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

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.

Acute rapamycin treatment reveals novel mechanisms of behavioral, physiological, and functional dysfunction in a maternal inflammation mouse model of autism and sensory over-responsivity

“…This is thought to be related to the role of this important pathway in controlling cell growth, survival, energy balance, proliferation, autophagy, and ion channel expression. The mTOR pathway can become hyper-activated by several known mutations in ASD-associated genes such as PTEN, TSC1, TSC2, FMR1, Mecp2, DEPDC5, CACNA1C, UBE3A, and CNTNAP2 28,[60][61][62][63][64][65][66] . ASD behaviors, macrocephaly, and epilepsy have also been recapitulated in a variety of PTEN and TSC murine knockout models in different cellular populations, developmental timeframes, and quantity of gene deletion.…”

Editorial: What's in a name? Drawing on the examples of autism and schizophrenia, some reflections on diagnostic labels and their future role in child and adolescent psychiatry

“…Has using a single label (ASD) affected translational science, for example, by reducing the ability to address heterogeneity in ASD? In this issue, we see research on ASD being carried out in Arenella et al's study (Arenella, Mota, Teunissen, Brunner, & Bralten, 2023). The authors test whether variants in mTOR-related genes are associated with ASD and if these genetic variants in some part help to explain the previously reported link between large brain volume and ASD.…”

“…Their results suggest that genes involved in mTOR signalling make up part of the genetic relationship between larger brain volume and ASD. One of the challenges that Arenella et al (2023) comment on is the heterogeneity in ASD. As Arenella et al (2023) say in this issue, 'Heterogeneity at the phenotypic and etiological level in ASD make it difficult to pinpoint the underlying biological mechanisms and to make steps towards better targeted (i.e.…”

“…One of the challenges that Arenella et al (2023) comment on is the heterogeneity in ASD. As Arenella et al (2023) say in this issue, 'Heterogeneity at the phenotypic and etiological level in ASD make it difficult to pinpoint the underlying biological mechanisms and to make steps towards better targeted (i.e. personalised) treatment options' (Arenella et al, 2023).…”

“…As Arenella et al (2023) say in this issue, 'Heterogeneity at the phenotypic and etiological level in ASD make it difficult to pinpoint the underlying biological mechanisms and to make steps towards better targeted (i.e. personalised) treatment options' (Arenella et al, 2023). It is known that the DSM-IV subtypes also had heterogeneity within them, but the ASD category, since it involves just one category, potentially has less specificity than a DSM-IV subtype.…”