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There is strong evidence to show that men and women differ in terms of neurodevelopment, neurochemistry and susceptibility to neurodegenerative and neuropsychiatric disease. The molecular basis of these differences remains unclear. Progress in this field has been hampered by the lack of genome-wide information on sex differences in gene expression and in particular splicing in the human brain. Here we address this issue by using post-mortem adult human brain and spinal cord samples originating from 137 neuropathologically confirmed control individuals to study whole-genome gene expression and splicing in 12 CNS regions. We show that sex differences in gene expression and splicing are widespread in adult human brain, being detectable in all major brain regions and involving 2.5% of all expressed genes. We give examples of genes where sex-biased expression is both disease-relevant and likely to have functional consequences, and provide evidence suggesting that sex biases in expression may reflect sex-biased gene regulatory structures.
Understanding the molecular basis of observed sex differences in structure, neurochemistry, behaviour and susceptibility to disease is of obvious importance both to basic neurobiology and neuropathophysiology. However, the limited scope and power of existing studies make it difficult to place these discussions in a molecular context. The maximum number of adults investigated within any single study is 18, with only one study exploring sex-biased alternative splicing in a genome-wide manner. Furthermore, while the existence of sex-specific genetic architectures in humans has been postulated, genome-wide analyses of genetic variants associated with variation in gene expression in one sex, but not the other, have never been conducted in human brain.
To address these limitations, we analysed data from the UK Brain Expression Consortium (UKBEC). This data set is particularly valuable because (i) it is large with post-mortem samples originating from 137 neuropathologically confirmed control individuals, (ii) up to 12 central nervous system (CNS) regions have been sampled from each individual and (iii) transcriptome profiling was performed using the Affymetrix Human Exon 1.0 ST Array, which features 1.4 million probe sets assaying expression across each individual exon. In order to explore the possibility of sex-biased gene regulatory architectures we also conducted an expression quantitative trait loci (eQTL) analysis with the aim of finding significant interactions between sex and genotype. To maximize power, we used paired genotyping and gene-level expression data provided jointly by the North American Brain Expression Consortium and UKBEC. In this way this study provides unequivocal evidence that sex-biased gene expression in the adult human brain is widespread in terms of both the number of genes and range of brain regions involved. We also show that in some specific cases, molecular differences are likely to have functional consequences relevant to human disease and finally that sex biases in expression may reflect sex-biased gene regulatory structures.