Autism spectrum disorder and brain volume link through a set of mTOR ‐related genes
Bibliographic Data
| ID | 21344242 |
|---|---|
| Authors | Martina Arenella (0000-0002-7216-5758, Department of Human Genetics Radboud university medical center Nijmegen The Netherlands), Nina Roth Mota (0000-0003-3504-759X, Radboud University Nijmegen), Mariel W A Teunissen (Department of Human Genetics Radboud university medical center Nijmegen The Netherlands), Han G Brunner (0000-0001-9274-8865, Department of Human Genetics Radboud university medical center Nijmegen The Netherlands), Janita Bralten (0000-0003-1440-8675, Department of Human Genetics Radboud university medical center Nijmegen The Netherlands, corresponding author) |
| Year | 2023 |
| Volume | 64 |
| Issue | 7 |
| Pages | 1007-1014 |
| Publication date | 2023-07-01 |
| Open Access | Yes |
| Type | ARTICLE |
| Venue | Journal of Child Psychology and Psychiatry (JOURNAL) |
| Journal identifiers | ISSN: 0021-9630 • E-ISSN: 1469-7610 |
| Publisher | Wiley (PUBLISHER • GB) |
| DOI | 10.1111/jcpp.13783 |
| PMID | 36922714 |
| OpenAlex | W4327612757 |
| Language | EN |
| References cited | 43 |
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
Autism · Autism spectrum disorder · Biology · Brain size · Developmental psychology · Gene · Link (geometry) · Magnetic resonance imaging · PI3K/AKT/mTOR pathway · Psychiatry · Set (abstract data type) · Signal transduction · Autism Spectrum Disorder Research · Genetics · Genetics and Neurodevelopmental Disorders · Genomics and Rare Diseases · Medicine · Neuroscience · Psychology
| Highly cited | No |
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