RT Journal Article
SR Electronic
T1 Differential functional neural circuitry behind autism subtypes with marked imbalance between social-communicative and restricted repetitive behavior symptom domains
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.05.08.083758
DO 10.1101/2020.05.08.083758
A1 Natasha Bertelsen
A1 Isotta Landi
A1 Richard A. I. Bethlehem
A1 Jakob Seidlitz
A1 Elena Maria Busuoli
A1 Veronica Mandelli
A1 Eleonora Satta
A1 Stavros Trakoshis
A1 Bonnie Auyeung
A1 Prantik Kundu
A1 Eva Loth
A1 Guillaume Dumas
A1 Sarah Baumeister
A1 Christian F. Beckmann
A1 Sven Bölte
A1 Thomas Bourgeron
A1 Tony Charman
A1 Sarah Durston
A1 Christine Ecker
A1 Rosemary Holt
A1 Mark H. Johnson
A1 Emily J. H. Jones
A1 Luke Mason
A1 Andreas Meyer-Lindenberg
A1 Carolin Moessnang
A1 Marianne Oldehinkel
A1 Antonio Persico
A1 Julian Tillmann
A1 Steven C. R. Williams
A1 Will Spooren
A1 Declan G. M. Murphy
A1 Jan K. Buitelaar
A1 the EU-AIMS LEAP group
A1 Simon Baron-Cohen
A1 Meng-Chuan Lai
A1 Michael V. Lombardo
YR 2020
UL http://biorxiv.org/content/early/2020/05/10/2020.05.08.083758.abstract
AB 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 StatementJKB 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.