# Higher Order Chromatin and  Genetic Risk for Schizophrenia

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $815,593

## Abstract

The large majority of genomic loci linked to schizophrenia heritability by genome-wide association harbor
regulatory non-coding DNA, including enhancers and repressors, that are not bound to the nearest TSS but
instead tethered via chromosomal contacts to genes located elsewhere on the chromosome. Therefore,
unsurprisingly, `linear genome' based approaches such as gene expression quantitative trait loci (eQTL) and
SNP prioritization algorithms have very limited success in assigning specific target genes to risk loci. Guided
by recent Hi-C genome-scale chromosomal contact mapping studies by us and others, we will test in this
proposal whether the genetic risk architecture of schizophrenia is associated with cell-type specific
vulnerabilities as it pertains to the developmental reorganization of the chromosomal connectome. We predict
that neuronal specification into glutamatergic, GABAergic and dopaminergic lineages associated with cell-type
specific genome-scale prunings of chromosomal contacts and loss of smaller-scaled chromatin domains. This
includes the domain protoype of many of the smaller self-folded `topologically-associated domain' (TAD), with
the developmental dissolution of many subTADs nested into larger and megadomain TADs. Furthermore, we
predict that differentiating neurons show a disproportionate increase in chromosomal contacts anchored in
sequences conferring heritable risk for schizophrenia and related cognitive disorders and traits. We will monitor
developmentally regulated shufflings of intranuclear positions for specific GWAS loci and predict mportant
differences between the various neural cell types isogenically generated from hiPSCs. If so, then the
`functional epistasis', or least co-regulation, of subsets of risk loci sharing the same nuclear sub-territory could
be highly dependent on cell type. Last but not least, we predict that targeted mobilization of specific chromatin
domains by CRISPR-Genome Organization (CRISPR-GO) approaches can be harnessed for simultaneous
targeting of multiple GWAS locis to to specific nuclear compartments such as the nuclear lamina or Cajal body,
resulting in multi-layered transcriptome and epigenome changes and cell-type specific phenotypic alterations.

## Key facts

- **NIH application ID:** 10468646
- **Project number:** 5R01MH106056-08
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Schahram Akbarian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $815,593
- **Award type:** 5
- **Project period:** 2015-01-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468646

## Citation

> US National Institutes of Health, RePORTER application 10468646, Higher Order Chromatin and  Genetic Risk for Schizophrenia (5R01MH106056-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10468646. Licensed CC0.

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