PMID- 36922714
OWN - NLM
STAT- MEDLINE
DCOM- 20230609
LR  - 20230611
IS  - 1469-7610 (Electronic)
IS  - 0021-9630 (Linking)
VI  - 64
IP  - 7
DP  - 2023 Jul
TI  - Autism spectrum disorder and brain volume link through a set of mTOR-related 
      genes.
PG  - 1007-1014
LID - 10.1111/jcpp.13783 [doi]
AB  - 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.
CI  - (c) 2023 The Authors. Journal of Child Psychology and Psychiatry published by John 
      Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.
FAU - Arenella, Martina
AU  - Arenella M
AD  - Department of Human Genetics, Radboud university medical center, Nijmegen, The 
      Netherlands.
AD  - Department of Forensic and Neurodevelopmental Science, Institute of Psychiatry, 
      Psychology and Neuroscience, King's College London, London, UK.
AD  - Donders Institute for Brain, Cognition and Behaviour, Radboud University, 
      Nijmegen, The Netherlands.
FAU - Mota, Nina R
AU  - Mota NR
AD  - Department of Human Genetics, Radboud university medical center, Nijmegen, The 
      Netherlands.
AD  - Donders Institute for Brain, Cognition and Behaviour, Radboud University, 
      Nijmegen, The Netherlands.
FAU - Teunissen, Mariel W A
AU  - Teunissen MWA
AD  - Department of Human Genetics, Radboud university medical center, Nijmegen, The 
      Netherlands.
AD  - Department of Neurology, Maastricht University Medical Centre, Maastricht, The 
      Netherlands.
FAU - Brunner, Han G
AU  - Brunner HG
AD  - Department of Human Genetics, Radboud university medical center, Nijmegen, The 
      Netherlands.
AD  - Department of Clinical Genetics, Maastricht University Medical Centre, 
      Maastricht, The Netherlands.
AD  - GROW School of Development and Oncology, MHENS School of Neuroscience, Maastricht 
      University, Maastricht, The Netherlands.
FAU - Bralten, Janita
AU  - Bralten J
AD  - Department of Human Genetics, Radboud university medical center, Nijmegen, The 
      Netherlands.
AD  - Donders Institute for Brain, Cognition and Behaviour, Radboud University, 
      Nijmegen, The Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230315
PL  - England
TA  - J Child Psychol Psychiatry
JT  - Journal of child psychology and psychiatry, and allied disciplines
JID - 0375361
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Humans
MH  - *Autism Spectrum Disorder/genetics
MH  - Brain
MH  - *Intellectual Disability
MH  - TOR Serine-Threonine Kinases/genetics
MH  - Genetic Predisposition to Disease
OTO - NOTNLM
OT  - Autism spectrum disorders
OT  - brain volume
OT  - genetics
OT  - mammalian target of rapamycin
OT  - stratified genetic correlation
EDAT- 2023/03/17 06:00
MHDA- 2023/06/09 06:42
CRDT- 2023/03/16 01:13
PHST- 2023/02/06 00:00 [accepted]
PHST- 2023/06/09 06:42 [medline]
PHST- 2023/03/17 06:00 [pubmed]
PHST- 2023/03/16 01:13 [entrez]
AID - 10.1111/jcpp.13783 [doi]
PST - ppublish
SO  - J Child Psychol Psychiatry. 2023 Jul;64(7):1007-1014. doi: 10.1111/jcpp.13783. 
      Epub 2023 Mar 15.