Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom.
Front Endocrinol (Lausanne). 2023 May 8;14:1126036. doi: 10.3389/fendo.2023.1126036. eCollection 2023.
Autism likelihood is a largely heritable trait. Autism prevalence has a skewed sex ratio, with males being diagnosed more often than females. Steroid hormones play a mediating role in this, as indicated by studies of both prenatal biology and postnatal medical conditions in autistic men and women. It is currently unclear if the genetics of steroid regulation or production interact with the genetic liability for autism.
To address this, two studies were conducted using publicly available datasets, which focused respectively on rare genetic variants linked to autism and neurodevelopmental conditions (study 1) and common genetic variants (study 2) for autism. In Study 1 an enrichment analysis was conducted, between autism-related genes (SFARI database) and genes that are differentially expressed (FDR<0.1) between male and female placentas, in 1 trimester chorionic villi samples of viable pregnancies (n=39). In Study 2 summary statistics of genome wide association studies (GWAS) were used to investigate the genetic correlation between autism and bioactive testosterone, estradiol and postnatal PlGF levels, as well as steroid-related conditions such as polycystic ovaries syndrome (PCOS), age of menarche, and androgenic alopecia. Genetic correlation was calculated based on LD Score regression and results were corrected for multiple testing with FDR.
In Study 1, there was significant enrichment of X-linked autism genes in male-biased placental genes, independently of gene length (n=5 genes, p<0.001). In Study 2, common genetic variance associated with autism did not correlate to the genetics for the postnatal levels of testosterone, estradiol or PlGF, but was associated with the genotypes associated with early age of menarche in females (b=-0.109, FDR-q=0.004) and protection from androgenic alopecia for males (b=-0.135, FDR-q=0.007).
The rare genetic variants associated with autism appear to interact with placental sex differences, while the common genetic variants associated with autism appear to be involved in the regulation of steroid-related traits. These lines of evidence indicate that the likelihood for autism is partly linked to factors mediating physiological sex differences throughout development.
自闭症的可能性在很大程度上是遗传的。自闭症的患病率存在性别偏倚，男性的诊断率高于女性。甾体激素在这方面起着中介作用，这一点可以通过对自闭症男性和女性的产前生物学和产后医疗条件的研究来证明。目前尚不清楚甾体调节或产生的遗传学是否与自闭症的遗传易感性相互作用。
为了解决这个问题，我们进行了两项研究，使用了公开可用的数据集，分别侧重于与自闭症和神经发育状况相关的罕见遗传变异（研究 1）和与自闭症相关的常见遗传变异（研究 2）。在研究 1 中，我们对自闭症相关基因（SFARI 数据库）和男性和女性胎盘之间差异表达的基因（FDR<0.1）之间进行了富集分析，在可行妊娠的 1 个孕早期绒毛样本中（n=39）。在研究 2 中，我们使用全基因组关联研究（GWAS）的汇总统计数据，研究了自闭症与生物活性睾酮、雌二醇和产后 PlGF 水平以及与甾体相关的状况（如多囊卵巢综合征（PCOS）、初潮年龄和雄激素性脱发）之间的遗传相关性。基于 LD 得分回归计算了遗传相关性，并用 FDR 进行了多重检验校正。
在研究 1 中，X 连锁自闭症基因在男性偏倚胎盘基因中显著富集，独立于基因长度（n=5 个基因，p<0.001）。在研究 2 中，与自闭症相关的常见遗传变异与产后睾酮、雌二醇或 PlGF 的遗传无关，但与女性初潮年龄相关的基因型相关（b=-0.109，FDR-q=0.004），与男性雄激素性脱发的保护相关（b=-0.135，FDR-q=0.007）。
与自闭症相关的罕见遗传变异似乎与胎盘性别差异相互作用，而与自闭症相关的常见遗传变异似乎参与了甾体相关特征的调节。这些证据表明，自闭症的可能性部分与发育过程中调节生理性别差异的因素有关。
