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

M. Arenella; N.R. Mota; M.W.A. Teunissen; H.G. Brunner; J. Bralten

doi:10.1111/jcpp.13783

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

M. Arenella, N.R. Mota, M.W.A. Teunissen, H.G. Brunner, J. Bralten^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BackgroundLarger 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. MethodsWe 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. ResultsOur 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). ConclusionsThis 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.

Original language	English
Pages (from-to)	1007-1014
Number of pages	8
Journal	Journal of Child Psychology and Psychiatry
Volume	64
Issue number	7
Early online date	1 Mar 2023
DOIs	https://doi.org/10.1111/jcpp.13783
Publication status	Published - Jul 2023

Keywords

Autism spectrum disorders
genetics
brain volume
mammalian target of rapamycin
stratified genetic correlation
HEAD CIRCUMFERENCE
INDIVIDUALS
METABOLISM
GROWTH

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10.1111/jcpp.13783Licence: CC BY

Cite this

@article{16d2336fc95946eaa49186900a0649a4,

title = "Autism spectrum disorder and brain volume link through a set of mTOR-related genes",

abstract = "BackgroundLarger 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. MethodsWe 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. ResultsOur 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). ConclusionsThis 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.",

keywords = "Autism spectrum disorders, genetics, brain volume, mammalian target of rapamycin, stratified genetic correlation, HEAD CIRCUMFERENCE, INDIVIDUALS, METABOLISM, GROWTH",

author = "M. Arenella and N.R. Mota and M.W.A. Teunissen and H.G. Brunner and J. Bralten",

note = "Funding Information: This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No. 847879 (PRIME, Prevention and Remediation of Insulin Multimorbidity in Europe). This publication is part of the project {\textquoteleft}No labels needed: understanding psychiatric disorders based on genetic traits{\textquoteright} (with project number 09150161910091) of the research program Veni, which is partly financed by the Dutch Research Council (NWO) Health Research and Development (ZonMW). The analyses were carried out on the Dutch national e‐infrastructure, and it is part of the research program Computing Time National Computing Facilities Processing Round pilots 2018 with project No. 17666, which is (partly) financed by the Dutch Research Council (NWO). H.G.B. is in part supported by the Solve‐RD project that has received funding from European Community's Horizon 2020 research and innovation program under agreement No. 779257. R.N.M. is supported by European Community's Horizon 2020 program (H2020/2014‐2020) under agreement No. 667302 (CoCA) and by funding from the Dutch National Science Agenda NeurolabNL project (grant 400‐17‐602). For the local ID cohort, diagnostic WES was approved by the medical ethics committees of Radboudumc (Commissie Mensegebonden Onderzoek; registration number 2011‐188). Written informed consent was obtained from all the families. Other datasets used in the current manuscript are based on publicly available datasets. In de‐novo‐db all participants in each study provided written informed consents and agreed with the use of their data for research purposes. All the individuals included in the PGC, iPSYCH, ENIGMA, and CHARGE cohort samples provided written informed consent. The authors have declared that they have no competing or potential conflicts of interest. Key points Publisher Copyright: {\textcopyright} 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.",

year = "2023",

month = jul,

doi = "10.1111/jcpp.13783",

language = "English",

volume = "64",

pages = "1007--1014",

journal = "Journal of Child Psychology and Psychiatry",

issn = "0021-9630",

publisher = "Wiley",

number = "7",

}

TY - JOUR

T1 - Autism spectrum disorder and brain volume link through a set of mTOR-related genes

AU - Arenella, M.

AU - Mota, N.R.

AU - Teunissen, M.W.A.

AU - Brunner, H.G.

AU - Bralten, J.

N1 - Funding Information: This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No. 847879 (PRIME, Prevention and Remediation of Insulin Multimorbidity in Europe). This publication is part of the project ‘No labels needed: understanding psychiatric disorders based on genetic traits’ (with project number 09150161910091) of the research program Veni, which is partly financed by the Dutch Research Council (NWO) Health Research and Development (ZonMW). The analyses were carried out on the Dutch national e‐infrastructure, and it is part of the research program Computing Time National Computing Facilities Processing Round pilots 2018 with project No. 17666, which is (partly) financed by the Dutch Research Council (NWO). H.G.B. is in part supported by the Solve‐RD project that has received funding from European Community's Horizon 2020 research and innovation program under agreement No. 779257. R.N.M. is supported by European Community's Horizon 2020 program (H2020/2014‐2020) under agreement No. 667302 (CoCA) and by funding from the Dutch National Science Agenda NeurolabNL project (grant 400‐17‐602). For the local ID cohort, diagnostic WES was approved by the medical ethics committees of Radboudumc (Commissie Mensegebonden Onderzoek; registration number 2011‐188). Written informed consent was obtained from all the families. Other datasets used in the current manuscript are based on publicly available datasets. In de‐novo‐db all participants in each study provided written informed consents and agreed with the use of their data for research purposes. All the individuals included in the PGC, iPSYCH, ENIGMA, and CHARGE cohort samples provided written informed consent. The authors have declared that they have no competing or potential conflicts of interest. Key points Publisher Copyright: © 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.

PY - 2023/7

Y1 - 2023/7

N2 - BackgroundLarger 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. MethodsWe 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. ResultsOur 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). ConclusionsThis 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.

AB - BackgroundLarger 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. MethodsWe 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. ResultsOur 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). ConclusionsThis 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.

KW - Autism spectrum disorders

KW - genetics

KW - brain volume

KW - mammalian target of rapamycin

KW - stratified genetic correlation

KW - HEAD CIRCUMFERENCE

KW - INDIVIDUALS

KW - METABOLISM

KW - GROWTH

U2 - 10.1111/jcpp.13783

DO - 10.1111/jcpp.13783

M3 - Article

C2 - 36922714

SN - 0021-9630

VL - 64

SP - 1007

EP - 1014

JO - Journal of Child Psychology and Psychiatry

JF - Journal of Child Psychology and Psychiatry

IS - 7

ER -