# Neurodevelopment and Psychosis in the 22q11.2 Deletion Syndrome

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $672,852

## Abstract

Abstract
Schizophrenia and other psychotic disorders are highly disabling conditions with poorly understood
pathophysiology. One of the central challenges in elucidating mechanisms of psychosis is its remarkable
genetic and phenotypic heterogeneity. Taking a `genetics first' approach (i.e., ascertaining patients based on a
known, homogeneous genetic etiology) may allow us to overcome the barriers posed by this complexity.
22q11.2 deletion syndrome (Velocardiofacial/DiGeorge syndrome; 22q11DS) is a particularly compelling
model, as it represents the greatest known genetic risk factor for psychosis identified to date. As the deletion
can be detected very early in development, it offers an extraordinary opportunity for prospective investigation
of early biomarkers of psychosis, long before disease-related processes begin to unfold. In the current funding
cycle we have elucidated key points of convergence between disturbances in cognition, neural circuitry and
gene expression relevant to psychosis in this genetic risk model and in idiopathic psychosis. In this competitive
renewal application we plan to continue to prospectively follow a large cohort of youth with 22q11DS (n=90)
through the highest risk period for illness onset, and demographically comparable typically developing controls
(n=45), in order to establish whether common mechanisms contribute to psychotic symptomatology in
22q11DS and in idiopathic psychosis. Our primary goals (building on our findings from the original funding
period) are to elucidate biological pathways and brain biomarkers which may represent convergent
mechanisms for disease evolution. Given new discoveries in clinical high risk populations implicating
inflammatory and neurohormonal processes in brain changes associated with the development of psychosis,
we have added novel measures to assess these domains. In particular, our aims are to: 1) Investigate baseline
and progressive abnormalities in structural and functional brain biomarkers, with the prediction that changes in
temporal gray matter and thalamo-cortical functional connectivity will predict worsening cognition, social
function and increased psychotic symptoms over time; 2) Determine the role of inflammatory mechanisms and
stress sensitivity in the evolution of psychotic symptoms, using assays of both peripheral and neural
inflammation [i.e., a novel free water diffusion imaging paradigm which is strongly correlated with positron
emission tomography (PET) indices of activated microglia] and cortisol at each timepoint; 3) Determine
biological pathways associated with psychosis-relevant phenotypes, by investigating upstream regulatory
processes of circulating inflammatory markers; and 4) Given the recent discovery that 22q11.2 duplications
may be protective against schizophrenia, we will prospectively follow 30 patients with gain of function
mutations in the identical locus in order to investigate gene dosage effects on neurobehavioral phenotypes.
This work will...

## Key facts

- **NIH application ID:** 9932494
- **Project number:** 5R01MH085953-10
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** CARRIE E BEARDEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $672,852
- **Award type:** 5
- **Project period:** 2009-12-14 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932494

## Citation

> US National Institutes of Health, RePORTER application 9932494, Neurodevelopment and Psychosis in the 22q11.2 Deletion Syndrome (5R01MH085953-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9932494. Licensed CC0.

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