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

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 in androgen receptor (AR), the TA repeat in estrogen receptor 1 (ESR1), the CA repeat in estrogen receptor 2 (ESR2), the TTTA repeat in cytochrome P450 family 19 subfamily A member 1 (CYP19), and the T>C SNP in cytochrome P450 family 17 subfamily A member 1 (CYP17). Pooled estimates indicated that transgender women have a significant overrepresentation of short ESR1 alleles 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.