# Neurodevelopment and Psychosis in the 22q11.2 Copy Number Variants

> **NIH NIH R37** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $717,590

## Abstract

PROJECT SUMMARY/ABSTRACT
The remarkable heterogeneity of developmental neuropsychiatric disorders has been a major barrier for
understanding disease mechanisms. 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. Notably,
a 1.5-2.6 Megabase deletion at the Chromosome 22q11.2 locus results in the most common known
microdeletion disorder, 22q11.2 Deletion Syndrome (22qDel), which is among the greatest known genetic risk
factors for schizophrenia (SCZ). As 22qDel can be detected very early in development, it allows a unique
opportunity for prospective investigation of early biomarkers of psychosis, long before disease-related processes
begin to unfold. Adding to the evidence that this genomic region is highly relevant to the development of
psychosis, the reciprocal 22q11.2 duplication (22qDup) is significantly less common in SCZ cases than in the
general population, suggesting the first putative protective mutation for SCZ. This proposal is for five years of
funding to continue our prospective longitudinal study of mechanisms relevant to neuropsychiatric disease risk
in 22q11.2 copy number variants (CNVs). Our work to date supports an emerging framework of a lifelong
biological vulnerability in 22qDel due to haploinsufficiency for specific genes critical for brain development, in
combination with background genetic risk. This vulnerability sets the stage for subsequent events during
adolescence, including changes in dendritic arborization and increased disruption of thalamocortical circuitry
(across sleep and wake), that lead to escalating clinical and cognitive manifestations. In this second competitive
renewal application we propose to continue our accelerated longitudinal design, prospectively following our large
cohort of youth with 22q11.2 deletions (n=90) through the highest risk period for illness onset, compared to both
demographically comparable typically developing controls (n=45) and youth with reciprocal 22q11.2 duplications
(n=45). Building on our previous findings, our primary goals are: (1) To investigate 22q11.2-related progressive
abnormalities in structural and functional brain biomarkers associated with psychosis risk, in order to identify
developmentally-specific periods of regional and circuit-specific structural and functional neuroanatomic
changes; 2) Using novel methods for real-world assessment of sleep physiology (electroencephalogram
headbands), to pursue the hypothesis that impoverished sleep spindle activity is linked with thalamocortical
network disruption, observed via resting state functional MRI during wake, and increased psychotic
symptomatology, suggesting a common mechanism; and (3) Given our findings that divergent psychosis risk is
underpinned by opposing effects of 22qDel and 22qDup on brain structure, to probe mechanisms underlying
22q11.2 gene dosage effects on neurobehavioral phenotypes...

## Key facts

- **NIH application ID:** 10660244
- **Project number:** 2R37MH085953-11
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** CARRIE E BEARDEN
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $717,590
- **Award type:** 2
- **Project period:** 2009-12-14 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10660244

## Citation

> US National Institutes of Health, RePORTER application 10660244, Neurodevelopment and Psychosis in the 22q11.2 Copy Number Variants (2R37MH085953-11). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10660244. Licensed CC0.

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