Mapping Subcortical Brain Alterations in 22q11.2 Deletion Syndrome: Effects of Deletion Size and Convergence With Idiopathic Neuropsychiatric Illness

Christopher R.k. Ching, Boris A. Gutman, Daqiang Sun, Julio Villalon Reina, Anjanibhargavi Ragothaman, Dmitry Isaev, Artemis Zavaliangos-petropulu, Amy Lin, Rachel K. Jonas, Leila Kushan, Laura Pacheco-hansen, Ariana Vajdi, Jennifer K. Forsyth, Maria Jalbrzikowski, Geor Bakker, Therese Van Amelsvoort, Kevin M. Antshel, Wanda Fremont, Wendy R. Kates, Linda E. CampbellKathryn L. Mccabe, Michael C. Craig, Eileen Daly, Maria Gudbrandsen, Clodagh M. Murphy, Declan G. Murphy, Kieran C. Murphy, Ania Fiksinski, Sanne Koops, Jacob Vorstman, T. Blaine Crowley, Beverly S. Emanuel, Raquel E. Gur, Donna M. Mcdonald-mcginn, David R. Roalf, Kosha Ruparel, J. Eric Schmitt, Elaine H. Zackai, Courtney A. Durdle, Naomi J. Goodrich-hunsaker, Tony J. Simon, Anne S. Bassett, Nancy J. Butcher, Eva W.c. Chow, Fidel Vila-rodriguez, Adam Cunningham, Joanne Doherty, David E. Linden, Hayley Moss, Michael J. Owen, Marianne Van Den Bree, Nicolas A. Crossley, Gabriela M. Repetto, Paul M. Thompson, Carrie E. Bearden

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Objective: 22q11.2 deletion syndrome (22q11DS) is among the strongest known genetic risk factors for schizophrenia. Previous studies have reported variable alterations in subcortical 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.

Original languageEnglish
Pages (from-to)589-600
Number of pages12
JournalAmerican Journal of Psychiatry
Issue number7
Early online date12 Feb 2020
Publication statusPublished - 1 Jul 2020


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