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Discovery of new genetic loci for male sexual orientation in Han population

Research group Swaab
Publication year 2021
Published in Cell discovery
Authors S.H. Hu, Hai-Mei Li, Hao Yu, Yan Liu, Chen-Xing Liu, Xian-Bo Zuo, Jing Lu, Jiajun Jiang, Cai-Xi Xi, Bochao Huang, Hu-Ji Xu, Jian-Bo Hu, Jian-Bo Lai, Manli Huang, Jian-Ning Liu, Dan-Ge Xu, Xi-Chao Guo, Zuo-Wei Wu, Xin Wu, Lei Jiang, Meng Li, Guang-Ping Zhang, Jin-Wen Huang, Ning Wei, Wen Lv, Jin-Feng Duan, Hong-Li Qi, Chan-Chan Hu, Jing-Kai Chen, Wei-Hua Zhou, Wei-Juan Xu, Chen-Feng Liu, Hai-Yong Liang, Jing Du, Shu-Fa Zheng, Qiao-Ling Lu, Lin Zheng, Xiao-Wei Hu, Feng-Xiang Chen, Peng Chen, Biao Zhu, Li-Jun Xu, Zhi-Min Ni, Ye-Zhen Fang, Zuo-Kai Yang, Xin-Ren Shan, En-de Zheng, Qi Fan Zhang, Qing-Qing Zhou, Yi Rao, D.F. Swaab, Wei-Hua Yue, Yi Xu

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.

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