Monday, June 30, 2025 6/30/2025

Noncoding mutations in neurodevelopmental disorders

Award Number: R01MH126933
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

Group Awards By:

View Award Description

Noncoding mutations in neurodevelopmental disorders - PROJECT SUMMARY Neurodevelopmental disorders (NDDs) affect >1% of the population and are comprised of multiple phenotypes including autism, intellectual disability, and other developmental delays. Over the last ten years, there has been considerable progress in understand the contribution of rare protein- coding variants in NDDs. However, the role of rare noncoding variation has been less clear due to the limited number of individuals with whole-genome sequencing (WGS) data previously available. We were one of the first to identify aggregate enrichment for promoters and enhancers in the first 516 families assessed by WGS; signals that have now been seen by multiple additional groups. Currently, we have analyzed ~2,700 families with autism and identified enrichment in a top enhancer. In Aim 1 of proposed studies we will expand this work to analyze 10,719 families with NDDs to identify specific noncoding regions using statistical tests to identify enrichment based on sequence context (fitDNM), enriched clustering of variants (GRUMP), and a transmission-disequilibrium based test, respectively. We will perform massively parallel reporter assays (MPRA) to follow up specific noncoding variants in the enriched elements and combine this with deep phylogenetic assessment using existing and new reference genomes (ACES). Our recent work suggests that dosage sensitivity is an important characteristic to consider when testing specific promoters and enhancers for enrichment in NDDs. In Aim 2, we will build a copy number map from 92,081 individuals, without NDDs, from the Centers for Common Disease Genomics dataset. We will specifically assess 1,327,879 noncoding regulatory regions for dosage-sensitivity in the human genome. As in Aim 1, we will follow up identified elements using MPRA and our ACES phylogenetic workup. The primary goal of proposed studies is to improve our understanding of noncoding variants in NDDs. We will do this by 1) identifying noncoding regulatory regions with enrichment of variation in NDDs and 2) developing a dosage sensitivity map of noncoding regulatory regions to inform studies of NDDs. This unique proposal, with its mirrored aims, focuses on noncoding variation as opposed to the majority NDD focus on protein- coding regions and it tests dosage in a large high-quality WGS dataset. This work will be integral to the genetic understanding of NDDs and the consequences of noncoding variation. It will also provide key insights into their role in the overall genetic architecture of NDDs.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $663,869 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	000	4	6/16/2025	NON-COMPETING CONTINUATION	$663,869
														Subtotal = $663,869

Issue Date FY: 2024 ( Subtotal = $718,294 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Mental Health Research Grants	000	3	4/23/2024	NON-COMPETING CONTINUATION	$718,294
														Subtotal = $718,294

Issue Date FY: 2023 ( Subtotal = $772,719 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	000	2	5/26/2023	NON-COMPETING CONTINUATION	$772,719
														Subtotal = $772,719

Issue Date FY: 2022 ( Subtotal = $779,342 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	000	1	7/1/2022	NEW	$779,342
														Subtotal = $779,342

Grand Total All Awards = $2,934,224

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Noncoding mutations in neurodevelopmental disorders

Award Number: R01MH126933

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer