Autism is associated with inter-individual variations of gray and white matter morphology

Background Although many studies have explored atypicalities in gray and white matter (GM, WM) morphology of autism, most of them rely on unimodal analyses that do not benefit from the likelihood that different imaging modalities may reflect common neurobiology. We aimed to establish multimodal brain patterns that differentiate between autism and typically developing (TD) controls and explore associations between these brain patterns and clinical measures. Methods We studied 183 individuals with autism and 157 TD individuals (6-30 years) in a large deeply phenotyped autism dataset (EU-AIMS LEAP). Linked Independent Component Analysis was utilized to link all participants’ GM and WM images, and group comparisons of modality shared variances were examined. Subsequently, we performed a canonical correlation analysis to explore the aggregated effects between all multimodal GM-WM covariations and clinical profiles. Results One multimodal pattern was significantly related to autism. This pattern was primarily associated with GM in bilateral insula, frontal, pre- and post-central, cingulate, and caudate areas, and co-occurred with altered WM features in the superior longitudinal fasciculus. The canonical analysis showed a significant multivariate correlation primarily between multimodal brain patterns that involved variation of corpus callosum, and symptoms of social affect in the autism group. Conclusions Our findings demonstrate the assets of integrated analyses of GM and WM alterations to study the brain mechanisms that underpin autism, and show that the complex clinical autism phenotype can be interpreted by multimodal brain patterns that are spread across the brain involving both cortical and subcortical areas. ### Competing Interest Statement TC has received consultancy from Roche and Servier and received book royalties from Guildford Press and Sage. DGM 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. CFB is director and shareholder in SBGNeuro Ltd. 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, and Oxford University Press. JKB has been a consultant to, advisory board member of, and a speaker for Janssen Cilag BV, Eli Lilly, Shire, Lundbeck, 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. The present work is unrelated to the above grants and relationships. The other authors report no biomedical financial interests or potential conflicts of interest.