Three Imaging Endophenotypes Characterize Neuroanatomical Heterogeneity of Autism Spectrum Disorder

Autism spectrum disorder (ASD) is associated with high structural heterogeneity in magnetic resonance imaging (MRI). This work uncovers three neuroanatomical dimensions of ASD ( N =307) using machine learning methods and constructs their characteristic MRI signatures. The presence of these signatures, along with their clinical profiles and genetic architectures, are investigated in the general population. High expression of the first dimension (A1, “aging-related”) is associated with globally reduced brain volume, cognitive dysfunction, and aging-related genetic variants. The second dimension (A2, “schizophrenia-like”) is characterized by enlarged subcortical volume, antipsychotic medication use, and partially overlapping genetic underpinnings to schizophrenia. The third dimension (A3, “classical ASD”) is distinguished by enlarged cortical volume, high non-verbal cognitive performance, and genes and biological pathways implicating brain development and abnormal apoptosis. Thus, we propose a three-dimensional endophenotypic representation to construe the heterogeneity in ASD, which can support precision medicine and the discovery of the biological mechanisms of ASD. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported in part by NIH grant R01MH112070 and R01MH123550. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used ONLY openly available human data from three studies or consortia: ABIDE, PHENOM, and UK Biobank. The ABIDE dataset is available from the National Institute of Mental Health Data Archive (NDA) upon permission (). The UK Biobank dataset is available from their website upon permission (). The dimension scores for both ASD and SCZ that support the findings of this study are available from the authors of the originating paper upon reasonable request (). All participants recruited in the above studies provided informed written consent according to the protocol approved by each of their Institutional Review Boards. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The ABIDE dataset is available from the National Institute of Mental Health Data Archive (NDA) upon permission (). The UK Biobank dataset is available from their website upon permission (). The dimension scores for both ASD and SCZ that support the findings of this study are available upon reasonable request. The GWAS summary statistics are available in the BRIDGEPORT web portal: . The MsigDB database for gene-set enrichment analysis is available at: .