W66. NEUROBIOLOGICAL CORRELATES OF MALE SEXUAL ORIENTATION

The causal factors related to human sexual orientation have remained largely unknown. In several countries, homosexuality has been considered as a degenerative cultural phenomenon and is prohibited under threat of death penalty. Homosexual individuals face discrimination and have substantially higher risk of suicide and mental disorders than heterosexual individuals. We studied the gene and protein expression phenotype in induced pluripotent stem cell (iPSC)- derived cortical neurons, corresponding to maturity at the late first trimester, among Finnish homosexual men (N=6), heterosexual men (N=6), and heterosexual women (N=5). Homosexual orientation was strongly linked to down-regulation of HHIP, GLI1, and several histone genes, and up-regulation of ZP3, FIRRE, miR-206, and miR-199a-5p. The findings were associated with DNA methylation and transcriptional repression, sonic hedgehog, and IL-33 signaling pathways. Among the most significant DEPs between homosexual and heterosexual men were downregulated collagen genes (COL8A1, COL6A1, and COL18A1), which were also enriched in the top GO and IPA pathways. Upregulated proteins found in homosexual men were related to neuronal firing (GNAO1), plasticity (CAMK2A), synapse modulation (SULT4A1), and dendrite development (ACTL6B), which could indicate improved neuronal maturation. The most significant DEP was NEDD4 Like E3 Ubiquitin Protein Ligase (NEDD4L) belonging to the ubiquitination machinery, which was upregulated in homosexual men compared to heterosexual men. The miRNA expression pattern and proteomics results indicate enhanced neuronal differentiation in homosexual men. Our findings suggest that sexual orientation is associated with the differential expression of genes coding for histone modification, left-right asymmetry, extracellular matrix modulation and X chromosome inactivation, as well as accelerated neuronal maturation, indicated by proteomic results. The results suggest that male homosexuality is a neurobiological phenotype of which correlates are present already during pregnancy. Elucidating the causal mechanism of homosexuality may help to reduce stigma and discrimination against sexual minorities.