自闭症谱系障碍和脑容量通过一组与 mTOR 相关的基因联系在一起。

Autism spectrum disorder and brain volume link through a set of mTOR-related genes.

机构信息

Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.

Department of Forensic and Neurodevelopmental Science, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

出版信息

J Child Psychol Psychiatry. 2023 Jul;64(7):1007-1014. doi: 10.1111/jcpp.13783. Epub 2023 Mar 15.

DOI:10.1111/jcpp.13783

Abstract

BACKGROUND

Larger than average head and brain sizes are often observed in individuals with autism spectrum disorders (ASDs). ASD and brain volume are both highly heritable, with multiple genetic variants contributing. However, it is unclear whether ASD and brain volume share any genetic mechanisms. Genes from the mammalian target of rapamycin (mTOR) pathway influence brain volume, and variants are found in rare genetic syndromes that include ASD features. Here we investigated whether variants in mTOR-related genes are also associated with ASD and if they constitute a genetic link between large brains and ASD.

METHODS

We extended our analyses between large heads (macrocephaly) and rare de novo mTOR-related variants in an intellectual disability cohort (N = 2,258). Subsequently using Fisher's exact tests we investigated the co-occurrence of mTOR-related de novo variants and ASD in the de-novo-db database (N = 23,098). We next selected common genetic variants within a set of 96 mTOR-related genes in genome-wide genetic association data of ASD (N = 46,350) to test gene-set association using MAGMA. Lastly, we tested genetic correlation between genome-wide genetic association data of ASD (N = 46,350) and intracranial volume (N = 25,974) globally using linkage disequilibrium score regression as well as mTOR specific by restricting the genetic correlation to the mTOR-related genes using GNOVA.

RESULTS

Our results show that both macrocephaly and ASD occur above chance level in individuals carrying rare de novo variants in mTOR-related genes. We found a significant mTOR gene-set association with ASD (p = .0029) and an mTOR-stratified positive genetic correlation between ASD and intracranial volume (p = .027), despite the absence of a significant genome-wide correlation (p = .81).

CONCLUSIONS

This work indicates that both rare and common variants in mTOR-related genes are associated with brain volume and ASD and genetically correlate them in the expected direction. We demonstrate that genes involved in mTOR signalling are potential mediators of the relationship between having a large brain and having ASD.

摘要

背景

在自闭症谱系障碍（ASD）患者中，经常观察到头部和大脑尺寸大于平均值。ASD 和脑容量都具有高度遗传性，多种遗传变异都有贡献。然而，尚不清楚 ASD 和脑容量是否具有任何遗传机制。雷帕霉素（mTOR）途径的基因影响脑容量，并且在包括 ASD 特征的罕见遗传综合征中发现了变体。在这里，我们研究了 mTOR 相关基因的变体是否也与 ASD 相关，以及它们是否构成大脑较大与 ASD 之间的遗传联系。

方法

我们在智力障碍队列（N=2258）中扩展了与大头（巨颅症）和罕见的 mTOR 相关新生变异相关的分析。随后，我们使用 Fisher 精确检验在 de-novo-db 数据库（N=23098）中研究了 mTOR 相关新生变异与 ASD 的共同发生。接下来，我们在 ASD 的全基因组遗传关联数据（N=46350）中选择了一组 96 个 mTOR 相关基因中的常见遗传变异，以使用 MAGMA 测试基因集关联。最后，我们使用连锁不平衡评分回归在 ASD 的全基因组遗传关联数据（N=46350）和颅内体积（N=25974）之间进行了全球遗传相关性测试，并且通过将遗传相关性限制在 mTOR 相关基因上来测试 mTOR 特定的遗传相关性使用 GNOVA。