# Functional methylomics approaches for schizophrenia in the frontal cortex and hippocampus

> **NIH NIH R01** · LIEBER INSTITUTE, INC. · 2021 · $418,024

## Abstract

Project Summary/Abstract
 Schizophrenia (SCZD) is a severe mental disorder that imposes a significant burden on public health,
and though the disorder is highly heritable, the nature of the genetic contribution is poorly understood. Recent
efforts in combining existing genome-wide association studies (GWAS) of SCZD by the Psychiatric Genomics
Consortium (PGC) have led to the strongest credible reports of genetic associations with the disorder.
However, the neurobiological mechanisms by which the implicated variants increase the risk for SCZD are
unknown. Here we will expand upon the rich genomic data generated from the Lieber Institute for Brain
Development (LIBD) by incorporating genome-scale DNA methylation (DNAm) data on the same carefully
characterized subjects that have RNA sequencing (RNA-seq) and genetic data to better determine how
genetic risk for SCZD manifests in the human brain. We will utilize new experimental approaches that can
quantify both methyl-cytosine (5mC) and hydroxymethyl-cytosine (5hmC) to untangle total methylation signal
present in previous smaller studies using whole genome bisulfite sequencing (WGBS).
 In this proposal we will perform whole genome bisulfite sequencing on 600 samples (300 donors
across 2 brain regions) and correlate the resulting DNAm levels with genotype, diagnosis, and local
expression levels to better understand epigenetic regulation of schizophrenia risk in the frontal cortex and
hippocampus. We will perform methylation. We will first perform methylation quantitative trait loci (meQTL)
analysis with genetic risk variants for SCZD identified in the PGC, as well as all common variants in these
samples, separately for 5mC and 5hmC levels to determine potential epigenetic mechanisms underlying risk,
and hypothesize increased statistical power by decomposing total DNAm signal. We will then identify genome-
wide significant differentially methylated regions (DMRs) comparing patients with schizophrenia to matched
non-psychiatric controls within and across brain regions using 5mC and 5hmC across both CpG and non-CpG
sites. These regions can then be interrogated for potential functionality by correlating DNAm levels within
DMRs to the matched expression data via RN-seq. Lastly, we will identify functional correlates of 5mC and
5hmC DNAm levels by combining WGBS and RNA-seq on the same samples across the entire methylome
and transcriptome, both within and across diagnostic groups - by further combining genetic data, we can
identify the subset of DNAm-expression correlations driven by genetic versus epigenetic variation.
 Proximal cellular phenotypes like DNAm levels may ultimately show strong and meaningful association
with risk alleles that can further mediate gene expression levels. In the grant, we aim to elucidate some of the
molecular biology underlying genetic risk and molecular signatures of schizophrenia and thereby help identify novel
targets for intervention in the disease process and potential tre...

## Key facts

- **NIH application ID:** 10136720
- **Project number:** 5R01MH112751-05
- **Recipient organization:** LIEBER INSTITUTE, INC.
- **Principal Investigator:** SHIZHONG HAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $418,024
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136720

## Citation

> US National Institutes of Health, RePORTER application 10136720, Functional methylomics approaches for schizophrenia in the frontal cortex and hippocampus (5R01MH112751-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10136720. Licensed CC0.

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