Bidirectional Mediation of Cognition by DNA Methylation and Lean Body Mass in Chinese Monozygotic Twins

This study explores whether DNA methylation (DNAm) mediates the association between lean body mass (LBM) and cognition, as well as whether LBM mediates the association between DNAm and cognition. Based on the data of 59 monozygotic twin pairs, mediation analyses were performed using causal inference test method and mediation analyses. Average causal mediation effect (ACME), average direct effect (ADE), and total effect (TE) were calculated. Among the CpGs associated with LBM, five located within <i>PDGFRB</i> and <i>RP11</i> genes (ACME: -0.0972-0.0463, |ACME/ADE|: 10.44%-18.30%) negatively mediated the association between LBM and cognition, while one in the <i>PAX2</i> gene (ACME: 0.3510, |ACME/TE|: 11.84%) positively mediated the association. Besides, the methylation risk score (MRS) of <i>RP11</i> gene (ACME: -0.0517, |ACME/ADE|: 10.64%) and MRS of all CpGs (ACME: -0.0511, |ACME/ADE|: 10.53%) negatively mediated the association of LBM with cognition. For another, LBM negatively mediated the association between the DNAm level of one CpG within <i>UBXN6</i> and cognition (ACME: -0.0732, |ACME/TE|: 20.78%), while positively mediated the association between the DNAm level of four CpGs within <i>FOXI2</i> and cognition (ACME: 0.2812-0.4496, |ACME/TE|: 18.15%-27.29%). It was found the DNAm in <i>PDGFRB</i>, <i>RP11</i> and <i>PAX2</i> partially mediates the association between LBM and cognition, and the association between DNAm in <i>UBXN6</i> and <i>FOXI2</i> with cognition is also partially mediated by LBM.