# Identifying enhancers in schizophrenia and bipolar disorder-associated noncoding eQTLs during cortical synaptic organization

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $39,162

## Abstract

PROJECT SUMMARY
Genome-wide association studies of psychiatric disease have repeatedly linked risk for schizophrenia and
bipolar disorder to noncoding regions that are in or near genes relevant in synaptic organization, including an
interval in the third intron of the gene CACNA1C, which encodes the pore-forming subunit of a pan-neuronal
postsynaptic voltage-gated calcium channel. As these variants are located in noncoding DNA, they do not alter
the subsequent amino acid sequence of the protein. Rather, many of the risk variants are expected to be
expression quantitative trait loci (eQTLs) of synaptic genes, and it is most likely that the risk-containing
sequences are enhancers that regulate transcription of a targeted synaptic gene. This adds to a wide body of
research that have identified schizophrenia and bipolar disorder as “disorders of the synapse.” However,
though there is strong evidence linking the risk eQTLs and synaptic organization, the nature of this relationship
is unclear. In this project, I aim to test the hypotheses that (1) non-coding psychotic disorder risk eQTLs of
synaptic genes are enhancers during juvenile or adolescent cortical synaptic development and (2) risk-
associated sequence variation in high-priority enhancers in CACNA1C disrupts the cell-type specific ability of
the sequence to act as an enhancer during cortical synaptogenesis. I will test the first hypothesis by conducting
a massively parallel reporter assay (MPRA) of candidate genomic enhancers that contain eQTLs that
contribute transdiagnostic risk for bipolar disorder and schizophrenia in vivo during cortical synaptogenesis in
mice. I will conduct this MPRA at two time points representing juvenile (P7) and adolescent (P56) synaptic
developmental processes. These experiments will allow me to determine the functional role of top psychotic
disorder-associated risk regions across development during mammalian cortical synaptogenesis. I will also test
for allelic effects, which may allow me to identify eQTLs whose risk allele has a strong effect on transcriptional
regulation. I will test the second hypothesis by conducting a reduced complexity MPRA of identified enhancers
in CACNA1C in vivo during mouse cortical synaptogenesis, including sequences containing the risk allele, the
reference allele, and a deletion centered at the risk-associated SNP. I will also test for cell-type or regional
specificity of expression of CACNA1C enhancers. By testing fewer sequences in my second aim, my sensitivity
to detect allelic differences in activity will be strongly improved and I anticipate being able to determine any
potential differences in activity related to risk-associated sequence variation. The results of these experiments
will clarify the link between risk-related noncoding genomic variation and mechanisms of disease etiology in
mammalian cortical synaptogenesis. Future directions from this research include determining how expression
changes associated with risk variant...

## Key facts

- **NIH application ID:** 10465623
- **Project number:** 1F31MH129135-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Tracy Leigh Warren
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,162
- **Award type:** 1
- **Project period:** 2022-04-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465623

## Citation

> US National Institutes of Health, RePORTER application 10465623, Identifying enhancers in schizophrenia and bipolar disorder-associated noncoding eQTLs during cortical synaptic organization (1F31MH129135-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10465623. Licensed CC0.

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