Fass Stuart B, Mulvey Bernard, Yang Wei, Selmanovic Din, Chaturvedi Sneha, Tycksen Eric, Weiss Lauren A, Dougherty Joseph D
Department of Genetics, Washington University School of Medicine, 660 S. Euclid Ave, Saint Louis MO, 63110, USA.
Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave, Saint Louis MO, 63110, USA.
medRxiv. 2023 Sep 1:2023.08.29.23294773. doi: 10.1101/2023.08.29.23294773.
Sex differences in the brain may play an important role in sex-differential prevalence of neuropsychiatric conditions. In order to understand the transcriptional basis of sex differences, we analyzed multiple, large-scale, human postmortem brain RNA-seq datasets using both within-region and pan-regional frameworks. We find evidence of sex-biased transcription in many autosomal genes, some of which provide evidence for pathways and cell population differences between chromosomally male and female individuals. These analyses also highlight regional differences in the extent of sex-differential gene expression. We observe an increase in specific neuronal transcripts in male brains and an increase in immune and glial function-related transcripts in female brains. Integration with single-cell data suggests this corresponds to sex differences in cellular states rather than cell abundance. Integration with case-control gene expression studies suggests a female molecular predisposition towards Alzheimer's disease, a female-biased disease. Autism, a male-biased diagnosis, does not exhibit a male predisposition pattern in our analysis. Finally, we provide region specific analyses of sex differences in brain gene expression to enable additional studies at the interface of gene expression and diagnostic differences.
大脑中的性别差异可能在神经精神疾病的性别差异患病率中起重要作用。为了了解性别差异的转录基础，我们使用区域内和全区域框架分析了多个大规模的人类死后大脑RNA测序数据集。我们在许多常染色体基因中发现了性别偏向转录的证据，其中一些为染色体上男性和女性个体之间的通路和细胞群体差异提供了证据。这些分析还突出了性别差异基因表达程度的区域差异。我们观察到男性大脑中特定神经元转录本增加，女性大脑中免疫和神经胶质功能相关转录本增加。与单细胞数据的整合表明，这对应于细胞状态的性别差异而非细胞丰度的差异。与病例对照基因表达研究的整合表明，女性在阿尔茨海默病（一种女性偏向性疾病）方面存在分子易感性。自闭症是一种男性偏向性诊断，在我们的分析中未表现出男性易感性模式。最后，我们提供了大脑基因表达性别差异的区域特异性分析，以便在基因表达与诊断差异的交叉领域开展更多研究。
