Christine Ecker1, Charlotte M Pretzsch1, Anke Bletsch1, Caroline Mann1, Tim Schaefer1, Sara Ambrosino1, Julian Tillmann1, Afsheen Yousaf1, Andreas Chiocchetti1, Michael V Lombardo1, Varun Warrier1, Nico Bast1, Carolin Moessnang1, Sarah Baumeister1, Flavio Dell'Acqua1, Dorothea L Floris1, Mariam Zabihi1, Andre Marquand1, Freddy Cliquet1, Claire Leblond1, Clara Moreau1, Nick Puts1, Tobias Banaschewski1, Emily J H Jones1, Luke Mason1, Sven Bölte1, Andreas Meyer-Lindenberg1, Antonio M Persico1, Sarah Durston1, Simon Baron-Cohen1, Will Spooren1, Eva Loth1, Christine M Freitag1, Tony Charman1, Guillaume Dumas1, Thomas Bourgeron1, Christian F Beckmann1, Jan K Buitelaar1, Declan G M Murphy1. 1. Department of Child and Adolescent Psychiatry, University Hospital, Goethe University, Frankfurt am Main, Germany (Ecker, Bletsch, Mann, Schaefer, Yousaf, Chiocchetti, Bast, Freitag); Department of Forensic and Neurodevelopmental Sciences (Ecker, Pretzsch, Dell'Acqua, Puts, Loth, Murphy) and Department of Psychology (Tillmann, Charman), Institute of Psychiatry, Psychology, and Neuroscience, King's College London; Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands (Ambrosino, Durston); Laboratory for Autism and Neurodevelopmental Disorders, Center for Neuroscience and Cognitive Systems, University of Trento, Istituto Italiano di Tecnologia, Rovereto, Italy (Lombardo); Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, U.K. (Lombardo, Warrier, Baron-Cohen); Department of Psychiatry and Psychotherapy (Moessnang, Baumeister, Meyer-Lindenberg) and Department of Child and Adolescent Psychiatry (Moessnang, Baumeister, Banaschewski), Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands (Floris, Zabihi, Marquand, Beckmann, Buitelaar); Human Genetics and Cognitive Functions Unit, Institut Pasteur, University of Paris, Paris (Cliquet, Leblond, Moreau, Dumas, Bourgeron); Centre for Brain and Cognitive Development, Birkbeck, University of London, London (Jones, Mason); Center for Neurodevelopmental Disorders (KIND), Center for Psychiatry Research, Department of Women's and Children's Health, Karolinska Institutet and Stockholm Health Care Services, and Department of Child and Adolescent Psychiatry, Stockholm Health Care Services, Region Stockholm, Sweden (Bölte); Department of Child and Adolescent Neuropsychiatry, Gaetano Martino University Hospital, University of Messina, Messina, Italy (Persico); Roche Pharmaceutical Research and Early Development, NORD Discovery and Translational Area, Roche Innovation Center Basel, Switzerland (Spooren).
Abstract
OBJECTIVE: Autism spectrum disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. This study aimed to link differences in brain anatomy to specific biological pathways to pave the way toward targeted therapeutic interventions. METHODS: The authors examined neurodevelopmental differences in cortical thickness and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 279 typically developing control subjects (ages 6-30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). The authors also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups that differed in the severity and pattern of sensory features. RESULTS: In addition to significant between-group differences in "core" ASD brain regions (i.e., fronto-temporal and cingulate regions), individuals with ASD manifested as neuroanatomical outliers within the neurotypical cortical thickness range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals' total (i.e., accumulated) degree of neuroanatomical atypicality was significantly correlated with higher polygenic scores for ASD and other psychiatric conditions, and it scaled with measures of symptom severity. Differences in cortical thickness deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission. CONCLUSIONS: The study findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping.
OBJECTIVE: Autism spectrum disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. This study aimed to link differences in brain anatomy to specific biological pathways to pave the way toward targeted therapeutic interventions. METHODS: The authors examined neurodevelopmental differences in cortical thickness and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 279 typically developing control subjects (ages 6-30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). The authors also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups that differed in the severity and pattern of sensory features. RESULTS: In addition to significant between-group differences in "core" ASD brain regions (i.e., fronto-temporal and cingulate regions), individuals with ASD manifested as neuroanatomical outliers within the neurotypical cortical thickness range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals' total (i.e., accumulated) degree of neuroanatomical atypicality was significantly correlated with higher polygenic scores for ASD and other psychiatric conditions, and it scaled with measures of symptom severity. Differences in cortical thickness deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission. CONCLUSIONS: The study findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping.
Authors: Sara Ambrosino; Hasnaa Elbendary; Maarten Lequin; Dominique Rijkelijkhuizen; Tobias Banaschewski; Simon Baron-Cohen; Nico Bast; Sarah Baumeister; Jan Buitelaar; Tony Charman; Daisy Crawley; Flavio Dell'Acqua; Hannah Hayward; Rosemary Holt; Carolin Moessnang; Antonio M Persico; Roberto Sacco; Antonia San José Cáceres; Julian Tillmann; Eva Loth; Christine Ecker; Bob Oranje; Declan Murphy; Sarah Durston Journal: Neuroimage Clin Date: 2022-07-16 Impact factor: 4.891
Authors: Valentina Bieneck; Anke Bletsch; Caroline Mann; Tim Schäfer; Hanna Seelemeyer; Njål Herøy; Jennifer Zimmermann; Charlotte Marie Pretzsch; Elke Hattingen; Christine Ecker Journal: Genes (Basel) Date: 2021-12-20 Impact factor: 4.096