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Mediation role of DNA methylation in association between handgrip strength and cognitive function in monozygotic twins

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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Correspondence to Dongfeng Zhang.

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This study followed the Helsinki Declaration and was approved by the Regional Ethics Committee of the Institutional Review Committee of Qingdao CDC.

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Supplementary information

The top five components from ReFACTor method

The results of epigenome-wide association analysis on handgrip strength (P < 1×10-4)

The CpGs significantly associated with cognitive functon(P < 0.05)

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 69, 357–363 (2024). https://doi.org/10.1038/s10038-024-01247-4

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