Summary: Those with 22q11.2 deletion syndrome had significantly lower brain volume, as well as lower volumes in specific structures, including the thalamus, hippocampus, and amygdala.
What if the key to a better understanding of schizophrenia has been here all along–but researchers haven’t had the resources to study it?
Now, thanks to the pooled data and insights from researchers around the world, USC researchers have the clearest picture yet of brain abnormalities associated with the serious mental illness that impacts 20 million people worldwide.
A new study, published February 12 in the American Journal of Psychiatry, analyzed MRI scans of individuals with 22q11.2 deletion syndrome, also referred to as “22q” or DiGeorge syndrome, a genetic disorder caused by a small segment of missing DNA on chromosome 22. This tiny missing portion of chromosome 22 can affect every system in the body and is the strongest known genetic risk factor for schizophrenia.
Compared to a control group, those with 22q had overall significantly lower brain volumes, as well as lower volumes in specific structures including the thalamus, hippocampus and amygdala, compared with the control group. They also had higher volumes in several brain structures. The magnitude of these abnormalities, especially in those 22q individuals with psychosis, was larger than is typical in many other common psychiatric conditions.
About a quarter of people with 22q develop schizophrenia or experience psychotic symptoms, so studying the syndrome provides a unique window into how such psychiatric problems develop over time. But the disorder is rare–about one in 4,000 people have it, making it tough for researchers at any single institution to study the syndrome.
To address that problem, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium launched a new working group to study 22q using data collected by researchers across the U.S., Canada, Europe, Australia and South America. ENIGMA is led by Paul Thompson, associate director of the Mark and Mary Stevens Neuroimaging and Informatics Institute (INI) at the Keck School of Medicine of USC, who has been uniting researchers around the world to pool data and insights on rare diseases for a decade.
“We’ve pieced together many of the major research centers studying 22q11DS around the world to create the largest-ever neuroimaging study of the disorder,” said Christopher Ching, a postdoctoral researcher at the INI and first author of the study.
To get a clear picture of the brain abnormalities associated with schizophrenia in individuals with 22q, the study’s authors examined magnetic resonance imaging (MRI) scans from 533 people with the disorder and 330 healthy control subjects. Using advanced analytic techniques developed at the INI, the authors measured and mapped structural differences between the brains of the two groups.
Notably, the brain changes seen in people with 22q and psychosis significantly overlapped with the brain changes observed in previous neuroimaging studies of schizophrenia and other serious mental illnesses including bipolar disorder, major depression and obsessive-compulsive disorder.
“That’s important because these overlapping brain signatures add evidence to support 22q11DS as a good model for understanding schizophrenia in the wider population,” Ching said. “And thanks to these large ENIGMA studies, we now have a way to directly compare standardized brain markers across major psychiatric illnesses on an unprecedented scale.”
In addition to Ching, other USC authors of the study include Thompson, Julio Villalon Reina and Artemis Zavaliangos-Petropulu. The study’s senior author is Carrie Bearden of UCLA.
Funding: The study was supported in part by NIH grant U54EB020403 from the Big Data to Knowledge (BD2K) Program, NIMH Grant RO1 MH085953, and NIA T32AG058507.
Leigh Hopper – USC
The image is adapted from the USC news release.
Original Research: Closed access
“Mapping Subcortical Brain Alterations in 22q11.2 Deletion Syndrome: Effects of Deletion Size and Convergence With Idiopathic Neuropsychiatric Illness”. Christopher R.K. Ching, Ph.D., Boris A. Gutman, Ph.D., Daqiang Sun, M.D., Julio Villalon Reina, M.D., Ph.D., Anjanibhargavi Ragothaman, M.S., Dmitry Isaev, M.S., Artemis Zavaliangos-Petropulu, B.A., Amy Lin, M.S., Rachel K. Jonas, Ph.D., Leila Kushan, M.S., Laura Pacheco-Hansen, M.A., Ariana Vajdi, B.S., Jennifer K. Forsyth, Ph.D., Maria Jalbrzikowski, Ph.D., Geor Bakker, Ph.D., Therese van Amelsvoort, M.D., Ph.D., Kevin M. Antshel, Ph.D., Wanda Fremont, M.D., Wendy R. Kates, Ph.D., Linda E. Campbell, Ph.D., Kathryn L. McCabe, Ph.D., Michael C. Craig, M.D., Eileen Daly, Ph.D., Maria Gudbrandsen, M.Sc., Clodagh M. Murphy, M.D., Ph.D., Declan G. Murphy, M.D., F.R.C.Psych., Kieran C. Murphy, M.D., Ph.D., Ania Fiksinski, M.Sc., Sanne Koops, Ph.D., Jacob Vorstman, M.D., Ph.D., T. Blaine Crowley, B.A., Beverly S. Emanuel, Ph.D., Raquel E. Gur, M.D., Ph.D., Donna M. McDonald-McGinn, M.S., L.C.G.C, David R. Roalf, Ph.D., Kosha Ruparel, M.S.E., J. Eric Schmitt, M.D., Ph.D., Elaine H. Zackai, M.D., Courtney A. Durdle, B.A., B.S., Naomi J. Goodrich-Hunsaker, Ph.D., Tony J. Simon, Ph.D., Anne S. Bassett, M.D., Nancy J. Butcher, Ph.D., Eva W.C. Chow, M.D., M.P.H., Fidel Vila-Rodriguez, M.D., Ph.D., Adam Cunningham, Ph.D., Joanne Doherty, Ph.D., David E. Linden, Ph.D., Hayley Moss, M.Sc., Michael J. Owen, M.D., Ph.D., Marianne van den Bree, Ph.D., Nicolas A. Crossley, M.D., Ph.D., Gabriela M. Repetto, M.D., Paul M. Thompson, Ph.D., Carrie E. Bearden, Ph.D.
American Journal of Psychiatry doi:10.1176/appi.ajp.2019.19060583.
Mapping Subcortical Brain Alterations in 22q11.2 Deletion Syndrome: Effects of Deletion Size and Convergence With Idiopathic Neuropsychiatric Illness
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.
Subcortical structures were measured using harmonized protocols for gross volume and subcortical shape morphometry in 533 individuals with 22q11DS and 330 matched healthy control subjects (age range, 6–56 years; 49% female).
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, −0.90 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, −0.91 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.
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.