# Causal biology of Chd8 haploinsufficiency in complex brain disorders

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $498,323

## Abstract

SUMMARY
Major gains have been in made in mapping the genetic causes of neurodevelopmental disorders (NDDs). In
autism spectrum disorder (ASD) and intellectual disability (ID), de novo mutations to a convergent network of
genes encoding chromatin remodeling factors (CRFs) has emerged as one of the strongest components of
genetic risk. A major challenge now facing the field is identifying the genomic mechanisms and
neurodevelopmental consequences associated with mutations of NDD-associated CRFs. The CRF gene
CHD8 has among the highest rates of de novo loss-of-function mutations observed in ASD and ID cohorts with
mutations also described in schizophrenia and obsessive compulsive disorder cases, and CHD8 mutation
carriers frequently also are diagnosed with macrocephaly. Our work and the work of others have confirmed
that Chd8 germline heterozygous mutation in mice causes NDD-relevant pathological changes across
genomic, neuroanatomical, and behavioral domains. Network analyses have linked functionality of CHD8 and
other NDD-associated CRFs in the developing brain, raising the possibility that understanding CHD8-
associated pathological mechanisms during neurodevelopment will reveal generalizable causal pathways
mediated by CRF haploinsufficiency. However, independent of a role in early brain development, CHD8, as
well as other NDD-associated CRFs, are expressed in neurons and mutation may drive behavioral pathology
via neuron-specific impacts in postnatal brain. Thus, resolving developmental versus neuronal causality is
essential for understanding CRF-associated mechanisms of NDDs. We will leverage conditional Chd8+/-
mice model to dissect in vivo the mechanisms by which Chd8 mutations cause NDD-associated
pathology. Our preliminary data suggests that macrocephaly and cognitive deficits are interdependent on
pathology during early brain development in Chd8+/- mice, and that the molecular mechanisms are associated
with chromatin-associated RNA processing mediated by Chd8. We will apply complementary -omics, cellular
assays, and mouse studies to test this model, specifically, we will: 1) establish the mechanisms through which
Chd8 haploinsufficiency impacts chromatin and transcription in embryonic brain, 2) characterize cell-type
specific impacts of Chd8 haploinsufficiency on neurogenesis during brain development, and 3) define
behavioral, EEG, and synaptic pathology caused by Chd8 haploinsufficiency and test whether such pathology
is driven via developmental versus neuronal mechanism. This research will map the effect of Chd8
haploinsufficiency in vivo, illuminating mechanisms via which CHD8 dosage-sensitivity contributes to NDD
pathology and linking molecular and cellular mechanisms to behavioral and systems level. Importantly, these
critical studies cannot be done using in vitro models and such studies of high interest NDD risk genes is
necessary to bridge genetic association and mechanistic understanding. By revealing causality for top risk
genes ...

## Key facts

- **NIH application ID:** 9974570
- **Project number:** 5R01MH120513-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Alexander Nord
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $498,323
- **Award type:** 5
- **Project period:** 2019-07-08 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974570

## Citation

> US National Institutes of Health, RePORTER application 9974570, Causal biology of Chd8 haploinsufficiency in complex brain disorders (5R01MH120513-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974570. Licensed CC0.

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