Gui Yuanyuan, Zhou Geyu, Cui Shuya, Li Hongyu, Lu Hui, Zhao Hongyu
Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
Transl Psychiatry. 2025 Jan 22;15(1):17. doi: 10.1038/s41398-025-03223-8.
Brain anatomy plays a key role in complex behaviors and mental disorders that are sexually divergent. While our understanding of the sex differences in the brain anatomy remains relatively limited, particularly of the underlying genetic and molecular mechanisms that contribute to these differences. We performed the largest study of sex differences in brain volumes (N = 33,208) by examining sex differences both in the raw brain volumes and after controlling the whole brain volumes. Genetic correlation analysis revealed sex differences only in the left amygdala. We compared transcriptome differences between males and females using data from GTEx and characterized cell-type compositions using GTEx bulk amygdala RNA-seq data and LIBD amygdala single-cell reference profiles. We also constructed polygenic risk scores (PRS) to investigate sex-specific genetic correlations between left amygdala volume and mental disorders (N = 25,576~105,318) of Psychiatric Genomics Consortium and other traits of UKB (N = 347,996). Although there were pronounced sex differences in brain volumes, there was no difference in the heritability between sexes. There was a significant sex-specific genetic correlation between male and female left amygdala. We identified sex-differentiated genetic effects of PRSs for schizophrenia on left amygdala volume, as well as significant sex-differentiated genetic correlations between PRSs of left amygdala and six traits in UKB. We also found several sex-differentially expressed genes in the amygdala. These findings not only advanced the current knowledge of genetic basis of sex differences in brain anatomy, but also presented an important clue for future research on the mechanism of sex differences in mental disorders and targeted treatments.
脑解剖结构在具有性别差异的复杂行为和精神障碍中起着关键作用。虽然我们对脑解剖结构中的性别差异的理解仍然相对有限，尤其是对导致这些差异的潜在遗传和分子机制的理解。我们通过检查原始脑容量以及控制全脑容量后的性别差异，进行了关于脑容量性别差异的最大规模研究（N = 33208）。遗传相关性分析仅揭示了左侧杏仁核的性别差异。我们使用来自GTEx的数据比较了男性和女性之间的转录组差异，并使用GTEx杏仁核批量RNA测序数据和LIBD杏仁核单细胞参考图谱来表征细胞类型组成。我们还构建了多基因风险评分（PRS），以研究左侧杏仁核体积与精神基因组学联盟的精神障碍（N = 25576~105318）以及英国生物银行（UKB）的其他特征（N = 347996）之间的性别特异性遗传相关性。虽然脑容量存在明显的性别差异，但两性之间的遗传力没有差异。男性和女性左侧杏仁核之间存在显著的性别特异性遗传相关性。我们确定了精神分裂症的PRS对左侧杏仁核体积的性别分化遗传效应，以及左侧杏仁核的PRS与UKB中的六个特征之间的显著性别分化遗传相关性。我们还在杏仁核中发现了几个性别差异表达基因。这些发现不仅推进了目前对脑解剖结构性别差异遗传基础的认识，也为未来研究精神障碍性别差异机制和靶向治疗提供了重要线索。
