TY - JOUR
T1 - Mutations associated with neuropsychiatric conditions delineate functional brain connectivity dimensions contributing to autism and schizophrenia
AU - Moreau, Clara A.
AU - Urchs, Sebastian G.W.
AU - Kuldeep, Kumar
AU - Orban, Pierre
AU - Schramm, Catherine
AU - Dumas, Guillaume
AU - Labbe, Aurélie
AU - Huguet, Guillaume
AU - Douard, Elise
AU - Quirion, Pierre Olivier
AU - Lin, Amy
AU - Kushan, Leila
AU - Grot, Stephanie
AU - Luck, David
AU - Mendrek, Adrianna
AU - Potvin, Stephane
AU - Stip, Emmanuel
AU - Bourgeron, Thomas
AU - Evans, Alan C.
AU - Bearden, Carrie E.
AU - Bellec, Pierre
AU - Jacquemont, Sebastien
N1 - Funding Information:
This research was supported by Calcul Quebec (http://www.calculquebec.ca) and Compute Canada (http://www.computecanada.ca), the Brain Canada Multi investigator research initiative (MIRI), funds from the Institute of Data Valorization (IVADO). S.J. is a recipient of a Canada Research Chair in neurodevelopmental disorders, and a chair from the Jeanne et Jean Louis Levesque Foundation. C.S. is supported by a fellowship from the Institute for Data Valorization. Kuldeep Kumar is supported by The Institute of Data Valorization (IVADO) Postdoctoral Fellowship program, through the Canada First Research Excellence Fund. This work was supported by a grant from the Brain Canada Multi-Investigator initiative (S.J.) and a grant from The Canadian Institutes of Health Research (S.J.). Dr P. Bellec is a fellow (“Chercheur boursier Junior 2”) of the “Fonds de recherche du Québec—Santé”, Data preprocessing and analyses were supported in part by the Courtois foundation (P.B.). We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, E. Wijsman). We appreciate obtaining access to imaging and phenotypic data on SFARI Base. Approved researchers can obtain the Simons Variation in Individuals Project population dataset described in this study by applying at https://base.sfari.org. ABIDE I is supported by NIMH (K23MH087770), NIMH (R03MH096321), the Leon Levy Foundation, Joseph P. Healy, and the Stavros Niarchos Foundation. Data in the schizophrenia dataset were accessed through the SchizConnect platform (http://schizconnect.org). As such, the investigators within SchizConnect contributed to the design and implementation of SchizConnect and/or provided data but did not participate in the data analysis or writing of this report. Funding of the SchizConnect project was provided by NIMH cooperative agreement 1U01 MH097435. SchizConnect enabled access to the following data repository: The Collaborative Informatics and Neuroimaging Suite Data Exchange tool (COINS; http:// coins.mrn.org/dx). Data from one study was collected at the Mind Research Network and funded by a Center of Biomedical Research Excellence (COBRE) grant, (5P20RR021938/ P20GM103472) from the NIH to Dr. Vince Calhoun. Data from two other studies were obtained from the Mind Clinical Imaging Consortium Database. The MCIC project was supported by the Department of Energy under award number DE-FG02-08ER6458. MCIC is the result of the efforts of co-investigators from the University of Iowa, University of Minnesota, University of New Mexico, and Massachusetts General Hospital. Data from another study were obtained from the Neuromorphometry by Computer Algorithm Chicago (NMorphCH) dataset (http://nunda.northwestern.edu/nunda/data/ projects/NMorphCH). As such, the investigators within NMorphCH contributed to the design and implementation of NMorphCH and/or provided data but did not participate in the data analysis or writing of this report. The NMorphCH project was funded by NIMH grant RO1 MH056584. Data from the UCLA cohort provided by C.E.B. (participants with 22q11.2 deletions or duplications and controls) was supported through grants from the NIH (U54EB020403), NIMH (R01MH085953, R01MH100900, R03MH105808), and the Simons Foundation (SFARI Explorer Award). Finally, data from another study were obtained through the OpenFMRI project (http://openfmri.org) from the Consortium for Neuropsychiatric Phenomics (CNP), which was supported by NIH Roadmap for Medical Research grants UL1-DE019580, RL1MH083268, RL1MH083269, RL1DA024853, RL1MH083270, RL1LM009833, PL1MH083271, and PL1NS062410.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 16p11.2 and 22q11.2 Copy Number Variants (CNVs) confer high risk for Autism Spectrum Disorder (ASD), schizophrenia (SZ), and Attention-Deficit-Hyperactivity-Disorder (ADHD), but their impact on functional connectivity (FC) remains unclear. Here we report an analysis of resting-state FC using magnetic resonance imaging data from 101 CNV carriers, 755 individuals with idiopathic ASD, SZ, or ADHD and 1,072 controls. We characterize CNV FC-signatures and use them to identify dimensions contributing to complex idiopathic conditions. CNVs have large mirror effects on FC at the global and regional level. Thalamus, somatomotor, and posterior insula regions play a critical role in dysconnectivity shared across deletions, duplications, idiopathic ASD, SZ but not ADHD. Individuals with higher similarity to deletion FC-signatures exhibit worse cognitive and behavioral symptoms. Deletion similarities identified at the connectivity level could be related to the redundant associations observed genome-wide between gene expression spatial patterns and FC-signatures. Results may explain why many CNVs affect a similar range of neuropsychiatric symptoms.
AB - 16p11.2 and 22q11.2 Copy Number Variants (CNVs) confer high risk for Autism Spectrum Disorder (ASD), schizophrenia (SZ), and Attention-Deficit-Hyperactivity-Disorder (ADHD), but their impact on functional connectivity (FC) remains unclear. Here we report an analysis of resting-state FC using magnetic resonance imaging data from 101 CNV carriers, 755 individuals with idiopathic ASD, SZ, or ADHD and 1,072 controls. We characterize CNV FC-signatures and use them to identify dimensions contributing to complex idiopathic conditions. CNVs have large mirror effects on FC at the global and regional level. Thalamus, somatomotor, and posterior insula regions play a critical role in dysconnectivity shared across deletions, duplications, idiopathic ASD, SZ but not ADHD. Individuals with higher similarity to deletion FC-signatures exhibit worse cognitive and behavioral symptoms. Deletion similarities identified at the connectivity level could be related to the redundant associations observed genome-wide between gene expression spatial patterns and FC-signatures. Results may explain why many CNVs affect a similar range of neuropsychiatric symptoms.
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U2 - 10.1038/s41467-020-18997-2
DO - 10.1038/s41467-020-18997-2
M3 - Article
C2 - 33077750
AN - SCOPUS:85092763274
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5272
ER -