Genetic Association Studies in Transgender Cohorts: A Systematic Review and Meta-Analysis

Abstract

According to twin studies, there is a heritable contribution to gender incongruence, but the genetic mechanisms of this are unknown. Recent efforts to identify an aetiology of gender incongruence have focused on the hypothesis that sex hormones establish gender identity through influencing the development of neuroanatomy. Candidate gene studies that have sought to elucidate whether polymorphisms in sex steroidogenesis genes are overrepresented in transgender populations have been equivocal. A systematic search for case-control genetic association studies in transgender populations was conducted. Mean (+SD) or allele frequencies were extracted and combined quantitatively in random effects meta-analysis, summarised as standardised mean difference for continuous alleles or odds ratios for allele frequencies. Eight studies were included in the analysis. These studies spanned polymorphisms in five genes; the CAG repeat inandrogen receptor, the TA repeat inestrogen receptor alpha, the CA repeat inestrogen receptor beta, the TTTA repeat inCYP19,and the T>C SNP inCYP17. Pooled estimates indicated that transgender women have a significant overrepresentation of shortESR1alleles compared to cisgender men (OR = 1.23, 95% CI: 1.06, 1.44, p = 0.0089). This may contribute an increased likelihood of developing gender incongruence amongst natal males. Future investigations into gender incongruence should use genome-wide methods.

The Origins of Gender, not Sex: Evolution and the Reproductive Axis

“…No single marker or gene thoroughly explains gender identity (Ashley & Harley, 2023); therefore, pre-or postnatal screening is not currently helpful. Research on candidate genes for transgenderism is limited by the scarcity of studies and factors such as the absence of controls for age, ethnicity, and selection biases (Ashley & Harley, 2023).…”