# High-throughput Functional Analysis of Autism Risk Genes

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $725,870

## Abstract

PROJECT SUMMARY
There is a critical need to advance from gene discovery to the identification of actionable biological mechanisms
in autism spectrum disorders (ASDs). Despite considerable progress in the identification of high confidence
genes that are strongly associated with risk, advancing from ASD genes to biologically relevant cellular and
circuit mechanisms remains a central challenge. We established a high-throughput zebrafish system for the in
vivo functional analysis of multiple ASD genes in parallel. Our analysis of 10 ASD genes in zebrafish mutants
revealed novel points of convergence at multiple neurodevelopmental levels and uncovered ASD gene
subgroups with shared functional effects. As a critical next step, we will leverage the zebrafish system to analyze
the function of 50 ASD genes in parallel at the whole-brain transcriptomic, structural, and circuit levels and
translate our findings to human induced pluripotent stem cells (hiPSCs). Our central objectives are to: (1)
identify convergent molecular signatures resulting from ASD gene LoF; (2) elucidate novel cellular and
circuit mechanisms contributing to whole-brain structural and activity phenotypes; and (3) uncover highly
conserved pharmacological pathways downstream of ASD genes. We hypothesize that ASD genes converge
on shared molecular, cellular, and circuit mechanisms in the developing vertebrate brain, which will allow us to
define novel ASD gene subgroups. This hypothesis is based on compelling evidence for biological convergence
across ASD genes from our group and others. To test this hypothesis, we perform molecular phenotyping of
ASD gene mutants using whole-brain single nuclear RNA-seq (Aim 1); identify cellular phenotypes contributing
to circuit deficits by combining in vivo imaging and cell-type-specific labeling (Aim 2); and conduct parallel
pharmacological screens to identify novel phenotypic suppressors in zebrafish and hiPSCs (Aim 3). The
expected outcomes of this research are to (1) define convergent molecular, cellular, and circuit phenotypes
downstream of ASD genes in the developing vertebrate brain; and (2) leverage the identification of
biologically relevant ASD gene subgoups with shared mechanisms to uncover novel pharmacological
pathways with translational relevance.

## Key facts

- **NIH application ID:** 11049823
- **Project number:** 2R01MH116002-06A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** ELLEN J HOFFMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $725,870
- **Award type:** 2
- **Project period:** 2018-03-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11049823

## Citation

> US National Institutes of Health, RePORTER application 11049823, High-throughput Functional Analysis of Autism Risk Genes (2R01MH116002-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11049823. Licensed CC0.

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