TY - JOUR
T1 - Mapping Subcortical Brain Alterations in 22q11.2 Deletion Syndrome
T2 - Effects of Deletion Size and Convergence With Idiopathic Neuropsychiatric Illness
AU - Ching, Christopher R. K.
AU - Gutman, Boris A.
AU - Sun, Daqiang
AU - Reina, Julio Villalon
AU - Ragothaman, Anjanibhargavi
AU - Isaev, Dmitry
AU - Zavaliangos-Petropulu, Artemis
AU - Lin, Amy
AU - Jonas, Rachel K.
AU - Kushan, Leila
AU - Pacheco-Hansen, Laura
AU - Vajdi, Ariana
AU - Forsyth, Jennifer K.
AU - Jalbrzikowski, Maria
AU - Bakker, Geor
AU - van Amelsvoort, Therese
AU - Antshel, Kevin M.
AU - Fremont, Wanda
AU - Kates, Wendy R.
AU - Campbell, Linda E.
AU - McCabe, Kathryn L.
AU - Craig, Michael C.
AU - Daly, Eileen
AU - Gudbrandsen, Maria
AU - Murphy, Clodagh M.
AU - Murphy, Declan G.
AU - Murphy, Kieran C.
AU - Fiksinski, Ania
AU - Koops, Sanne
AU - Vorstman, Jacob
AU - Crowley, T. Blaine
AU - Emanuel, Beverly S.
AU - Gur, Raquel E.
AU - McDonald-McGinn, Donna M.
AU - Roalf, David R.
AU - Ruparel, Kosha
AU - Schmitt, J. Eric
AU - Zackai, Elaine H.
AU - Durdle, Courtney A.
AU - Goodrich-Hunsaker, Naomi J.
AU - Simon, Tony J.
AU - Bassett, Anne S.
AU - Butcher, Nancy J.
AU - Chow, Eva W. C.
AU - Vila-Rodriguez, Fidel
AU - Cunningham, Adam
AU - Doherty, Joanne
AU - Linden, David E.
AU - Moss, Hayley
AU - Owen, Michael J.
AU - van den Bree, Marianne
AU - Crossley, Nicolas A.
AU - Repetto, Gabriela M.
AU - Thompson, Paul M.
AU - Bearden, Carrie E.
N1 - Funding Information:
Dr. Ching is supported in part by National Institute on Aging (NIA) grant T32AG058507, NIMH grant 5T32MH073526, and NIH/National Institute of Biomedical Imaging and Bioengineering (NIBIB) grant U54EB020403 from the Big Data to Knowledge (BD2K) Program. Dr. Bearden is supported by NIH/NIBIB grant U54EB020403 (BD2K) and NIMH grants RO1 MH085953, R01MH100900, U01MH101719, and U01MH101719-04S1.
Funding Information:
Dr.ChinghasreceivedgrantsupportfromBiogen.Dr.Antshelhasreceived investigator-initiated research funds from Shire and has participated in an advisory panel for Arbor Pharmaceuticals. Dr. D.G. Murphy has served on an advisory board for Roche. Dr. Vila-Rodriguez has received research support from Brain Canada, the Canadian Institutes of Health Research, the Michael Smith Foundation for Health Research, and the Vancouver Coastal Health Research Institute and in-kind equipment support from MagVenture, and he has served on an advisory board for Janssen. Dr. Linden receives editorial fees from Elsevier and book royalties from Springer Nature and Oxford University Press. Dr. Owen has received research support from Takeda. Dr. van den Bree has received research support from Takeda. Dr. Thompson has received grant support from Biogen. The other authors report no financial relationships with commercial interests.
Funding Information:
Dr. Thompson is supported by NIH/NIBIB grant U54EB020403 (BD2K), NIMH grant R01MH116147, NIBIB grant P41 EB015922, NIMH grant R01MH111671, and NIA grant R56AG058854. Dr. Kates is supported by NIMH grant MH064824. Dr. D.G. Murphy is supported by the National Institute for Health Research Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London and EU-AIMS (European Autism Interventions)/EU AIMS-2-TRIALS, a European Innovative Medicines Initiative Joint Undertaking under grant agreements 115300 and 777394. Dr. Roalf is supported by NIMH grant R01 MH119185, a NARSAD Young Investigators Award, and the Life Span Brain Institute (a collaboration between the University of Pennsylvania School of Medicine and Children’s Hospital of Philadelphia). Dr. Emanuel is supported by National Institute of Child Health and Human Development (NICHD) grant PO1-HD070454, NIH grant UO1-MH191719, NIMH grant R01 MH087636-01A1, and National Institute of General Medical Sciences grant R01 GM125757. Ms. McDonald-McGinn is supported by NICHD grant PO1-HD070454, NIH grant UO1-MH191719, and NIMH grant R01 MH087636-01A1. Mr. Crowley is supported by NICHD grant PO1-HD070454, NIH grant UO1-MH191719, and NIMH grant R01 MH087636-01A1. Dr. Zackai is supported by NICHD grant PO1-HD070454, NIH grant UO1-MH191719, and NIMH grant R01 MH087636-01A1. Dr. Simon is supported by NIH grants R01MH107108, R01HD042794, and HDU54079125. Dr. Bassett is supported by the Dalglish Family Chair in 22q11.2 Deletion Syndrome, Canadian Institutes of Health Research (CIHR) grants MOP-79518, MOP-89066, MOP-97800, and MOP-111238, and NIMH grant U01MH101723–01(3/5). Dr. Chow is supported by CIHR grant MOP-74631 and NIMH grant U01MH101723–01(3/5). Dr. Vila-Rodriguez is supported by the Michael Smith Foundation for Health Research and the Seedlings Foundation. Dr. Doherty is supported by Wellcome Trust grant 102003/Z/13/Z. Dr. Cunningham and Dr. van den Bree are supported by MRC Centre grant MR/L010305/1. Dr. Linden is supported by Wellcome Trust grant 100202/Z/12/Z. Dr. Owen is supported by MRC Centre grant MR/ L010305/1 and Wellcome Trust grant 100202/Z/12/Z. Ms. Moss is supported by MRC Centre grant MR/L010305/1. Dr. Repetto is supported by FONDECYT Chile grant 1171014. Dr. Crossley is supported by FONDECYT regular grant 1160736 and Anillo PIA ACT192064 from Comisión Nacional de Investigación Científica y Tecnológica (CONICYT), Chile. Dr. C.M. Murphy is supported by the National Institute for Health Research Maudsley Biomedical Research Centre at South London Maudsley Foundation Trust and King’s College London. The authors acknowledge the ENIGMA psychiatric disorder working groups for providing published data from their neuroimaging studies of subcortical brain structures in their respective working groups, which allowed for the cross-disorder comparison in this study. The authors especially acknowledge Lianne Schmaal and Dick J. Veltman from the ENIGMA Major Depression Working Group, Derrek P. Hibar and Ole A. Andreassen from the ENIGMA Bipolar Disorder Working Group, Theo G. van Erp and Jessica A. Turner from the ENIGMA Schizophrenia Working Group, Premika S. Boedhoe, Dan J. Stein, and Odile A. van den Heuvel from the ENIGMA OCD Working Group, Martine Hoogman and Barbara Franke from the ENIGMA ADHD Working Group, and Daan van Rooij and Jan K. Buitelaar from the ENIGMA Autism Spectrum Disorders Working Group. TheauthorsalsothankAgnesMcMahonandSophiaThomopoulos,former and current ENIGMA program managers, for all their efforts in helping this international consortium effort thrive.
Publisher Copyright:
© 2020 American Psychiatric Association. All rights reserved.
PY - 2020/7
Y1 - 2020/7
N2 - Objective: 22q11.2 deletion syndrome (22q11DS) is among the strongest known genetic risk factors for schizophrenia. Previous studies have reported variable alterations in sub-cortical brain structures in 22q11DS. To better characterize subcortical alterations in 22q11DS, including modulating effects of clinical and genetic heterogeneity, the authors studied a large multicenter neuroimaging cohort from the ENIGMA 22q11.2 Deletion Syndrome Working Group.Methods: Subcortical structures were measured using harmonized protocols for gross volume and subcortical shape morphometry in 533 individualswith 22q11DS and 330matched healthy control subjects (age range, 6-56 years; 49% female).Results: Compared with the control group, the 22q11DS group showed lower intracranial volume (ICV) and thalamus, putamen, hippocampus, and amygdala volumes and greater lateral ventricle, caudate, and accumbens volumes (Cohen's d values, 20.90 to 0.93). Shape analysis revealed complex differences in the 22q11DS group across all structures. The larger A-D deletion was associated with more extensive shape alterations compared with the smaller A-B deletion. Participants with 22q11DS with psychosis showed lower ICV and hippocampus, amygdala, and thalamus volumes (Cohen's d values, 20.91 to 0.53) compared with participants with 22q11DS without psychosis. Shape analysis revealed lower thickness and surface area across subregions of these structures. Compared with subcortical findings from other neuropsychiatric disorders studied by the ENIGMA consortium, significant convergence was observed between participants with 22q11DS with psychosis and participants with schizophrenia, bipolar disorder, major depressive disorder, and obsessive-compulsive disorder.Conclusions: In the largest neuroimaging study of 22q11DS to date, the authors found widespread alterations to subcortical brain structures, which were affected by deletion size and psychotic illness. Findings indicate significant overlap between 22q11DS-associated psychosis, idiopathic schizophrenia, and other severe neuropsychiatric illnesses.
AB - Objective: 22q11.2 deletion syndrome (22q11DS) is among the strongest known genetic risk factors for schizophrenia. Previous studies have reported variable alterations in sub-cortical brain structures in 22q11DS. To better characterize subcortical alterations in 22q11DS, including modulating effects of clinical and genetic heterogeneity, the authors studied a large multicenter neuroimaging cohort from the ENIGMA 22q11.2 Deletion Syndrome Working Group.Methods: Subcortical structures were measured using harmonized protocols for gross volume and subcortical shape morphometry in 533 individualswith 22q11DS and 330matched healthy control subjects (age range, 6-56 years; 49% female).Results: Compared with the control group, the 22q11DS group showed lower intracranial volume (ICV) and thalamus, putamen, hippocampus, and amygdala volumes and greater lateral ventricle, caudate, and accumbens volumes (Cohen's d values, 20.90 to 0.93). Shape analysis revealed complex differences in the 22q11DS group across all structures. The larger A-D deletion was associated with more extensive shape alterations compared with the smaller A-B deletion. Participants with 22q11DS with psychosis showed lower ICV and hippocampus, amygdala, and thalamus volumes (Cohen's d values, 20.91 to 0.53) compared with participants with 22q11DS without psychosis. Shape analysis revealed lower thickness and surface area across subregions of these structures. Compared with subcortical findings from other neuropsychiatric disorders studied by the ENIGMA consortium, significant convergence was observed between participants with 22q11DS with psychosis and participants with schizophrenia, bipolar disorder, major depressive disorder, and obsessive-compulsive disorder.Conclusions: In the largest neuroimaging study of 22q11DS to date, the authors found widespread alterations to subcortical brain structures, which were affected by deletion size and psychotic illness. Findings indicate significant overlap between 22q11DS-associated psychosis, idiopathic schizophrenia, and other severe neuropsychiatric illnesses.
KW - MOUSE MODEL
KW - SCHIZOPHRENIA SPECTRUM
KW - VOLUME
KW - DISORDERS
KW - CHILDREN
KW - MORPHOMETRY
KW - BEHAVIOR
KW - DOSAGE
KW - CORTEX
U2 - 10.1176/appi.ajp.2019.19060583
DO - 10.1176/appi.ajp.2019.19060583
M3 - Article
C2 - 32046535
SN - 0002-953X
VL - 177
SP - 589
EP - 600
JO - American Journal of Psychiatry
JF - American Journal of Psychiatry
IS - 7
ER -