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Massive-scale genomic risk assessment to inform precision medicine across the spectrum of monogenic and common forms of diabetes

Award Number: R01DK140545
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/19/2025
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Massive-scale genomic risk assessment to inform precision medicine across the spectrum of monogenic and common forms of diabetes - Diabetes represents one of the biggest global health problems of the 21st century. Genome wide association studies (GWAS) have identified hundreds of common genetic variants associated with the most prevalent forms of diabetes, type 1 (T1D) and type 2 (T2D). Additionally, monogenic diabetes accounts for approximately 2-6% of pediatric-onset diabetes cases and is caused by rare variants with large effect. Monogenic diabetes is often undiagnosed, particularly in people of non-European genetic ancestry. Determining whether a given rare variant causes monogenic diabetes remains challenging in people of all ancestries but is particularly problematic for populations of non-European ancestry. An important class of genetic variants increasingly being recognized are rare variants of intermediate penetrance (VIP), which are associated with an intermediate diabetes subtype between common and monogenic forms of diabetes. It is currently unknown whether or how to document VIPs in clinical reports, and as a result, reporting approaches by clinical labs vary widely, creating confusion for providers and patients. This group of genetic variants highlights the continuum of diabetes subtypes that exists and underscores how the current framework for categorizing diabetes into monogenic vs common diabetes is likely over-simplified. A unified framework and updated guidelines for interpretation, classification, and reporting, i.e. for diagnostic and screening purposes, of variants across the spectrum of penetrance are urgently needed. To address these limitations, we will analyze the largest ever dataset of rare variation linked to diabetes phenotyping, comprising > 1.1M participants (33% non-European) to assess variant penetrance (Aim 1). We will integrate this resource with i) high-throughput cellular assays to allow functional validation rare variants at scale and with ii) deep phenotypic characterization of variant carriers in the world largest monogenic diabetes registries (Aim 2). We will work with the Clinical Genome Resource (ClinGen) Monogenic Diabetes Expert Panel (MDEP) and ClinGen Low Penetrance/Risk allele working groups to improve variant interpretation, develop a new variant classification framework, and create a prototype of a more comprehensive report that incorporates genetic variation across the allele frequency spectrum (Aim 3). Accomplishing the aims of this proposal will demonstrate how genomic data from ancestrally diverse populations can improve diagnosis of diabetes subtypes, thereby advancing precision medicine for all. Additionally, the framework we develop for classifying and reporting findings will serve as a paradigm for many other diseases with complex and monogenic forms.


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: 2026 ( Subtotal = $765,305 )
2026	2026	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	2	8/12/2026	SUPPLEMENT FOR EXPANSION	$0
2026	2026	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	8/5/2026	SUPPLEMENT FOR EXPANSION	$64,682
2026	2026	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/27/2026	NON-COMPETING CONTINUATION	$668,223
2026	2026	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	8/6/2026	SUPPLEMENT FOR EXPANSION	$32,400
														Subtotal = $765,305

Issue Date FY: 2025 ( Subtotal = $882,180 )
2025	2025	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/17/2025	NEW	$785,491
2025	2025	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	1	9/23/2025	NEW	$0
2025	2025	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	9/18/2025	SUPPLEMENT FOR EXPANSION	$32,400
2025	2025	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	9/18/2025	SUPPLEMENT FOR EXPANSION	$64,289
														Subtotal = $882,180

Grand Total All Awards = $1,647,485

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Massive-scale genomic risk assessment to inform precision medicine across the spectrum of monogenic and common forms of diabetes

Award Number: R01DK140545

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/19/2025

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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