# Deciphering the role of histone methyltransferase SETD1A in schizophrenia susceptibility

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $495,202

## Abstract

PROJECT SUMMARY
 Collective data from recent whole exome sequencing studies in schizophrenia
confirmed a prominent enrichment of gene-disruptive de novo loss-of-function mutations
and led to the identification of the contribution of SETD1A, which encodes for a histone
methyltransferase. Notably, SETD1A mutations confer a large increase in disease risk,
which provides a good starting point for disease modeling.
 Unambiguous identification of SETD1A as a SCZ risk gene emphasizes the important
role that neural gene regulation plays in the genetic architecture of schizophrenia,
consistent with accumulating evidence supporting an important role of regulatory
common and rare variants in neuropsychiatric disease risk. This finding is also
consistent with several lines of evidence suggesting that histone methylation is more
broadly relevant to SCZ including the recent observation that histone methylation
showed the strongest statistical enrichment among 4,939 biological pathways in GWAS
data of psychiatric disorders. The fact that both common and rare risk variants
aggregate in this particular biological pathway highlights its importance for the etiology of
schizophrenia. However it is not clear at this stage how to translate a ubiquitous
molecular process such as chromatin modification into a mechanistic and disease-
specific insight. In this regard, the SETD1A finding provides a handle, a starting point
from which to build a model and test hypotheses.
 The goal of this proposal is to address the critical question of how chromatin
regulation deficits play a role in the pathogenesis of SCZ by (i) investigating the
developmental requirement of Setd1a on cognitive and synaptic function in mice and the
nature of the neural circuits affected by its deficiency (ii) identifying direct neuronal
targets of Setd1a in the prefrontal cortex and (iii) generating and analyzing human
SETD1A-deficient cortical neurons.
 The ultimate goal of the proposed studies of chromatin regulation in mental illness is
to understand when/where/how genetic vulnerabilities affect gene expression in the
brain and shape brain circuitry and function. The proposed studies will also reveal a host
of schizophrenia candidate genes and promise important advances in our
understanding, diagnosis, and treatment of debilitating psychiatric disorders, such as
schizophrenia.

## Key facts

- **NIH application ID:** 10114328
- **Project number:** 5R01MH112860-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** JOSEPH A GOGOS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $495,202
- **Award type:** 5
- **Project period:** 2017-06-02 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114328

## Citation

> US National Institutes of Health, RePORTER application 10114328, Deciphering the role of histone methyltransferase SETD1A in schizophrenia susceptibility (5R01MH112860-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10114328. Licensed CC0.

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