Werling Donna M, Parikshak Neelroop N, Geschwind Daniel H
Center for Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
Nat Commun. 2016 Feb 19;7:10717. doi: 10.1038/ncomms10717.
Autism spectrum disorder (ASD) is more prevalent in males, and the mechanisms behind this sex-differential risk are not fully understood. Two competing, but not mutually exclusive, hypotheses are that ASD risk genes are sex-differentially regulated, or alternatively, that they interact with characteristic sexually dimorphic pathways. Here we characterized sexually dimorphic gene expression in multiple data sets from neurotypical adult and prenatal human neocortical tissue, and evaluated ASD risk genes for evidence of sex-biased expression. We find no evidence for systematic sex-differential expression of ASD risk genes. Instead, we observe that genes expressed at higher levels in males are significantly enriched for genes upregulated in post-mortem autistic brain, including astrocyte and microglia markers. This suggests that it is not sex-differential regulation of ASD risk genes, but rather naturally occurring sexually dimorphic processes, potentially including neuron-glial interactions, that modulate the impact of risk variants and contribute to the sex-skewed prevalence of ASD.
自闭症谱系障碍（ASD）在男性中更为普遍，而这种性别差异风险背后的机制尚未完全了解。有两种相互竞争但并非相互排斥的假说：一是ASD风险基因存在性别差异调控，二是它们与具有特征性的性二态性通路相互作用。在这里，我们对来自神经典型的成年和产前人类新皮质组织的多个数据集中的性二态性基因表达进行了表征，并评估了ASD风险基因是否存在性别偏向性表达的证据。我们没有发现ASD风险基因存在系统性性别差异表达的证据。相反，我们观察到在男性中高表达的基因显著富集了在死后自闭症大脑中上调的基因，包括星形胶质细胞和小胶质细胞标记物。这表明，调节风险变异的影响并导致ASD性别偏向患病率的，不是ASD风险基因的性别差异调控，而是自然发生的性二态性过程，可能包括神经元-胶质细胞相互作用。
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