefGoogle Scholar
  48. Weinsier RL, Hunter GR, Heini AF, Goran MI, Sell SM (1998) The etiology of obesity: relative contribution of metabolic factors, diet, and physical activity. Am J Med 105(2):145–150PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • M. Gielen
    • 2
  • M. S. Westerterp-Plantenga
    • 1
  • F. G. Bouwman
    • 1
  • A. M. C. P. Joosen
    • 1
  • R. Vlietinck
    • 3
  • C. Derom
    • 3
  • M. P. Zeegers
    • 2
  • E. C. M. Mariman
    • 1
  • K. R. Westerterp
    • 1
  1. 1.Department of Human BiologyMaastricht University Medical CentreMaastrichtThe Netherlands
  2. 2.Department of Complex Genetics, Cluster of Genetics and Cell Biology and Nutrition and Toxicology Research Institute Maastricht (NUTRIM)Maastricht University Medical CentreMaastrichtThe Netherlands
  3. 3.Department for Human Genetics, Faculty of MedicineCatholic University of LeuvenLouvainBelgium

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