Abstract
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 is 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 (96-98%) 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 replicable somatomotor-perisylvian hypoconnectivity in the SC>RRB subtype versus a typically-developing (TD) comparison group. In contrast, replicable motor-anterior salience hyperconnectivity is apparent in the SC=RRB subtype versus TD. Autism-associated genes affecting astrocytes, excitatory, and inhibitory neurons are highly expressed specifically within SC>RRB hypoconnected networks, but not SC=RRB hyperconnected networks. SC-RRB balance subtypes may indicate different paths individuals take from genome, neural circuitry, to the clinical phenotype.
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 Röntgen 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 für 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.