# Unraveling the Genetic Programs Engaged in ASD Neurons Through Coupled Transcriptomic and Phenotypic Readouts

> **NIH NIH R01** · BROAD INSTITUTE, INC. · 2022 · $761,381

## Abstract

Autism spectrum disorders (ASD) are genetically diverse, characterized by both rare variants of large effect size
and common variants of small effect size. Identifying the molecular mechanisms resulting from these variants
presents a key challenge for the development of clinical interventions. Human pluripotent stem-cell derived
neurons (hPSC-Ns) allow studies against a human genetic background, and show altered morphology and
electrophysiology in ASD conditions. However, identifying mechanisms remains difficult with small numbers of
lines, especially for common genetic variants. To overcome this challenge, we will leverage multi-omic
characterization of hPSC-Ns perturbed with CRISPRi knockdown of both large effect size ASD risk genes and
genes related to neuronal morphology (Aim 1) and electrophysiology (Aim 2). We will complement these screens
with a characterization (Aim 3) of a larger, diverse cohort of 46 ASD lines and 46 matched controls which do not
harbor coding variants in the genes perturbed in the previous Aims. An integrative analysis of this data (Aim 4)
will generate interpretable genetic signatures related to each of these phenotypes and will show how these
signatures interact with ASD risk genes. This approach is made possible by new techniques for pooled stem cell
culture developed in Dr. Ralda Nehme’s lab, high content optical profiling methods developed by Dr. Samouil
Farhi’s team, and data integration tools developed by Dr. Ernest Fraenkel’s group. The overall project will provide
a basic neurobiological understanding of hPSC-Ns; provide valuable insight into how both common and rare
variants induce observed cell-intrinsic phenotypes; and define an analytic framework and genetic signatures
which can be used to understand mechanistic recruitment of new genetic risk loci and other psychiatric diseases.

## Key facts

- **NIH application ID:** 10521895
- **Project number:** 1R01MH128366-01A1
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** Samouil Farhi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $761,381
- **Award type:** 1
- **Project period:** 2022-08-10 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10521895

## Citation

> US National Institutes of Health, RePORTER application 10521895, Unraveling the Genetic Programs Engaged in ASD Neurons Through Coupled Transcriptomic and Phenotypic Readouts (1R01MH128366-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10521895. Licensed CC0.

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