{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:12:33Z","timestamp":1772169153701,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.21305.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T00:00:00Z","timestamp":1745971200000}}],"reference-count":33,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T00:00:00Z","timestamp":1745971200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000925","name":"John Templeton Foundation","doi-asserted-by":"publisher","award":["61917"],"award-info":[{"award-number":["61917"]}],"id":[{"id":"10.13039\/100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000925","name":"John Templeton Foundation","doi-asserted-by":"publisher","award":["60828"],"award-info":[{"award-number":["60828"]}],"id":[{"id":"10.13039\/100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["217065"],"award-info":[{"award-number":["217065"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["060984"],"award-info":[{"award-number":["060984"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Medical Research Council"}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns7:p>Background The FRAXE site on the X-chromosome has a variable number of trinucleotide repeats. The rare condition Fragile XE has &gt;200 repeats, but most X chromosomes have &lt;60 such repeats, with evidence of a bimodal distribution. It is known that when the number of repeats is &lt;60, the repeat number can increase from mother to son, which raises the question as to whether there is an evolutionary advantage in the increased size of these repeats. This paper investigates whether the higher of the &lt;60 repeats are associated with neurocognitive differences among boys in a general population. We hypothesised that although there was previous evidence of a link between higher numbers of repeats in the boys in this population having maternal grandmothers with schizophrenia, there may be cognitive or behavioural advantages to their grandsons of increased levels of repeats. Methods We compared 1951 behavioural, psychiatric, and cognitive outcomes of 5060 boys from the Avon Longitudinal Study of Parents and Children (ALSPAC) using a phenome scan. Results We found that boys with relatively high levels of repeats (&gt;24) had a higher risk of certain neurocognitive outcomes (P&lt;0.01). Boys with &gt;24 repeats were more likely to report: (a) psychosis-like experiences; (b) increased ability to recognise facial signs of anger; (c) increased risk of eating disorders; (d) increased likelihood of smoking cigarettes and using illicit drugs during adolescence than would be expected by chance. There was no sign of associations with cognitive abilities. Conclusions We concluded that there was little evidence that higher levels of the normal range of FRAXE repeats were associated with a difference in cognitive abilities, but there was evidence of increased reports of psychotic-like experiences and other behaviour problems in this group. There was no evidence of evolutionary neurocognitive advantage.<\/ns7:p>","DOI":"10.12688\/wellcomeopenres.21305.2","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T07:15:10Z","timestamp":1745997310000},"page":"238","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Behavioural, psychiatric, and cognitive phenotypes associated with numbers of repeats of the FRAXE allele on the FMR2 gene"],"prefix":"10.12688","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2826-3307","authenticated-orcid":false,"given":"Jean","family":"Golding","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcus E.","family":"Pembrey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1247-4636","authenticated-orcid":false,"given":"Rosie","family":"Clark","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9965-9133","authenticated-orcid":false,"given":"Yasmin","family":"Iles-Caven","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1529-9338","authenticated-orcid":false,"given":"Steven","family":"Gregory","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3103-9330","authenticated-orcid":false,"given":"Susan M.","family":"Ring","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Ennis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Suderman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2025,4,30]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"1126-35","DOI":"10.1016\/j.dnarep.2006.05.010","article-title":"Common fragile sites as targets for chromosome rearrangements.","volume":"5","author":"M Arlt","year":"2006","journal-title":"DNA Repair (Amst)."},{"key":"ref-2","article-title":"U.S. Patent No. 6,309,821.","author":"J Au-Young","year":"2001"},{"key":"ref-3","doi-asserted-by":"publisher","DOI":"10.1332\/9781447340423","article-title":"Pioneering ethics in a longitudinal study.","author":"K Birmingham","year":"2018"},{"key":"ref-4","doi-asserted-by":"publisher","first-page":"111-27","DOI":"10.1093\/ije\/dys064","article-title":"Cohort profile: the \u2018children of the 90s\u2019--the index offspring of the Avon Longitudinal Study of Parents and Children.","volume":"42","author":"A Boyd","year":"2013","journal-title":"Int J Epidemiol."},{"key":"ref-5","doi-asserted-by":"publisher","first-page":"116","DOI":"10.12688\/wellcomeopenres.15342.2","article-title":"The FRAXA and FRAXE allele repeat size of boys from the Avon Longitudinal Study of Parents and Children (ALSPAC) [version 2; 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Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-238\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-238\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-238\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T07:55:09Z","timestamp":1753257309000},"score":1,"resource":{"primary":{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-238\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,30]]},"references-count":33,"URL":"https:\/\/doi.org\/10.12688\/wellcomeopenres.21305.2","relation":{"has-version":[{"id-type":"doi","id":"10.12688\/wellcomeopenres.21305.1","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.21956\/wellcomeopenres.25480.r123577","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.25480.r125809","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.25480.r125809","asserted-by":"object"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.25480.r123577","asserted-by":"object"}]},"ISSN":["2398-502X"],"issn-type":[{"value":"2398-502X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,30]]},"assertion":[{"value":"Indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-238\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.23565.r83713, Paul J Hagerman, University of California, Davis, CA, 95616, 30 May 2024, version 1, 2 approved with reservations","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-238\/v1#referee-response-83713","order":0,"name":"referee-response-83713","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Yasmin Iles-Caven<\/b>; \n<i>Posted: 16 Sep 2024<\/i>; The authors presented an analysis of the relationship between the number of GCC repeats in the3 range &lt;60 and various neurocognitive and behavioral phenotypes, largely developed through surveys. The authors had speculated that the apparent instability in mother-to-son transmission, with increasing GCC repeat number in the offspring, might reflect an evolutionary advantage. However, they saw no cognitive benefit, and noted that the larger repeats were associated with several disadvantageous neurocognitive traits. The results are intriguing, although the basis for the observed associations is not known. This study should provide a stimulus for follow-on investigations with additional cohorts. \n<b>Response:&nbsp;<\/b>\n<b>Thank you for pointing out the way in which these results should provide a stimulus for analyses using other cohort studies. As we have now made clearer, this is likely to be the only way in which statistical certainty can be achieved.<\/b>  The authors should describe how they corrected their measures of significance for multiple outcomes, since they are looking at a very large set of measures. \n<b>Response:&nbsp;We have added a paragraph in the introduction to emphasise that the study is expected to find pleiotropic effects rather than a single outcome. This makes it difficult to choose a sensible cut-point for a P value cut-point such as Bonferroni, which is basically concentrated on a single outcome. The most feasible way of strengthening the findings is by testing them in other large populations We have emphasised that in the revised Abstract and in the Conclusions. <\/b>  The authors speak of the possibility of an evolutionary advantage of having a larger number of GCC repeats, but the study would not appear to be able to address that issue. First, if the population of GCC repeats is in equilibrium, then their data in Figure 1, suggests that there is a relative disadvantage of having a larger repeat (ext. &lt; 10% with alleles &gt; 24 repeats), with any net drive (instability) to larger repeats counterbalance by some disadvantage(s). Second, whether or not there is some advantage to the individual of having the larger number of repeats, how might that translate to increased fitness? \n<b>Response: The possibility of an evolutionary advantage was suggested from the observations, in other studies, that the inheritance of the X chromosome from mother to son tended to be accompanied by an increase in the number of FRAXE repeats. This raised the question as to why that happened \u2013 and the hypothesis that the increase might convey some evolutionary advantage. We investigated this hypothesis with respect to neurocognitive traits and observed no sign of an advantage, but rather a decided disadvantage. We have not, at this stage, tested the hypothesis in other areas such as biological markers. This is mentioned in the Discussion section.<\/b>","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-238\/v2#referee-comment-5810","order":1,"name":"referee-comment-5810","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.23565.r86731, Marsha R Mailick, Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, 03 Jul 2024, version 1, 2 approved with reservations","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-238\/v1#referee-response-86731","order":2,"name":"referee-response-86731","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Yasmin Iles-Caven<\/b>; \n<i>Posted: 16 Sep 2024<\/i>; \n<b>Thank you for the suggestion of using a Bonferroni type method to reduce the large number of associations. We have now pointed out in the paper the dangers of this approach in that one is likely to make both Type I and Type II errors. It is also important to note that such an approach fails to consider the likelihood of pleiotropic effects, which we have now emphasised. Ideally, these findings will in future be tested in other large populations.<\/b>  Very few studies have focused on phenotypic variations associated with repeat numbers below clinical thresholds, and the present study potentially would open the door to this type of investigation, especially if some approach to data reduction would be employed. \n<b>We did consider data reduction to avoid strong collinearity between traits. However, we decided against it as any observed associations would be difficult to interpret. We hope that our study will indeed open the door to similar studies in other populations in which replication of our findings can be investigated.<\/b>","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-238\/v2#referee-comment-5811","order":3,"name":"referee-comment-5811","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.25480.r123577, Chioma N. P. Mbachu, Nnamdi Azikiwe University, Nnewi, Anambra, 03 Jun 2025, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-238\/v2#referee-response-123577","order":4,"name":"referee-response-123577","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.25480.r125809, Kayla Smith, University of Warwick, Coventry, England, 23 Jul 2025, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/9-238\/v2#referee-response-125809","order":5,"name":"referee-response-125809","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The identification of the FRAXE repeats was supported by Wellcome [060984, awarded to Professor Patricia Jacobs]. The UK Medical Research Council and Wellcome [217065] and the University of Bristol currently provide core support for ALSPAC. A comprehensive list of grant funding for ALSPAC is available on the ALSPAC website (http:\/\/www.bristol.ac.uk\/alspac\/external\/documents\/grant-acknowledgements.pdf. The final cleaning and writing of this paper was undertaken using funds from the John Templeton Foundation [60828 and 61917].","order":6,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}