# Multimodal Developmental Neurogenetics of Females with ASD

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2021 · $2,281,273

## Abstract

Project Summary
Autism Spectrum Disorder (ASD) disproportionately affects males (♂) over females (♀), possibly because of a
Female Protective Effect (FPE). Characterizing the FPE may help us to understand and treat ASD in both sexes.
Our Network has contributed to understanding sex differences in ASD at the levels of gene structure and
expression, neural dynamics, brain function and connectivity. We have curated an unprecedented sex-balanced,
age-, IQ- and severity-matched cohort of cognitively-able school-age ♂, and ♀ with ASD, age- and IQ-matched
typically developing (TD) children and unaffected siblings (US). At T1, we conducted behavioral phenotyping and
measured key neural systems at the levels of brain structure, connectivity, function and temporal dynamics.
Genotyping, whole-genome sequencing and gene expression analyses are underway. We now seek to pursue
an extraordinary opportunity to assess our participants again (T2) as they make the transition through
adolescence and into young adulthood. Our field has failed to generate a sufficient knowledge base to help
optimize this transition for people living with ASD and their families. We will leverage the expertise of our Network
to identify sex differences in ASD longitudinal brain development during this important transition. We will clarify
both temporal and spatial characteristics of developing social perception, emotion regulation, reward and implicit
language learning circuits, in addition to neural mechanisms for sensory habituation, creating dimensional, multi-
level neural signatures of brain development. We will bridge DNA sequence and brain development and relate
neural signatures to behavior and genetics to predict “real-world” functioning in young adulthood. We will combine
multiple levels of biology and endophenotypes—SNVs, CNVs, clinical measures, pubertal status, presence of
seizures/epilepsy, sex hormones and multimodal, longitudinal measures of brain development—into one
framework using an Integrated Weighted Gene Coexpression Network Analysis (iWGCNA). Finally, we will extend
our T1 systems-biology approach through a collaboration*with ASD self-advocates/participants to evaluate the
experiential validity of our findings. The proposed research marks the start of a new era in which advanced
multimodal neuroimaging and genetic analyses will evolve into an integral part of a translational research chain.
Novel behavioral treatment and pharmacotherapies for ASD may be further developed in adolescence and young
adulthood with the tremendous benefit of directly and more precisely assessing impairment and change in neural
circuits. By providing information about distinct, sex/gender-based developmental pathways in ASD, this study
will identify if intervention/prevention strategies should include sex-based modifications.

## Key facts

- **NIH application ID:** 10227950
- **Project number:** 5R01MH100028-11
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Kevin A Pelphrey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $2,281,273
- **Award type:** 5
- **Project period:** 2019-01-31 → 2022-09-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10227950

## Citation

> US National Institutes of Health, RePORTER application 10227950, Multimodal Developmental Neurogenetics of Females with ASD (5R01MH100028-11). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10227950. Licensed CC0.

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