AUTHOR=Luo Jia , Wang Weijing , Li Jingxian , Duan Haiping , Xu Chunsheng , Tian Xiaocao , Zhang Dongfeng 

TITLE=Epigenome-wide association study identifies DNA methylation loci associated with handgrip strength in Chinese monozygotic twins

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=12

YEAR=2024

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2024.1378680

DOI=10.3389/fcell.2024.1378680

ISSN=2296-634X

ABSTRACT=<p><bold>Background:</bold> The decline in muscle strength and function with aging is well recognized, but remains poorly characterized at the molecular level. Here, we report the epigenetic relationship between genome-wide DNA methylation and handgrip strength (HGS) among Chinese monozygotic (MZ) twins.</p><p><bold>Methods:</bold> DNA methylation (DNAm) profiling was conducted in whole blood samples through Reduced Representation Bisulfite Sequencing method. Generalized estimating equation was applied to regress the DNAm of each CpG with HGS. The Genomic Regions Enrichment of Annotations Tool was used to perform enrichment analysis. Differentially methylated regions (DMRs) were detected using <italic>comb-p</italic>. Causal inference was performed using Inference about Causation through Examination of Familial Confounding method. Finally, we validated candidate CpGs in community residents.</p><p><bold>Results:</bold> We identified 25 CpGs reaching genome-wide significance level. These CpGs located in 9 genes, especially <italic>FBLN1</italic>, <italic>RXRA</italic>, and <italic>ABHD14B</italic>. Many enriched terms highlighted calcium channels, neuromuscular junctions, and skeletal muscle organ development. We identified 21 DMRs of HGS, with several DMRs within <italic>FBLN1</italic>, <italic>SLC30A8</italic>, <italic>CST3</italic>, and <italic>SOCS3</italic>. Causal inference indicated that the DNAm of 16 top CpGs within <italic>FBLN1</italic>, <italic>RXRA</italic>, <italic>ABHD14B</italic>, <italic>MFSD6</italic>, and <italic>TYW1B</italic> might influence HGS, while HGS influenced DNAm at two CpGs within <italic>FBLN1</italic> and <italic>RXRA</italic>. In validation analysis, methylation levels of six CpGs mapped to <italic>FLBN1</italic> and one CpG mapped to <italic>ABHD14B</italic> were negatively associated with HGS weakness in community population.</p><p><bold>Conclusion:</bold> Our study identified multiple DNAm variants potentially related to HGS, especially CpGs within <italic>FBLN1</italic> and <italic>ABHD14B</italic>. These findings provide new clues to the epigenetic modification underlying muscle strength decline.</p>