The link between autism and sex-specific neuroanatomy, and associated cognition and gene expression

Objectives The male preponderance in autism spectrum conditions (ASC) prevalence is among the most pronounced sex ratios across different neurodevelopmental conditions. Here, we aimed to elucidate the relationship between autism and typical sex-differential neuroanatomy, cognition, and related gene expression. Methods Using a novel deep learning framework trained to predict biological sex, we compared sex prediction model performance across neurotypical and autistic males and females. Multiple large-scale datasets were employed at different stages of the analysis pipeline: a) Pre-training: the UK Biobank sample (>10.000 individuals); b) Transfer learning and validation: the ABIDE datasets (1,412 individuals, 5-56 years of age); c) Test and discovery: the EU-AIMS/AIMS-2-TRIALS LEAP dataset (681 individuals, 6-30 years of age) and d) Specificity: the Neuroimage and ADHD200 datasets (887 individuals, 7-26 years of age). Results Across both ABIDE and LEAP we showed that features positively predictive of neurotypical males were on average more predictive of autistic males ( P =1.1e-23). Features positively predictive of neurotypical females were on average less predictive of autistic females ( P =1.2e-22). These accuracy differences in autism were not observed in individuals with ADHD. In autistic females the male-shifted neurophenotype was further associated with poorer social sensitivity and emotional face processing while also with associated gene expression patterns of midgestational cell types. Conclusions Our results demonstrate a shift in both autistic male and female individuals’ neuroanatomy towards male-characteristic patterns associated with typically sex-differential, social cognitive features and related gene expression patterns. Findings hold promise for future research aimed at refining the quest for biological mechanisms underpinning the etiology of autism. ### Competing Interest Statement JKB has been a consultant to, advisory board member of, and a speaker for Takeda/Shire, Medice, Roche, and Servier. He is not an employee of any of these companies and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, or royalties. CFB is director and shareholder in SBGneuro Ltd. TC has received consultancy from Roche and Servier and received book royalties from Guildford Press and Sage. JT is a current full-time employee of F. Hoffmann La Roche Ltd. DM has been a consultant to, and advisory board member, for Roche and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. TB served in an advisory or consultancy role for ADHS digital, Infectopharm, Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Roche, and Takeda. He received conference support or speaker's fee by Medice and Takeda. He received royalities from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press; the present work is unrelated to these relationships. The other authors report no biomedical financial interests or potential conflicts of interest. ### Funding Statement This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115300 (for EU-AIMS) and No 777394 (for AIMS-2-TRIALS). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ethics committee (London Queen Square Health Research Authority Research Ethics Committee) of KCL and University of Cambridge gave ethical approval for this work (13/LO/1156). The ethics committee (Radboud Universitair Medisch Centrum Instituut Waarborging Kwaliteit en Veiligheid Commissie Mensgebonden Onderzoek and Regio Arnhem-Nijmegen (Radboud University Medical Centre Institute Ensuring Quality and Safety Committee on Research Involving Human Subjects Arnhem-Nijmegen) of Radboud UMC gave ethical approval of this work (2013/455). The ethics committee of Central Institute of Mannheim (UMM Universitaetsmedizin Mannheim, Medizinische Ethik Commission II (UMM University Medical Mannheim, Medical Ethics Commission II) gave ethical approval for this work (2014-540N-MA). The ethics committee of University of Rome (Universita Campus Bio-Medica De Roma Comitato Etico (University Campus Bio-Medical Ethics Committee De Roma) gave ethical approval of this work (8/14 PAR ComET CBM). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Reproducible code can be found at [https://github.com/ha-ha-ha-han/UKBiobank\_deep\_pretrain][1]. [http://fcon\_1000.projects.nitrc.org/indi/abide/abide\_II.html][2] [1]: https://github.com/ha-ha-ha-han/UKBiobank_deep_pretrain [2]: http://fcon_1000.projects.nitrc.org/indi/abide/abide_II.html