The neuroanatomical substrates of autism and ADHD and their link to putative genomic underpinnings
Authors: Berg Lisa M. , Gurr Caroline , Leyhausen Johanna , Seelemeyer Hanna , Bletsch Anke , Schaefer Tim , Pretzsch Charlotte M. , Oakley Bethany , Loth Eva , Floris Dorothea L. , Buitelaar Jan K. , Beckmann Christian F. , Banaschewski Tobias , Charman Tony , Jones Emily J. H. , Tillmann Julian , Chatham Chris H. , Bourgeron Thomas ,   The EU-AIMS LEAP Group, Ahmad Jumana , Ambrosino Sara , Auyeung Bonnie , Baron-Cohen Simon , Baumeister Sarah , Bölte Sven , Bours Carsten , Brammer Michael , Brandeis Daniel , Brogna Claudia , de Bruijn Yvette , Chakrabarti Bhismadev , Cornelissen Ineke , Crawley Daisy , Dell’Acqua Flavio , Dumas Guillaume , Durston Sarah , Faulkner Jessica , Frouin Vincent , Garcés Pilar , Goyard David , Ham Lindsay , Hayward Hannah , Hipp Joerg , Holt Rosemary , Johnson Mark H. , Kundu Prantik , Lai Meng-Chuan , D’Ardhuy Xavier Liogier , Lombardo Michael V. , Lythgoe David J. , Mandl René , Marquand Andre , Mason Luke , Mennes Maarten , Meyer-Lindenberg Andreas , Moessnang Carolin , Bast Nico , O’Dwyer Laurence , Oldehinkel Marianne , Oranje Bob , Pandina Gahan , Persico Antonio M. , Ruggeri Barbara , Ruigrok Amber , Sabet Jessica , Sacco Roberto , Cáceres Antonia San José , Simonoff Emily , Spooren Will , Toro Roberto , Tost Heike , Waldman Jack , Williams Steve C. R. , Wooldridge Caroline , Zwiers Marcel P. , Murphy Declan G. , Ecker Christine 
Published: October 2023

Abstract
Background
Autism spectrum disorders (ASD) are neurodevelopmental conditions accompanied by differences in brain development. Neuroanatomical differences in autism are variable across individuals and likely underpin distinct clinical phenotypes. To parse heterogeneity, it is essential to establish how the neurobiology of ASD is modulated by differences associated with co-occurring conditions, such as attention-deficit/hyperactivity disorder (ADHD). This study aimed to (1) investigate between-group differences in autistic individuals with and without co-occurring ADHD, and to (2) link these variances to putative genomic underpinnings.

Methods
We examined differences in cortical thickness (CT) and surface area (SA) and their genomic associations in a sample of 533 individuals from the Longitudinal European Autism Project. Using a general linear model including main effects of autism and ADHD, and an ASD-by-ADHD interaction, we examined to which degree ADHD modulates the autism-related neuroanatomy. Further, leveraging the spatial gene expression data of the Allen Human Brain Atlas, we identified genes whose spatial expression patterns resemble our neuroimaging findings.

Results
In addition to significant main effects for ASD and ADHD in fronto-temporal, limbic, and occipital regions, we observed a significant ASD-by-ADHD interaction in the left precentral gyrus and the right frontal gyrus for measures of CT and SA, respectively. Moreover, individuals with ASD + ADHD differed in CT to those without. Both main effects and the interaction were enriched for ASD—but not for ADHD-related genes.

Limitations
Although we employed a multicenter design to overcome single-site recruitment limitations, our sample size of N = 25 individuals in the ADHD only group is relatively small compared to the other subgroups, which limits the generalizability of the results. Also, we assigned subjects into ADHD positive groupings according to the DSM-5 rating scale. While this is sufficient for obtaining a research diagnosis of ADHD, our approach did not take into account for how long the symptoms have been present, which is typically considered when assessing ADHD in the clinical setting.

Conclusion
Thus, our findings suggest that the neuroanatomy of ASD is significantly modulated by ADHD, and that autistic individuals with co-occurring ADHD may have specific neuroanatomical underpinnings potentially mediated by atypical gene expression.