# A novel method to resolve the complex genome rearrangements of the large copy number variants (CNVs) associated with psychiatric disorders

> **NIH NIH K01** · STANFORD UNIVERSITY · 2022 · $179,388

## Abstract

Project Summary
 The proposed project serves as a platform to obtain the key training and research experiences in
achieving the long-term career goal of becoming a leading academic principal investigator with a primary focus
of developing and applying genomic methods to understand the complex genetic components and biological
mechanisms of neuropsychiatric disorders.
 Chromosomal aberrations in the form of large deletions or duplications (copy number variants, CNVs),
such as those on 1q21.1, 16p11.2, and 22q11.2, are the strongest known risk factors for neuropsychiatric
disorders. For this reason, these large CNVs serve as key points of entry for investigating the molecular
etiology. However, it is unknown why each of these CNVs is associated with diverse clinical outcomes. For
example, deletions and duplications at 16p11.2 are strong risk factors for schizophrenia (SZ) and autism
spectrum disorder (ASD). Duplications produce a greater than 10-fold increase in risk for SZ, but ASD is
frequent in carriers of deletions as well as duplications. The large stretches of human-specific segmental
duplications (HSDs) that both constitute and mediate the formation of these large “neuropsychiatric” CNVs are
inaccessible to current genome sequencing analysis due to their high degree of repetitiveness and complexity.
CNV studies to date have not been able to consider the genetic variations inside these hundreds of kilobases
to megabases of HSDs. Thus, we do not know the exact “genomic scar” of each CNV in individual carriers
including additional smaller-scale rearrangements, gene fusions, and copy number changes of paralogs, the
diversity HSD rearrangements across different CNV carriers, and the concomitant functional effects.
 The major aims here are to (1) develop generalizable genome analysis methods to solve this important
problem in psychiatric genetics in established cell lines carrying the 16p11.2 deletions and duplications as the
first targets of this new approach, (2) to develop high-throughput genotyping assays so that studying the
diversity of HSD rearrangements can be applied to expanded groups of affected individuals where only DNA
sample (no cell lines) is available and to future cohort association studies, and (3) to investigate the functional
effects of HSD rearrangement diversity on CNV biology using cortical organoid models.
 To facilitate career development and transition to an independent investigator, the following five training
goals will be achieved under the support and guidance of the mentorship team: (1) developing expertise in
targeted genome assembly analysis and optical DNA mapping; (2) expanding knowledge in developmental
neuroscience and pathophysiology of psychiatric disorders; (3) gaining hands-on expertise in neuronal
organoid modelling (4) acquiring expertise in chromatin interaction analysis and single-cell RNA expression
analysis of neural organoids; (5) gaining experience in grant writing. The hands-on training will prima...

## Key facts

- **NIH application ID:** 10429771
- **Project number:** 1K01MH129758-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Bo Zhou
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $179,388
- **Award type:** 1
- **Project period:** 2022-02-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10429771

## Citation

> US National Institutes of Health, RePORTER application 10429771, A novel method to resolve the complex genome rearrangements of the large copy number variants (CNVs) associated with psychiatric disorders (1K01MH129758-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10429771. Licensed CC0.

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