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The Link Between Autism and Sex-Related Neuroanatomy, and Associated Cognition and Gene Expression
Dorothea L Floris1, Han Peng1, Varun Warrier1
1Methods of Plasticity Research, Department of Psychology, University of Zurich, Zurich (Floris); Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen, and Department for Cognitive Neuroscience, Radboud University Medical Center Nijmegen, Nijmegen, the Netherlands (Floris, Mennes, Llera, van Rooij, Oldehinkel, Forde, Marquand, Buitelaar, Beckmann); Wellcome Centre for Integrative Neuroimaging (Peng, Gong, Beckmann), and Visual Geometry Group (Peng), University of Oxford, Oxford, U.K.; Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, U.K. (Warrier, Tsompanidis, Holt, Lai, Baron-Cohen); Laboratory for Autism and Neurodevelopmental Disorders, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Rovereto, Italy (Lombardo); Department of Forensic and Neurodevelopmental Sciences (Pretzsch, Ecker, Dell'Acqua, Loth, Murphy), Department of Psychology (Charman), Sackler Institute for Translational Neurodevelopment (Dell'Acqua, Loth, Murphy), and Department of Neuroimaging (Marquand), Institute of Psychiatry, Psychology, and Neuroscience, King's College London; Institut Pasteur, Human Genetics and Cognitive Functions Unity, IUF, Université Paris Cité, Paris (Moreau, Bourgeron); Roche Pharma Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland (Tillmann); Department of Child and Adolescent Psychiatry (Banaschewski) and Department of Psychiatry and Psychotherapy (Moessnang), Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Applied Psychology, SRH University, Heidelberg, Germany (Moessnang); Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands (Durston); Department of Child and Adolescent Psychiatry, University Hospital, Goethe University, Frankfurt am Main, Germany (Ecker); Margaret and Wallace McCain Centre for Child, Youth, and Family Mental Health and Azrieli Adult Neurodevelopmental Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto (Lai); Department of Psychiatry and Autism Research Unit, Hospital for Sick Children, Toronto (Lai); Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto (Lai); Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei (Lai); Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, the Netherlands (Buitelaar).
Objective:
The male preponderance in prevalence of autism is among the most pronounced sex ratios across neurodevelopmental conditions. The authors sought 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 based on T1-weighted structural brain images, the authors compared sex prediction model performance across neurotypical and autistic males and females. Multiple large-scale data sets comprising T1-weighted MRI data were employed at four stages of the analysis pipeline: 1) pretraining, with the UK Biobank sample (>10,000 individuals); 2) transfer learning and validation, with the ABIDE data sets (1,412 individuals, 5-56 years of age); 3) test and discovery, with the EU-AIMS/AIMS-2-TRIALS LEAP data set (681 individuals, 6-30 years of age); and 4) specificity, with the NeuroIMAGE and ADHD200 data sets (887 individuals, 7-26 years of age).
Results:
Across both ABIDE and LEAP, features positively predictive of neurotypical males were on average significantly more predictive of autistic males (ABIDE: Cohen's d=0.48; LEAP: Cohen's d=1.34). Features positively predictive of neurotypical females were on average significantly less predictive of autistic females (ABIDE: Cohen's d=1.25; LEAP: Cohen's d=1.29). These differences in sex prediction accuracy 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 associated with gene expression patterns of midgestational cell types.
Conclusions:
The results demonstrate an increased resemblance in both autistic male and female individuals' neuroanatomy with male-characteristic patterns associated with typically sex-differential social cognitive features and related gene expression patterns. The findings hold promise for future research aimed at refining the quest for biological mechanisms underpinning the etiology of autism.
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