# Whole genome dissection of genetic mechanisms that underlie the phenotypic spectrum of autism

> **NIH NIH R56** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $739,129

## Abstract

Whole genome dissection of genetic mechanisms that underlie the phenotypic spectrum
of autism
It is recognized that the genetic etiology of Autism Spectrum Disorder (ASD) is multifactorial,
with contributions from multiple factors including de novo mutations, rare inherited variants,
polygenic risk scores (PRS) and sex. Genetic studies have identified >100 ASD susceptibility
genes. However, studies have each been carried out one modality at a time (GWAS, exome or
genome). Consequently, there are major gaps in our understanding of the genetic mechanisms
underlying ASD. For instance, the heritability of ASD explained has not been systematically
characterized for all forms of rare and common variant risk, including structural variant (SVs)
and tandem repeats (TRs). Non-additive effects of rare and common variants have not been
systematically explored. Furthermore, it is not understood how rare and common variants, in
genes and neurodevelopmental pathways, influence ASD symptom domains and ultimately
converge to a diagnosis of ASD. Recent studies from our labs (PMID: 35654974, 33442040)
have shown that multiple factors act in combination in the individual to determine risk for ASD,
and each genetic factor has distinct phenotypic correlates. These results highlight knowledge
that can be gained from an integrated analysis of genomic and phenotypic datasets in ASD
families. With a vast increase in sample size, we have sufficient power to address these
questions in the following aims (1) Complete assembly of genomic and phenotypic data on
62,328 ASD families (N = 204,428 subjects) and perform a whole genome analysis of the
heritability explained by common and rare SNVs, SVs, and TRs; (2) Investigate novel genetic
mechanisms that could explain missing heritability, including gene x gene and gene x sex,
interactions; and (3) Dissect the genetic effects of molecular and cellular pathways on cognitive
traits. An integrated analysis of variant types across a range of frequencies could set a new bar
for the heritability of ASD explained, could yield clues to the nature of the unexplained, and
could provide mechanistic basis insights into the effects of genes on cognition

## Key facts

- **NIH application ID:** 10891821
- **Project number:** 1R56MH133899-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Jonathan Sebat
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $739,129
- **Award type:** 1
- **Project period:** 2023-09-08 → 2025-09-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891821

## Citation

> US National Institutes of Health, RePORTER application 10891821, Whole genome dissection of genetic mechanisms that underlie the phenotypic spectrum of autism (1R56MH133899-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10891821. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*