Summary: Individuals with 22q11.2 deletion syndrome show significantly reduced overall brain volume and smaller volumes in key subcortical structures—particularly the thalamus, hippocampus, and amygdala—compared with controls.
Source: USC
What if a clearer understanding of schizophrenia could come from a rare but revealing genetic condition?
Pooling magnetic resonance imaging (MRI) data from researchers around the world, investigators at the University of Southern California (USC) have produced the most comprehensive picture to date of brain differences linked to 22q11.2 deletion syndrome (22q11DS), a genetic disorder caused by a small missing segment on chromosome 22. That deletion is one of the strongest known genetic risk factors for schizophrenia, a serious psychiatric illness that affects millions globally.
Published February 12 in the American Journal of Psychiatry, the new multicenter study examined structural brain scans from 533 people with 22q11DS and 330 matched healthy controls, spanning ages 6 to 56. Using harmonized analytic methods developed at USC’s Mark and Mary Stevens Neuroimaging and Informatics Institute (INI), investigators measured intracranial and subcortical volumes and mapped localized shape differences across multiple brain regions.
Key findings include significantly lower intracranial volume (ICV) in the 22q group and reduced volumes in several subcortical structures: the thalamus, putamen, hippocampus, and amygdala. In contrast, several other regions—such as the lateral ventricles, caudate, and nucleus accumbens—were larger in individuals with 22q. Effect sizes for these differences were substantial (Cohen’s d values ranged roughly between −0.90 and 0.93), indicating pronounced structural alterations.
Beyond gross volume changes, detailed shape analyses revealed complex regional patterns of thinning and surface-area differences throughout subcortical structures. The study also compared individuals with different deletion sizes: those with the larger A-D deletion exhibited more extensive shape abnormalities than those with the smaller A-B deletion, suggesting genetic heterogeneity influences the degree of brain alteration.
Crucially, when the researchers compared scans from people with 22q who had psychosis to those without psychosis, the psychosis group showed even larger reductions in ICV and in hippocampal, amygdala, and thalamic volumes. Shape metrics likewise indicated lower thickness and reduced surface areas across subregions of these structures among participants with psychotic illness.
These brain changes in 22q-associated psychosis overlapped significantly with patterns previously reported in idiopathic schizophrenia and with alterations seen across other major psychiatric disorders—bipolar disorder, major depressive disorder, and obsessive-compulsive disorder—based on ENIGMA consortium data. That convergence strengthens the view that 22q11.2 deletion syndrome can serve as a powerful biological model for understanding mechanisms that contribute to schizophrenia and related conditions in the general population.
The study was performed through the ENIGMA 22q11.2 Deletion Syndrome Working Group, a global collaboration led by Paul Thompson at USC’s INI that gathers standardized neuroimaging data from centers across North America, Europe, Australia, and South America to overcome the sample-size limits of studying a rare disorder (occurring in about 1 in 4,000 people).
Christopher R.K. Ching, Ph.D., a postdoctoral researcher at the INI, is first author of the paper. Other key contributors include Paul Thompson and USC colleagues Julio Villalon Reina and Artemis Zavaliangos-Petropulu; the study’s senior author is Carrie E. Bearden, Ph.D., of UCLA. Funding came in part from NIH awards including U54EB020403 (BD2K), R01 MH085953, and T32AG058507.
Source:
USC
Media Contacts:
Leigh Hopper – USC
Image Source:
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”.
Abstract (condensed)
Objective: 22q11.2 deletion syndrome (22q11DS) represents a strong genetic risk factor for schizophrenia. Prior reports on subcortical alterations in 22q11DS varied. This study aimed to characterize subcortical volume and shape differences in a large, harmonized, multicenter neuroimaging cohort.
Methods: Using standardized protocols, the team measured gross volumes and subcortical shapes in 533 individuals with 22q11DS and 330 healthy controls (age range 6–56 years; 49% female).
Results: The 22q11DS group showed lower ICV and reduced thalamus, putamen, hippocampus, and amygdala volumes, alongside enlargement of lateral ventricles, caudate, and accumbens. Shape analyses revealed complex spatial differences, with larger genetic deletions producing more extensive alterations. Within 22q11DS, psychosis was associated with greater reductions in ICV and limbic and thalamic structures. Comparisons with ENIGMA findings showed substantial convergence between 22q11DS-associated psychosis and idiopathic schizophrenia and other severe psychiatric illnesses.
Conclusions: In the largest neuroimaging study of 22q11DS to date, widespread subcortical alterations were evident and were modulated by deletion size and the presence of psychosis. The observed overlap with idiopathic psychiatric disorders supports using 22q11DS as a model to investigate the biological origins of schizophrenia and related illnesses.