Rare Genetic Variants of Cell Adhesion Molecules in Transgender Men Suggest a Potential Role in Gender Dysphoria

Introduction: Transgender identity is a complex and multifactorial condition shaped by the effects of environmental and cultural factors as well as its biological basis. Genes involved in neurodevelopment and neuroplasticity may contribute to brain sexual differentiation, and rare variants in these genes could play a role in gender diversity. This study aimed to enhance explanations for the genetic component of transgender identity.

After the filtering process applied to the WES analysis data obtained from eight transgender men (TM), the gene list was generated. Previously reported genes were scanned in the gene list with a detailed literature review and data mining. Functional enrichment, protein classification, pathway, and genetic interaction network analysis were performed to determine the salient genes.

A total of 30 variants were detected in 18 genes reported in the literature. The rs879121178 (GOLGA8J) variant, previously reported in 1 TW (transgender woman) and 1 TM, and the rs548940626 (PCDHA8) variant, previously reported in 1 TW, were present in two different individuals (individuals 5 and 6, respectively). In the functional enrichment analysis, the highest enrichment score in biological processes was detected in the cluster related to cell adhesion (enrichment score: 12.91) and the most enriched term was "homophilic cell adhesion via plasma membrane adhesion molecules" with 54 genes (p: 3.1E-11).

Our study shows that rare variants in cell adhesion genes, previously reported in TW, are also prominent in TM. These findings may help guide further investigations into genes that could be relevant to neurodevelopmental pathways, including those involved in brain sexual differentiation.