ABSTRACT
Epidemiological studies have demonstrated that the genetic factors partly influence the development of same-sex sexual behavior, but most genetic studies have focused on people of primarily European ancestry, potentially missing important biological insights. Here, we performed a two-stage genome-wide association study (GWAS) with a total sample of 1478 homosexual males and 3313 heterosexual males in Han Chinese populations and identified two genetic loci (rs17320865, Xq27.3, FMR1NB, Pmeta = 8.36 × 10-8, OR = 1.29; rs7259428, 19q12, ZNF536, Pmeta = 7.58 × 10-8, OR = 0.75) showing consistent association with male sexual orientation. A fixed-effect meta-analysis including individuals of Han Chinese (n = 4791) and European ancestries (n = 408,995) revealed 3 genome-wide significant loci of same-sex sexual behavior (rs9677294, 2p22.1, SLC8A1, Pmeta = 1.95 × 10-8; rs2414487, 15q21.3, LOC145783, Pmeta = 4.53 × 10-9; rs2106525, 7q31.1, MDFIC, Pmeta = 6.24 × 10-9). These findings may provide new insights into the genetic basis of male sexual orientation from a wider population scope. Furthermore, we defined the average ZNF536-immunoreactivity (ZNF536-ir) concentration in the suprachiasmatic nucleus (SCN) as lower in homosexual individuals than in heterosexual individuals (0.011 ± 0.001 vs 0.021 ± 0.004, P = 0.013) in a postmortem study. In addition, compared with heterosexuals, the percentage of ZNF536 stained area in the SCN was also smaller in the homosexuals (0.075 ± 0.040 vs 0.137 ± 0.103, P = 0.043). More homosexual preference was observed in FMR1NB-knockout mice and we also found significant differences in the expression of serotonin, dopamine, and inflammation pathways that were reported to be related to sexual orientation when comparing CRISPR-mediated FMR1NB knockout mice to matched wild-type target C57 male mice.
ABSTRACT
BACKGROUND: Sexual orientation has been suggested to affect executive function, of which the neurobiological basis is still largely unknown. In this study, we explored the interrelationship between neuropsychological characteristics in homosexual and heterosexual men and their anatomical connectome by graph theoretical analysis. METHODS: Fifty-three homosexual and 47 heterosexual males underwent diffusion tensor magnetic resonance imaging (MRI) and neuropsychological assessments. Whole-brain anatomical networks were constructed using white matter tractography, performed on the diffusion tensor imaging data. Neuropsychological tests included the Wisconsin Card Sorting Test (WCST), the Continuous Performance Test (CPT) and the Trail-Making Test (TMT). RESULTS: The cognitive performance of homosexual men was significantly poorer than their heterosexual counterparts in terms of WCST total correct responses. Anatomical connectome analysis revealed a lower (P=0.001) anatomical connectivity between left PoCG and left SMG (P=0.003) in homosexual men as compared to heterosexual men. Linear regression analyses showed that the WCST total correct responses score was significantly linked with sexual orientation (P=0.001). The anatomical connectivity strength between left PoCG and left SMG was also shown to be significantly correlated with sexual orientation (P=0.039) and education (P=0.047). CONCLUSIONS: Our study demonstrated the differences in the performance of WCST and anatomical connectome of large-scale brain networks between homosexual and heterosexual men, extending our understanding of the brain's circuitry and the characteristics of executive function in men of different sexual orientation.
