CBLL1 is hypomethylated and correlates with cortical thickness in transgender men before gender affirming hormone treatment

Abstract

Abstract Background:Gender identity refers to the consciousness of being a man, a woman or other condition. Generally, it is congruent with the sex assigned at birth; however, for some people, it is not. If the incongruity is distressing, it is defined as gender dysphoria (GD). Here, we measured whole-genome DNA methylation by the Illumina Infinium Human Methylation 850 array and report its correlation with cortical thickness (CTh) in 22 transgender men (TM) experiencing GD versus 25 cisgender men (CM) and 28 cisgender women (CW). Results: With respect to the methylation analysis, TM vs.CW showed significant differences in methylation in 35 CpG sites, while 2,155 CpG sites were found when TM and CM were compared. With respect to correlation analysis, TM showed differences in the methylation degree of CBLL1 and DLG1 genes that correlated with global and left hemisphere CTh. Both genes were hypomethylated in TM compared to the cisgender groups. These genes are involved in neuronal myelination and CBLL1modulates alpha estrogen receptor transactivation through competitive interference with the estrogen receptor coactivators SRC1 and SRC2. Early onset TM showed a positive correlation between CBLL1and several cortical regions. Methylation of CBLL1 positively correlated with CTh in the frontal (left caudal middle frontal), temporal (right inferior temporal, left fusiform) and parietal cortices (left supramarginal and right paracentral). Conclusions: This is the first study relating CBLL1 methylation with CTh in transgender persons and supports a neurodevelopmental hypothesis of gender identity.