Abstract
Hand grip strength (GS) is a predictor of mortality in older adults and is moderately to highly heritable, but no genetic variants have been consistently identified. We aimed to identify single nucleotide polymorphisms (SNPs) associated with GS in middle-aged to older adults using a genome-wide association study (GWAS). GS was measured using handheld dynamometry in community-dwelling men and women aged 55–85 from the Hunter Community Study (HCS, N = 2088) and the Sydney Memory and Ageing Study (Sydney MAS, N = 541). Genotyping was undertaken using Affymetrix microarrays with imputation to HapMap2. Analyses were performed using linear regression. No genome-wide significant results were observed in HCS nor were any of the top signals replicated in Sydney MAS. Gene-based analyses in HCS identified two significant genes (ZNF295, C2CD2), but these results were not replicated in Sydney MAS. One out of eight SNPs previously associated with GS, rs550942, located near the CNTF gene, was significantly associated with GS (p = 0.005) in the HCS cohort only. Study differences may explain the lack of consistent results between the studies, including the smaller sample size of the Sydney MAS cohort. Our modest sample size also had limited power to identify variants of small effect. Our results suggest that similar to various other complex traits, many genetic variants of small effect size may influence GS. Future GWAS using larger samples and consistent measures may prove more fruitful at identifying genetic contributors for GS in middle-aged to older adults.
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References
Alfred T et al (2012) A multi-cohort study of polymorphisms in the GH/IGF axis and physical capability: the HALCyon programme. PLoS One 7:e29883. doi:10.1371/journal.pone.0029883
Arking DE et al (2006) Variation in the ciliary neurotrophic factor gene and muscle strength in older Caucasian women. J Am Geriatr Soc 54:823–826. doi:10.1111/j.1532-5415.2006.00693.x
Aulchenko Y, Struchalin M, van Duijn C (2010) ProbABEL package for genome-wide association analysis of imputed data. BMC Bioinforma 11:134
Bailey JN, Pericak-Vance MA, Haines JL (2014) The impact of the human genome project on complex disease. Genes 5:518–535. doi:10.3390/genes5030518
Barsh GS, Copenhaver GP, Gibson G, Williams SM (2012) Guidelines for genome-wide association studies. PLoS Genet 8:e1002812. doi:10.1371/journal.pgen.1002812
Carmelli D, Reed T (2000) Stability and change in genetic and environmental influences on hand-grip strength in older male twins. J Appl Physiol (Bethesda, Md: 1985) 89:1879–1883
Cesari M et al (2012) Biomarkers of sarcopenia in clinical trials-recommendations from the International Working Group on Sarcopenia. J Cachex Sarcopenia Muscle 3:181–190. doi:10.1007/s13539-012-0078-2
Crocco P, Montesanto A, Passarino G, Rose G (2011) A common polymorphism in the UCP3 promoter influences hand grip strength in elderly people. Biogerontology 12:265–271. doi:10.1007/s10522-011-9321-z
Dato S, Krabbe KS, Thinggaard M, Pedersen BK, Christensen K, Bruunsgaard H, Christiansen L (2010) Commonly studied polymorphisms in inflammatory cytokine genes show only minor effects on mortality and related risk factors in nonagenarians. J Gerontol A Biol Sci Med Sci 65:225–235. doi:10.1093/gerona/glp210
Dato S, Montesanto A, Lagani V, Jeune B, Christensen K, Passarino G (2012a) Frailty phenotypes in the elderly based on cluster analysis: a longitudinal study of two Danish cohorts. Evidence for a genetic influence on frailty. Age (Dordr) 34:571–582. doi:10.1007/s11357-011-9257-x
Dato S, Soerensen M, Montesanto A, Lagani V, Passarino G, Christensen K, Christiansen L (2012b) UCP3 polymorphisms, hand grip performance and survival at old age: association analysis in two Danish middle aged and elderly cohorts. Mech Ageing Dev 133:530–537. doi:10.1016/j.mad.2012.06.004
Dayem Ullah AZ, Lemoine NR, Chelala C (2013) A practical guide for the functional annotation of genetic variations using SNPnexus. Brief Bioinform 14:437–447. doi:10.1093/bib/bbt004
Deelen J, Beekman M, Capri M, Franceschi C, Slagboom PE (2013) Identifying the genomic determinants of aging and longevity in human population studies: progress and challenges. Bioessays 35:386–396
Estrada K et al (2009) A genome-wide association study of northwestern Europeans involves the C-type natriuretic peptide signaling pathway in the etiology of human height variation. Hum Mol Genet 18:3516–3524. doi:10.1093/hmg/ddp296
Finkel D, Pedersen NL, Reynolds CA, Berg S, de Faire U, Svartengren M (2003) Genetic and environmental influences on decline in biobehavioral markers of aging. Behav Genet 33:107–123
Frederiksen H, Gaist D, Petersen HC, Hjelmborg J, McGue M, Vaupel JW, Christensen K (2002) Hand grip strength: a phenotype suitable for identifying genetic variants affecting mid- and late-life physical functioning. Genet Epidemiol 23:110–122. doi:10.1002/gepi.1127
Frederiksen H, Hjelmborg J, Mortensen J, McGue M, Vaupel JW, Christensen K (2006) Age trajectories of grip strength: cross-sectional and longitudinal data among 8,342 Danes aged 46 to 102. Ann Epidemiol 16:554–562. doi:10.1016/j.annepidem.2005.10.006
Global Lipids Genetics C et al (2013) Discovery and refinement of loci associated with lipid levels. Nat Genet 45:1274–1283. doi:10.1038/ng.2797
Gogarten SM et al (2012) GWASTools: an R/Bioconductor package for quality control and analysis of genome-wide association studies. Bioinformatics 28:3329–3331. doi:10.1093/bioinformatics/bts610
Guillet C, Auguste P, Mayo W, Kreher P, Gascan H (1999) Ciliary neurotrophic factor is a regulator of muscular strength in aging. J Neurosci 19:1257–1262
Li Y, Willer C, Sanna S, Abecasis G (2009) Genotype imputation. Annu Rev Genomics Hum Genet 10:387–406. doi:10.1146/annurev.genom.9.081307.164242
Li Y, Willer CJ, Ding J, Scheet P, Abecasis GR (2010) MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 34:816–834. doi:10.1002/gepi.20533
Liu JZ et al (2010) A versatile gene-based test for genome-wide association studies. Am J Hum Genet 87:139–145. doi:10.1016/j.ajhg.2010.06.009
Matteini AM et al (2010) Heritability estimates of endophenotypes of long and health life: the Long Life Family Study. J Gerontol A Biol Sci Med Sci 65:1375–1379. doi:10.1093/gerona/glq154
McDonald ML et al (2014) Common genetic variants associated with resting oxygenation in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 51:678–687. doi:10.1165/rcmb.2014-0135OC
McEvoy M et al (2010) Cohort profile: the Hunter Community Study. Int J Epidemiol 39:1452–1463. doi:10.1093/ije/dyp343
Murabito JM, Yuan R, Lunetta KL (2012) The search for longevity and healthy aging genes: insights from epidemiological studies and samples of long-lived individuals. J Gerontol A Biol Sci Med Sci 67:470–479. doi:10.1093/gerona/gls089
Neale BM, Sham PC (2004) The future of association studies: gene-based analysis and replication. Am J Hum Genet 75:353–362. doi:10.1086/423901
Reed T, Fabsitz RR, Selby JV, Carmelli D (1991) Genetic influences and grip strength norms in the NHLBI twin study males aged 59-69. Ann Hum Biol 18:425–432
Ribom EL, Mellstrom D, Ljunggren O, Karlsson MK (2011) Population-based reference values of handgrip strength and functional tests of muscle strength and balance in men aged 70-80 years. Arch Gerontol Geriatr 53:e114–e117. doi:10.1016/j.archger.2010.07.005
Roth SM et al (2001) CNTF genotype is associated with muscular strength and quality in humans across the adult age span. J Appl Physiol (1985) 90:1205–1210
Sachdev PS et al (2010) The Sydney Memory and Ageing Study (MAS): methodology and baseline medical and neuropsychiatric characteristics of an elderly epidemiological non-demented cohort of Australians aged 70-90 years. Int Psychogeriatr 22:1248–1264. doi:10.1017/s1041610210001067
Sayer AA et al (2002) Polymorphism of the IGF2 gene, birth weight and grip strength in adult men. Age Ageing 31:468–470
Semba RD et al (2012) Relationship of low plasma klotho with poor grip strength in older community-dwelling adults: the InCHIANTI study. Eur J Appl Physiol 112:1215–1220. doi:10.1007/s00421-011-2072-3
Stenholm S, Tiainen K, Rantanen T, Sainio P, Heliovaara M, Impivaara O, Koskinen S (2012) Long-term determinants of muscle strength decline: prospective evidence from the 22-year mini-Finland follow-up survey. J Am Geriatr Soc 60:77–85. doi:10.1111/j.1532-5415.2011.03779.x
Taekema DG, Gussekloo J, Maier AB, Westendorp RGJ, de Craen AJM (2010) Handgrip strength as a predictor of functional, psychological and social health. A prospective population-based study among the oldest old. Age Ageing 39:331–337. doi:10.1093/ageing/afq022
United Nations (2002) World Population Ageing: 1950-2050. United Nations Department of Economic and Social Affairs: Population Division. http://www.un.org/esa/population/publications/worldageing19502050/index.htm. Accessed 2 Oct 2013
Werle S, Goldhahn J, Drerup S, Simmen BR, Sprott H, Herren DB (2009) Age- and gender-specific normative data of grip and pinch strength in a healthy adult Swiss population. J Hand Surg Eur 34:76–84. doi:10.1177/1753193408096763
Willer CJ, Li Y, Abecasis GR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26:2190–2191. doi:10.1093/bioinformatics/btq340
Yoshihara A et al (2009) Physical function is weakly associated with angiotensin-converting enzyme gene I/D polymorphism in elderly Japanese subjects. Gerontology 55:387–392. doi:10.1159/000222429
Acknowledgments
We would like to acknowledge and thank the HCS and Sydney MAS participants, their supporters and their research teams. This work was supported by various agencies. Sydney MAS is supported by the Australian National Health and Medical Research Council (NHMRC) Program Grants 350833 and 568969. For Sydney MAS, DNA was extracted by Genetic Repositories Australia, an Enabling Facility supported by the NHMRC Grant 401184. The HCS is supported by the University of Newcastle, the Gladys M Brawn Senior Research Fellowship Scheme and the Fairfax Family Foundation. Henry Brodaty is partly supported by the NHMRC-funded Dementia Collaborative Research Centre at the University of New South Wales. Nicola Armstrong is supported by the NHMRC Project Grant 525453, and Karen Mather is supported by an Alzheimer’s Australia Dementia Research Foundation Postdoctoral Fellowship and NHMRC Capacity Building Grant 568940. Amelia Assareh was supported by a PhD scholarship from the Dementia Collaborative Research Centre, UNSW. Elizabeth Holliday is supported by the Australian Heart Foundation and National Stroke Foundation (100071).
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Chan, J.P.L., Thalamuthu, A., Oldmeadow, C. et al. Genetics of hand grip strength in mid to late life. AGE 37, 3 (2015). https://doi.org/10.1007/s11357-015-9745-5
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DOI: https://doi.org/10.1007/s11357-015-9745-5