美国加州大学圣迭戈分校Jonathan Sebat研究组发现，自闭症的表型谱系可归因于罕见变体、多基因风险和性别的综合影响。相关论文于2022年6月2日在线发表在《自然—遗传学》杂志上。

据研究人员介绍，自闭症谱系障碍（ASD）的遗传病因是多因素的，但遗传因素的组合如何决定风险还不清楚。

在一个大的家族样本中，研究人员发现，罕见和多基因风险的遗传负荷在病例中呈反比，女性大于男性，这与不同性别的责任阈值相一致。新生突变（DNM）、罕见的遗传变异和多基因分数与儿童和父母的症状严重程度的不同方面有关。父母年龄对后代ASD风险的影响可归因于多种遗传机制，包括在父系生殖系中积累的DNM和影响父母行为的遗传风险。与普通变体牵连的基因相比，稀有变体牵连的基因在兴奋性和抑制性神经元中富集。

这些结果表明，ASD的表型谱系可归因于影响不同神经发育过程的一系列遗传因素。

附：英文原文

Title: A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex

Author: Antaki, Danny, Guevara, James, Maihofer, Adam X., Klein, Marieke, Gujral, Madhusudan, Grove, Jakob, Carey, Caitlin E., Hong, Oanh, Arranz, Maria J., Hervas, Amaia, Corsello, Christina, Vaux, Keith K., Muotri, Alysson R., Iakoucheva, Lilia M., Courchesne, Eric, Pierce, Karen, Gleeson, Joseph G., Robinson, Elise B., Nievergelt, Caroline M., Sebat, Jonathan

Issue&Volume: 2022-06-02

Abstract: The genetic etiology of autism spectrum disorder (ASD) is multifactorial, but how combinations of genetic factors determine risk is unclear. In a large family sample, we show that genetic loads of rare and polygenic risk are inversely correlated in cases and greater in females than in males, consistent with a liability threshold that differs by sex. De novo mutations (DNMs), rare inherited variants and polygenic scores were associated with various dimensions of symptom severity in children and parents. Parental age effects on risk for ASD in offspring were attributable to a combination of genetic mechanisms, including DNMs that accumulate in the paternal germline and inherited risk that influences behavior in parents. Genes implicated by rare variants were enriched in excitatory and inhibitory neurons compared with genes implicated by common variants. Our results suggest that a phenotypic spectrum of ASD is attributable to a spectrum of genetic factors that impact different neurodevelopmental processes. Integrated analyses in a large collection of families provide insights into the combined effects of rare variants and polygenic risk on autism spectrum disorder.

DOI: 10.1038/s41588-022-01064-5

Source: https://www.nature.com/articles/s41588-022-01064-5