Differential functional neural circuitry behind autism subtypes with marked imbalance between social-communicative and restricted repetitive behavior symptom domains
Richard A.I. Bethlehem,
Elena Maria Busuoli,
Christian F Beckmann,
Mark H Johnson,
Emily J. H. Jones,
Steven C. R. Williams,
Declan G. M. Murphy,
EU-AIMS LEAP group,
Michael V. Lombardo
Posted 10 May 2020
bioRxiv DOI: 10.1101/2020.05.08.083758
Posted 10 May 2020
Social-communication (SC) and restricted repetitive behaviors (RRB) are autism diagnostic symptom domains. SC and RRB severity can markedly differ within and between individuals and may be underpinned by different neural circuitry and genetic mechanisms. Modeling SC-RRB balance could help identify how neural circuitry and genetic mechanisms map onto such phenotypic heterogeneity. Here we developed a phenotypic stratification model that makes highly accurate (97-99%) out-of-sample SC=RRB, SC>RRB, and RRB>SC subtype predictions. Applying this model to resting state fMRI data from the EU-AIMS LEAP dataset (n=509), we find that while the phenotypic subtypes share many commonalities in terms of intrinsic functional connectivity, they also show subtype-specific qualitative differences compared to a typically-developing group (TD). Specifically, the somatomotor network is hypoconnected with perisylvian circuitry in SC>RRB and visual association circuitry in SC=RRB. The SC=RRB subtype also showed hyperconnectivity between medial motor and anterior salience circuitry. Genes that are highly expressed within these subtype-specific networks show a differential enrichment pattern with known ASD associated genes, indicating that such circuits are affected by differing autism-associated genomic mechanisms. These results suggest that SC-RRB imbalance subtypes share some commonalities but also express subtle differences in functional neural circuitry and the genomic underpinnings behind such circuitry. ### Competing Interest Statement 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. CFB is director and shareholder in SBGneuro Ltd. SB discloses that he has in the last 5 years acted as an author, consultant, or lecturer for Shire/Takeda, Medice, Roche, Eli Lilly, and Prima Psychiatry. He receives royalties for textbooks and diagnostic tools from Huber/Hogrefe, Kohlhammer, and UTB. TC has received consultancy from Roche and Servier and received book royalties from Guildford Press and Sage. DGMM 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. AML has received consultant fees from Boehringer Ingelheim, Elsevier, Brainsway, Lundbeck Int. Neuroscience Foundation, Lundbeck A/S, The Wolfson Foundation, Bloomfield Holding Ltd, Shanghai Research Center for Brain Science, Thieme Verlag, Sage Therapeutics, v Behring Rontgen Stiftung, Fondation FondaMental, Janssen-Cilag GmbH, MedinCell, Brain Mind Institute, Agence Nationale de la Recherche, CISSN (Catania Internat. Summer School of Neuroscience), Daimler und Benz Stiftung and American Association for the Advancement of Science. Additionally, he has received speaker fees from Italian Society of Biological Psychiatry, Merz-Stiftung, Forum Werkstatt Karlsruhe, Lundbeck SAS France, BAG Psychiatrie Oberbayern, Klinik fur Psychiatrie und Psychotherapie Ingolstadt, med Update GmbH, Society of Biological Psychiatry and Siemens Healthineers. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. JT is a consultant to Roche. The other authors report no biomedical financial interests or potential conflicts of interest.
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