Patterns of Brain Maturation in Autism and Their Molecular Associations
Authors: Pretzsch Charlotte M. , Arenella Martina , Lerch Jason P. , Lombardo Michael V. , Beckmann Christian , Schaefer Tim , Leyhausen Johanna , Gurr Caroline , Bletsch Anke , Berg Lisa M. , Seelemeyer Hanna , Floris Dorothea L. , Oakley Bethany , Loth Eva , Bourgeron Thomas , Charman Tony , Buitelaar Jan , McAlonan Grainne , Murphy Declan , Ecker Christine ,   EU-AIMS LEAP Group, Ahmad Jumana , Ambrosino Sara , Auyeung Bonnie , Banaschewski Tobias , Baron-Cohen Simon , Baumeister Sarah , Beckmann Christian F. , Bölte Sven , Bourgeron Thomas , Bours Carsten , Brammer Michael , Brandeis Daniel , Brogna Claudia , de Bruijn Yvette , Buitelaar Jan K. , Chakrabarti Bhismadev , Charman Tony , Cornelissen Ineke , Crawley Daisy , Dell'Acqua Flavio , Dumas Guillaume , Durston Sarah , Ecker Christine , Faulkner Jessica , Frouin Vincent , Garcés Pilar , Goyard David , Ham Lindsay , Hayward Hannah , Hipp Joerg , Holt Rosemary , Johnson Mark H. , Jones Emily J.H. , Kundu Prantik , Lai Meng-Chuan , Liogier D'Ardhuy Xavier , Lombardo Michael V. , Loth Eva , Lythgoe David J. , Mandl René , Marquand Andre , Mason Luke , Mennes Maarten , Meyer-Lindenberg Andreas , Moessnang Carolin , Mueller Nico , Murphy Declan GM , Oakley Bethany , O'Dwyer Laurence , Oldehinkel Marianne , Oranje Bob , Pandina Gahan , Persico Antonio M. , Ruggeri Barbara , Ruigrok Amber , Sabet Jessica , Sacco Roberto , San José Cáceres Antonia , Simonoff Emily , Spooren Will , Tillmann Julian , Toro Roberto , Tost Heike , Waldman Jack , Williams Steve CR , Wooldridge Caroline , Zwiers Marcel 
Published: October 2024

ImportanceIn the neurotypical brain, regions develop in coordinated patterns, providing a fundamental scaffold for brain function and behavior. Whether altered patterns contribute to clinical profiles in neurodevelopmental conditions, including autism, remains unclear.ObjectivesTo examine if, in autism, brain regions develop differently in relation to each other and how these differences are associated with molecular/genomic mechanisms and symptomatology.Design, Setting, and ParticipantsThis study was an analysis of one the largest deep-phenotyped, case-control, longitudinal (2 assessments separated by approximately 12-24 months) structural magnetic resonance imaging and cognitive-behavioral autism datasets (EU-AIMS Longitudinal European Autism Project [LEAP]; study dates, February 2014-November 2017) and an out-of-sample validation in the Brain Development Imaging Study (BrainMapASD) independent cohort. Analyses were performed during the 2022 to 2023 period. This multicenter study included autistic and neurotypical children, adolescents, and adults. Autistic participants were included if they had an existing autism diagnosis (DSM-IV/International Statistical Classification of Diseases and Related Health Problems, Tenth Revision or DSM-5 criteria). Autistic participants with co-occurring psychiatric conditions (except psychosis/bipolar disorder) and those taking regular medications were included.ExposuresNeuroanatomy of neurotypical and autistic participants.Main Outcomes and MeasuresIntraindividual changes in surface area and cortical thickness over time, analyzed via surface-based morphometrics.ResultsA total of 386 individuals in the LEAP cohort (6-31 years at first visit; 214 autistic individuals, mean [SD] age, 17.3 [5.4] years; 154 male [72.0%] and 172 neurotypical individuals, mean [SD] age, 16.35 [5.7] years; 108 male [62.8%]) and 146 individuals in the BrainMapASD cohort (11-18 years at first visit; 49 autistic individuals, mean [SD] age, 14.31 [2.4] years; 42 male [85.7%] and 97 neurotypical individuals, mean [SD] age, 14.10 [2.5] years; 58 male [59.8%]). Maturational between-group differences in cortical thickness and surface area were established that were mostly driven by sensorimotor regions (eg, across features, absolute loadings for early visual cortex ranged from 0.07 to 0.11, whereas absolute loadings for dorsolateral prefrontal cortex ranged from 0.005 to 0.06). Neurodevelopmental differences were transcriptomically enriched for genes expressed in several cell types and during various neurodevelopmental stages, and autism candidate genes (eg, downregulated genes in autism, including those regulating synaptic transmission; enrichment odds ratio =3.7; P =2.6 × −10). A more neurotypical, less autismlike maturational profile was associated with fewer social difficulties and more typical sensory processing (false discovery rate P &amp;lt;.05; Pearson r ≥0.17). Results were replicated in the independently collected BrainMapASD cohort.Conclusions and RelevanceResults of this case-control study suggest that the coordinated development of brain regions was altered in autism, involved a complex interplay of temporally sensitive molecular mechanisms, and may be associated with both lower-order (eg, sensory) and higher-order (eg, social) clinical features of autism. Thus, examining maturational patterns may provide an analytic framework to study the neurobiological origins of clinical profiles in neurodevelopmental/mental health conditions.