Altered structural brain asymmetry in autism spectrum disorder in a study of 54 datasets

Merel C. Postema, Daan van Rooij, Evdokia Anagnostou, Celso Arango, Guillaume Auzias, Marlene Behrmann, Geraldo Busatto Filho, Sara Calderoni, Rosa Calvo, Eileen Daly, Christine Deruelle, Adriana Di Martino, Ilan Dinstein, Fabio Luis S. Duran, Sarah Durston, Christine Ecker, Stefan Ehrlich, Damien Fair, Jennifer Fedor, Xin FengJackie Fitzgerald, Dorothea L. Floris, Christine M. Freitag, Louise Gallagher, David C. Glahn, Ilaria Gori, Shlomi Haar, Liesbeth Hoekstra, Neda Jahanshad, Maria Jalbrzikowski, Joost Janssen, Joseph A. King, Xiang Zhen Kong, Luisa Lazaro, Jason P. Lerch, Beatriz Luna, Mauricio M. Martinho, Jane McGrath, Sarah E. Medland, Filippo Muratori, Clodagh M. Murphy, Declan G.M. Murphy, Kirsten O’Hearn, Bob Oranje, Mara Parellada, Olga Puig, Alessandra Retico, Pedro Rosa, Katya Rubia, Devon Shook, Margot J. Taylor, Michela Tosetti, Gregory L. Wallace, Fengfeng Zhou, Paul M. Thompson, Simon E. Fisher, Jan K. Buitelaar, Clyde Francks

Research output: Contribution to journalArticlepeer-review

90 Scopus citations


Altered structural brain asymmetry in autism spectrum disorder (ASD) has been reported. However, findings have been inconsistent, likely due to limited sample sizes. Here we investigated 1,774 individuals with ASD and 1,809 controls, from 54 independent data sets of the ENIGMA consortium. ASD was significantly associated with alterations of cortical thickness asymmetry in mostly medial frontal, orbitofrontal, cingulate and inferior temporal areas, and also with asymmetry of orbitofrontal surface area. These differences generally involved reduced asymmetry in individuals with ASD compared to controls. Furthermore, putamen volume asymmetry was significantly increased in ASD. The largest case-control effect size was Cohen’s d = −0.13, for asymmetry of superior frontal cortical thickness. Most effects did not depend on age, sex, IQ, severity or medication use. Altered lateralized neurodevelopment may therefore be a feature of ASD, affecting widespread brain regions with diverse functions. Large-scale analysis was necessary to quantify subtle alterations of brain structural asymmetry in ASD.

Original languageEnglish (US)
Article number4958
JournalNature communications
Issue number1
StatePublished - Dec 1 2019
Externally publishedYes

Bibliographical note

Funding Information:
We thank the participants of all studies who have contributed data to the ENIGMA-ASD working group ( This research was funded by the Max Planck Society (Germany). This study was further supported by the ENIGMA Center for Worldwide Medicine, Imaging & Genomics grant (NIH U54 EB020403) to Paul Thompson, and further supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement number 115300 (EU-AIMS) and 777394 (AIMS-2-TRIALS), resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme and Horizon2020 programs and the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in-kind contribution. The Canadian samples were collected as part of the POND network funded by the Ontario Brain Institute (grant IDS-I l-02 to Anagnostou / Lerch). Thanks to Derrek Hibar for helping to generate Fig. 1.

Funding Information:
Dr. Anagnostou has served as a consultant or advisory board member for Roche and Takeda; she has received funding from the Alva Foundation, Autism Speaks, Brain Canada, the Canadian Institutes of Health Research, the Department of Defense, the National Centers of Excellence, NIH, the Ontario Brain Institute, the Physicians’ Services Incorporated (PSI) Foundation, Sanofi-Aventis, and SynapDx, as well as in-kind research support from AMO Pharma; she receives royalties from American Psychiatric Press and Springer and an editorial honorarium from Wiley. Her contribution is on behalf of the POND network. Dr. Arango has served as a consultant for or received honoraria or grants from Acadia, Abbott, Amgen, CIBERSAM, Fundación Alicia Koplowitz, Instituto de Salud Carlos III, Janssen-Cilag, Lundbeck, Merck, Instituto de Salud Carlos III (cofinanced by the European Regional Development Fund “A way of making Europe,” CIBERSAM, the Madrid Regional Government [S2010/BMD-2422 AGES], the European Union Structural Funds, and the European Union Seventh Framework Programmeunder grant agreements FP7-HEALTH-2009-2.2.1-2-241909, FP7-HEALTH-2009-2.2.1-3- 242114, FP7-HEALTH-2013-2.2.1-2-603196, and FP7-HEALTH-2013-2.2.1-2-602478), Otsuka, Pfizer, Roche, Servier, Shire, Takeda, and Schering-Plough. Dr. Freitag has served as a consultant for Desitin regarding issues on ASD. Dr. Di Martino is a coauthor of the Italian version of the Social Responsiveness Scale, for which she may receive royalties. Her contribution is on behalf of the ABIDE and ABIDEII consortia. Dr. Rubia has received speaking honoraria from Eli Lilly, Medice, and Shire, and a grant from Shire for another project. Dr. Thompson received partial research support from Biogen, Inc. (Boston), for research unrelated to the topic of this manuscript. Dr. Buitelaar has served as a consultant, advisory board member, or speaker for Eli Lilly, Janssen-Cilag, Lundbeck, Medice, Novartis, Servier, Shire, and Roche, and he has received research support from Roche and Vifor. The remaining authors declare no competing interests.

Publisher Copyright:
© 2019, The Author(s).


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