{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T06:22:18Z","timestamp":1781763738897,"version":"3.54.5"},"reference-count":44,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T00:00:00Z","timestamp":1678838400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["667302"],"award-info":[{"award-number":["667302"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["779257"],"award-info":[{"award-number":["779257"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["847879"],"award-info":[{"award-number":["847879"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["09150161910091"],"award-info":[{"award-number":["09150161910091"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["17666"],"award-info":[{"award-number":["17666"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acamh.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Child Psychology Psychiatry"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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\u2010related genes are also associated with ASD and if they constitute a genetic link between large brains and ASD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We extended our analyses between large heads (macrocephaly) and rare de novo mTOR\u2010related variants in an intellectual disability cohort (\n                      <jats:italic>N<\/jats:italic>\n                      \u00a0=\u00a02,258). Subsequently using Fisher's exact tests we investigated the co\u2010occurrence of mTOR\u2010related de novo variants and ASD in the\n                      <jats:italic>de\u2010novo\u2010db<\/jats:italic>\n                      database (\n                      <jats:italic>N<\/jats:italic>\n                      \u00a0=\u00a023,098). We next selected common genetic variants within a set of 96 mTOR\u2010related genes in genome\u2010wide genetic association data of ASD (\n                      <jats:italic>N<\/jats:italic>\n                      \u00a0=\u00a046,350) to test gene\u2010set association using MAGMA. Lastly, we tested genetic correlation between genome\u2010wide genetic association data of ASD (\n                      <jats:italic>N<\/jats:italic>\n                      \u00a0=\u00a046,350) and intracranial volume (\n                      <jats:italic>N<\/jats:italic>\n                      \u00a0=\u00a025,974) globally using linkage disequilibrium score regression as well as mTOR specific by restricting the genetic correlation to the mTOR\u2010related genes using GNOVA.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our results show that both macrocephaly and ASD occur above chance level in individuals carrying rare de novo variants in mTOR\u2010related genes. We found a significant mTOR gene\u2010set association with ASD (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a0.0029) and an mTOR\u2010stratified positive genetic correlation between ASD and intracranial volume (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a0.027), despite the absence of a significant genome\u2010wide correlation (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a0.81).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This work indicates that both rare and common variants in mTOR\u2010related 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/jcpp.13783","type":"journal-article","created":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T01:05:06Z","timestamp":1678928706000},"page":"1007-1014","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Autism spectrum disorder and brain volume link through a set of\n                    <scp>mTOR<\/scp>\n                    \u2010related genes"],"prefix":"10.1111","volume":"64","author":[{"given":"Martina","family":"Arenella","sequence":"first","affiliation":[{"name":"Department of Human Genetics Radboud university medical center  Nijmegen The Netherlands"},{"name":"Department of Forensic and Neurodevelopmental Science Institute of Psychiatry, Psychology and Neuroscience, King's College London  London UK"},{"name":"Donders Institute for Brain, Cognition and Behaviour Radboud University  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina R.","family":"Mota","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Radboud university medical center  Nijmegen The Netherlands"},{"name":"Donders Institute for Brain, Cognition and Behaviour Radboud University  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariel W. A.","family":"Teunissen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Radboud university medical center  Nijmegen The Netherlands"},{"name":"Department of Neurology Maastricht University Medical Centre  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han G.","family":"Brunner","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Radboud university medical center  Nijmegen The Netherlands"},{"name":"Department of Clinical Genetics Maastricht University Medical Centre  Maastricht The Netherlands"},{"name":"GROW School of Development and Oncology, MHENS School of Neuroscience Maastricht University  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janita","family":"Bralten","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Radboud university medical center  Nijmegen The Netherlands"},{"name":"Donders Institute for Brain, 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