Abstract
Handgrip strength is a crucial indicator to monitor the change of cognitive function over time, but its mechanism still needs to be further explored. We sampled 59 monozygotic twin pairs to explore the potential mediating effect of DNA methylation (DNAm) on the association between handgrip strength and cognitive function. The initial step was the implementation of an epigenome-wide association analysis (EWAS) in the study participants, with the aim of identifying DNAm variations that are associated with handgrip strength. Following that, we conducted an assessment of the mediated effect of DNAm by the use of mediation analysis. In order to do an ontology enrichment study for CpGs, the GREAT program was used. There was a significant positive association between handgrip strength and cognitive function (β = 0.194, P < 0.001). The association between handgrip strength and DNAm of 124 CpGs was found to be statistically significant at a significance level of P < 1 × 10−4. Fifteen differentially methylated regions (DMRs) related to handgrip strength were found in genes such as SNTG2, KLB, CDH11, and PANX2. Of the 124 CpGs, 4 within KRBA1, and TRAK1 mediated the association between handgrip strength and cognitive function: each 1 kg increase in handgrip strength was associated with a potential decrease of 0.050 points in cognitive function scores, mediated by modifications in DNAm. The parallel mediating effect of these 4 CpGs was −0.081. The presence of DNAm variation associated with handgrip strength may play a mediated role in the association between handgrip strength and cognitive function.
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References
Kabayama M, Mikami H, Kamide K. Factors associated with risk for assisted living among community-dwelling older Japanese. Arch Gerontol Geriatr. 2016;65:63–9.
Chang K-V, Hsu T-H, Wu W-T, Huang K-C, Han D-S. Association between sarcopenia and cognitive impairment: a systematic review and meta-analysis. J Am Med Dir Assoc. 2016;17:1164.e7–1164.e15.
Prince M, Wimo A, Guerchet M, Ali G-C, Wu Y-T, Prina M. World Alzheimer report 2015. The global impact of dementia: an analysis of prevalence, incidence, cost and trends: Alzheimer’s Disease International; 2015.
Gharbi-Meliani A, Dugravot A, Sabia S, Regy M, Fayosse A, Schnitzler A, et al. The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study. Alzheimers Res Ther. 2021;13:5.
Kaivola K, Chia R, Ding J, Rasheed M, Fujita M, Menon V, et al. Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias. Cell Genom. 2023;3:100316.
Sorrentino F, Fenoglio C, Sacchi L, Serpente M, Arighi A, Carandini T, et al. Klotho gene expression is decreased in peripheral blood mononuclear cells in patients with Alzheimer’s disease and frontotemporal dementia. J Alzheimers Dis. 2023;94:1225–31.
Xu Y, Sun Z, Jonaitis E, Deming Y, Lu Q, Johnson SC, et al. Apolipoprotein E moderates the association between non-APOE polygenic risk score for Alzheimer’s disease and aging on preclinical cognitive function. Alzheimers Dement. 2024;20:1063–75.
Fritz NE, McCarthy CJ, Adamo DE. Handgrip strength as a means of monitoring progression of cognitive decline - A scoping review. Ageing Res Rev. 2017;35:112–23.
Liu J, Zhang T, Luo J, Chen S, Zhang D. Association between sleep duration and grip strength in U.S. Older Adults: An NHANES analysis (2011-2014). Int J Environ Res Public Health. 2023;20:3416.
Luo J, Yao W, Zhang T, Ge H, Zhang D. Exploring the bidirectional associations between handgrip strength and depression in middle and older Americans. J Psychosom Res. 2021;152:110678.
Radavelli-Bagatini S, Macpherson H, Scott D, Daly RM, Hodgson JM, Laws SM, et al. Impaired muscle function, including its decline, is related to greater long-term late-life dementia risk in older women. J Cachexia Sarcopenia Muscle. 2023;14:1508–19.
Duchowny KA, Ackley SF, Brenowitz WD, Wang J, Zimmerman SC, Caunca MR, et al. Associations between handgrip strength and dementia risk, cognition, and neuroimaging outcomes in the UK Biobank cohort study. JAMA Netw Open. 2022;5:e2218314.
Jia S, Zhao W, Ge M, Zhou L, Sun X, Zhao Y, et al. Association of handgrip strength weakness and asymmetry with incidence of motoric cognitive risk syndrome in the China Health and retirement longitudinal study. Neurology. 2023;100:e2342–e9.
McGrath R, Robinson-Lane SG, Cook S, Clark BC, Herrmann S, O’Connor ML, et al. HanDGRIP STRENGTH IS ASSOCIATED WITH POORER COGNITIVE FUNCTIONING IN AGing Americans. J Alzheimers Dis. 2019;70:1187–96.
Rijk JM, Roos PR, Deckx L, van den Akker M, Buntinx F. Prognostic value of handgrip strength in people aged 60 years and older: a systematic review and meta-analysis. Geriatr Gerontol Int. 2016;16:5–20.
Weaver JD, Huang MH, Albert M, Harris T, Rowe JW, Seeman TE. Interleukin-6 and risk of cognitive decline: MacArthur studies of successful aging. Neurology. 2002;59:371–8.
Raji MA, Kuo Y-F, Snih SA, Markides KS, Peek MK, Ottenbacher KJ. Cognitive status, muscle strength, and subsequent disability in older Mexican Americans. J Am Geriatr Soc. 2005;53:1462–8.
Alece Arantes Moreno I, Rodrigues de Oliveira D, Ribeiro Borçoi A, Fungaro Rissatti L, Vitorino Freitas F, Arantes LMRB, et al. Methylation of BDNF gene in association with episodic memory in women. Front Neurosci. 2023;17:1092406.
Di Francesco A, Arosio B, Falconi A, Micioni Di Bonaventura MV, Karimi M, Mari D, et al. Global changes in DNA methylation in Alzheimer’s disease peripheral blood mononuclear cells. Brain Behav Immun. 2015;45:139–44.
Peterson MD, Collins S, Meier HCS, Brahmsteadt A, Faul JD. Grip strength is inversely associated with DNA methylation age acceleration. J Cachexia Sarcopenia Muscle. 2023;14:108–15.
Li W, Christiansen L, Hjelmborg J, Baumbach J, Tan Q. On the power of epigenome-wide association studies using a disease-discordant twin design. Bioinformatics. 2018;34:4073–8.
Tan Q, Christiansen L, von Bornemann Hjelmborg J, Christensen K. Twin methodology in epigenetic studies. J Exp Biol. 2015;218:134–9.
Duan H, Ning F, Zhang D, Wang S, Zhang D, Tan Q, et al. The Qingdao twin registry: a status update. Twin Res Hum Genet. 2013;16:79–85.
Chen K-L, Xu Y, Chu A-Q, Ding D, Liang X-N, Nasreddine ZS, et al. Validation of the Chinese version of montreal cognitive assessment basic for screening mild cognitive impairment. J Am Geriatr Soc. 2016;64:e285–e90.
Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, et al. The montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53:695–9.
Peavy GM, Jenkins CW, Little EA, Gigliotti C, Calcetas A, Edland SD, et al. Community memory screening as a strategy for recruiting older adults into Alzheimer’s disease research. Alzheimers Res Ther. 2020;12:78.
Krueger F, Andrews SR. Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications. Bioinformatics. 2011;27:1571–2.
Hebestreit K, Dugas M, Klein H-U. Detection of significantly differentially methylated regions in targeted bisulfite sequencing data. Bioinformatics. 2013;29:1647–53.
Jaffe AE, Irizarry RA. Accounting for cellular heterogeneity is critical in epigenome-wide association studies. Genome Biol. 2014;15:R31.
Rahmani E, Zaitlen N, Baran Y, Eng C, Hu D, Galanter J, et al. Sparse PCA corrects for cell type heterogeneity in epigenome-wide association studies. Nat Methods. 2016;13:443–5.
Millstein J, Zhang B, Zhu J, Schadt EE. Disentangling molecular relationships with a causal inference test. BMC Genet. 2009;10:23.
Tingley D, Yamamoto T, Hirose K, Keele L, Imai K. Mediation: R package for causal mediation analysis. J Stat Softw. 2014;59:1–38.
Pedersen BS, Schwartz DA, Yang IV, Kechris KJ. Comb-p: software for combining, analyzing, grouping and correcting spatially correlated P-values. Bioinformatics. 2012;28:2986–8.
Wang W, Li W, Jiang W, Lin H, Wu Y, Wen Y, et al. Genome-wide DNA methylation analysis of cognitive function in middle and old-aged Chinese monozygotic twins. J Psychiatr Res. 2021;136:571–80.
Wang W, Li W, Wu Y, Tian X, Duan H, Li S, et al. Genome-wide DNA methylation and gene expression analyses in monozygotic twins identify potential biomarkers of depression. Transl Psychiatry. 2021;11:416.
McLean CY, Bristor D, Hiller M, Clarke SL, Schaar BT, Lowe CB, et al. GREAT improves functional interpretation of cis-regulatory regions. Nat Biotechnol. 2010;28:495–501.
Wang W, Li W, Duan H, Xu C, Tian X, Li S, et al. Mediation by DNA methylation on the association of BMI and serum uric acid in Chinese monozygotic twins. Gene. 2023;850:146957.
Wang W, Yao J, Li W, Wu Y, Duan H, Xu C, et al. Epigenome-wide association study in Chinese monozygotic twins identifies DNA methylation loci associated with blood pressure. Clin Epigenetics. 2023;15:38.
Moon JY, Choi SJ, Heo CH, Kim HM, Kim HS. α-Syntrophin stabilizes catalase to reduce endogenous reactive oxygen species levels during myoblast differentiation. FEBS J. 2017;284:2052–65.
Galmés S, Rupérez AI, Sánchez J, Moreno LA, Foraita R, Hebestreit A, et al. KLB and NOX4 expression levels as potential blood-based transcriptional biomarkers of physical activity in children. Sci Rep. 2023;13:5563.
Chen X, Xiang H, Yu S, Lu Y, Wu T. Research progress in the role and mechanism of Cadherin-11 in different diseases. J Cancer. 2021;12:1190–9.
Alexander J, Kalev O, Mehrabian S, Traykov L, Raycheva M, Kanakis D, et al. Familial early-onset dementia with complex neuropathologic phenotype and genomic background. Neurobiol Aging. 2016;42:199–204.
Samim Khan S, Janrao S, Srivastava S, Bala Singh S, Vora L, Kumar Khatri D. GSK-3β: An exuberating neuroinflammatory mediator in Parkinson’s disease. Biochem Pharmacol. 2023;210:115496.
Barel O, Malicdan MCV, Ben-Zeev B, Kandel J, Pri-Chen H, Stephen J, et al. Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy. Brain. 2017;140:568–81.
MacKinnon D. Introduction to Statistical Mediation Analysis (1st ed.). Routledge.
MacKinnon DP, Krull JL, Lockwood CM. Equivalence of the mediation, confounding and suppression effect. Prev Sci. 2000;1:173–81.
MacKinnon DP, Lockwood CM, Hoffman JM, West SG, Sheets V. A comparison of methods to test mediation and other intervening variable effects. Psychol Methods. 2002;7:83–104.
Shrout PE, Bolger N. Mediation in experimental and nonexperimental studies: new procedures and recommendations. Psychol Methods. 2002;7:422–45.
Wang Y, Tzeng J-Y, Huang Y, Maguire R, Hoyo C, Allen TK. Duration of exposure to epidural anesthesia at delivery, DNA methylation in umbilical cord blood and their association with offspring asthma in Non-Hispanic Black women. Environ Epigenet. 2023;9:dvac026.
Briollais L, Rustand D, Allard C, Wu Y, Xu J, Rajan SG, et al. DNA methylation mediates the association between breastfeeding and early-life growth trajectories. Clin Epigenetics. 2021;13:231.
Euclydes VLV, Gastaldi VD, Feltrin AS, Hoffman DJ, Gouveia G, Cogo H, et al. DNA methylation mediates a randomized controlled trial home-visiting intervention during pregnancy and the Bayley infant’s cognitive scores at 12 months of age. J Dev Orig Health Dis. 2022;13:556–65.
Luo J. Heritability and genome-wide association study of handgrip strength and lower limb motor function in twins [Master]: Qingdao University; 2023.
Xu C, Zhang D, Wu Y, Tian X, Pang Z, Li S, et al. A genome-wide association study of cognitive function in Chinese adult twins. Biogerontology. 2017;18:811–9.
Samson MM, Meeuwsen IB, Crowe A, Dessens JA, Duursma SA, Verhaar HJ. Relationships between physical performance measures, age, height and body weight in healthy adults. Age Ageing. 2000;29:235–42.
Suo J, Shen X, He J, Sun H, Shi Y, He R, et al. Exploring cognitive trajectories and their association with physical performance: evidence from the China Health and Retirement Longitudinal Study. Epidemiol Health. 2023;45:e2023064.
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10038_2024_1247_MOESM4_ESM.tif
The bar chart of top 50 GREAT ontology enrichments potentially related to handgrip strength for CpGs (P-value < 0.05) in Model 2 by using binomial test
10038_2024_1247_MOESM5_ESM.tif
The bar chart of GREAT ontology enrichments potentially related to cognitive function for candidate CpG mediators by using binomial test in Model 3
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Liu, J., Wang, W., Luo, J. et al. Mediation role of DNA methylation in association between handgrip strength and cognitive function in monozygotic twins. J Hum Genet (2024). https://doi.org/10.1038/s10038-024-01247-4
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DOI: https://doi.org/10.1038/s10038-024-01247-4