Genetic evidence of gender difference in autism spectrum disorder supports the female-protective effect.,Translational Psychiatry

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Genetic evidence of gender difference in autism spectrum disorder supports the female-protective effect.
Translational Psychiatry ( IF 5.8 ) Pub Date : 2020-01-15 , DOI: 10.1038/s41398-020-0699-8
Yi Zhang _{1,

2} , Na Li ₁ , Chao Li ₁ , Ze Zhang ₁ , Huajing Teng ₃ , Yan Wang ₃ , Tingting Zhao ₁ , Leisheng Shi _{1,

4} , Kun Zhang ₁ , Kun Xia ₅ , Jinchen Li _{2,

5} , Zhongsheng Sun _{1,

3}

Affiliation

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a male-to-female prevalence of 4:1. However, the genetic mechanisms underlying this gender difference remain unclear. Mutation burden analysis, a TADA model, and co-expression and functional network analyses were performed on de novo mutations (DNMs) and corresponding candidate genes. We found that the prevalence of putative functional DNMs (loss-of-function and predicted deleterious missense mutations) in females was significantly higher than that in males, suggesting that a higher genetic load was required in females to reach the threshold for a diagnosis. We then prioritized 174 candidate genes, including 60 shared genes, 91 male-specific genes, and 23 female-specific genes. All of the three subclasses of candidate genes were significantly more frequently co-expressed in female brains than male brains, suggesting that compensation effects of the deficiency of ASD candidate genes may be more likely in females. Nevertheless, the three subclasses of candidate genes were co-expressed with each other, suggesting a convergent functional network of male and female-specific genes. Our analysis of different aspects of genetic components provides suggestive evidence supporting the female-protective effect in ASD. Moreover, further study is needed to integrate neuronal and hormonal data to elucidate the underlying gender difference in ASD.

中文翻译：

自闭症谱系中性别差异的遗传证据支持女性保护作用。

自闭症谱系障碍（ASD）是一种复杂的神经发育障碍，男女患病率为4：1。但是，这种性别差异的遗传机制仍不清楚。对突变基因（DNM）和相应的候选基因进行了突变负担分析，TADA模型以及共表达和功能网络分析。我们发现，女性中假定的功能性DNM（功能缺失和预测的有害错义突变）的患病率明显高于男性，这表明女性需要更高的遗传负荷才能达到诊断的阈值。然后，我们对174个候选基因进行了优先排序，包括60个共有基因，91个雄性特异性基因和23个雌性特异性基因。候选基因的所有三个亚类在女性大脑中的共表达显着高于男性大脑，这表明ASD候选基因缺乏的补偿效应在女性中的可能性更大。然而，候选基因的三个亚类彼此共表达，表明雄性和雌性特异性基因的融合功能网络。我们对遗传成分不同方面的分析提供了支持ASD中女性保护作用的提示性证据。此外，还需要进一步研究以整合神经元和激素数据，以阐明ASD中潜在的性别差异。候选基因的三个亚类彼此共表达，表明雄性和雌性特异性基因的融合功能网络。我们对遗传成分不同方面的分析提供了支持ASD中女性保护作用的提示性证据。此外，还需要进一步研究以整合神经元和激素数据，以阐明ASD中潜在的性别差异。候选基因的三个亚类彼此共表达，表明雄性和雌性特异性基因的融合功能网络。我们对遗传成分不同方面的分析提供了支持ASD中女性保护作用的提示性证据。此外，还需要进一步研究以整合神经元和激素数据，以阐明ASD中潜在的性别差异。

更新日期：2020-01-15

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