# SZ-associated loci: Functional consequences and treatment opportunities

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $717,442

## Abstract

Normal development and healthy life are the result of the coordinated function of gene networks that
appropriately adjust their equilibrium as needed. Functional genetic variation can shift network equilibrium and
under unfavorable circumstances make networks fail, leading to disease. Most common functional genetic
variants have small effects at the organism level, however our and others' data suggest that they may have
much larger effects on isolated cells, in the absence of the organism's buffering defense mechanisms. In cells
changes can be more striking, the most immediate change being in the cell's transcriptional output. The
transcriptional signature of a functional variant reflects the specific networks it disrupts and when studied
across many variants can help identify intervention targets. We propose to study 10 SZ associated loci and
identify their common networks and candidate pharmacological interventions through the following specific
aims: 1) We will choose loci where one or few experiments can confidently achieve targeting the functional
variant. We will edit the genome of one male and one female induced pluripotent stem cell (iPSc) line to
generate homozygotes for the risk and non-risk allele. These will be a resource for the next aims and for
sharing with others. 2) We will differentiate the iPSc to cortical neurons and to astrocytes and compare the
transcriptomes of the two homozygotes that are otherwise isogenic. We will perform 20 locus specific
transcriptome analyses per cell type (10 in male and 10 in female cells) and compare results. 3) We will
analyze all loci together to identify gene clusters that similarly change their expression in response to many
modified loci. We will perform exploratory analyses that may offer insights in the involvement of these clusters
in disease risk, the best candidate cluster for follow up and the specific relationship of each cluster to clinical
presentation. We will then do a first screen for complementary drug signatures utilizing public resources, follow
up select compounds to verify complementarity in neurons and astrocytes, test for rescue of the SZ variant
induced changes and identify possible male-female differences. At the end of the project we will have created
the first resource of modified iPS cells carrying functionally confirmed SZ-risk alleles. We will have identified
gene clusters reflecting signatures of network disruptions shared by many SZ loci. We will have determined the
specificity each cluster contributes to the disease phenotype and identified candidate pharmacological
interventions for further testing.

## Key facts

- **NIH application ID:** 10143301
- **Project number:** 5R01MH113215-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Dimitrios Avramopoulos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $717,442
- **Award type:** 5
- **Project period:** 2018-08-03 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143301

## Citation

> US National Institutes of Health, RePORTER application 10143301, SZ-associated loci: Functional consequences and treatment opportunities (5R01MH113215-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10143301. Licensed CC0.

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