U01HG011723

Development of Polygenic Risk Scores for Diabetes and Complications Across the Life-Span in Populations of Diverse Ancestry - Abstract

Large-scale genome-wide association studies (GWAS) have identified a large number of genetic variants associated with complex diseases. The aggregation of all the variants that are known to contribute to the disease in the form of polygenic risk scores (PRS) improves the prediction of a range of complex diseases. Most PRS have been developed within European ancestry study samples and have shown to perform poorly in other race/ethnic groups, further exaggerating health disparities across ancestries.

As genetic approaches for precision medicine become more popular, there is a critical need to responsively and proactively expand access to accurate PRS. Specifically, diabetes, and its associated complications, are one of the biggest global health problems of the 21st century. In fact, Type 1 and Type 2 diabetes (T1D and T2D), gestational diabetes (GDM), and related complications are excellent disease models to study the utility of PRS for predicting heterogeneous and complex health outcomes in a setting where dramatic racial/ethnic and socioeconomic disparities exist.

Not only are PRS useful to predict T1D and T2D, but they can distinguish between T1D and T2D, and between T2D subtypes. The wealth of existing trans-ancestry GWAS data from diabetes subtypes, complications, and quantitative traits recently generated provides a unique opportunity for constructing highly transferable PRS across populations.

To address the disparities in PRS across ancestries, we have assembled a multi-disciplinary team to aggregate and analyze the largest existing genetic data from more than 1.8 million individuals (35% non-European) with T1D, T2D, GDM, and glycemia-related complications and quantitative traits to improve the PRS prediction of diabetes and progression across the lifespan in diverse ancestries with these aims:

(1) Collection, harmonization, and integration of large-scale, multi-ancestry cohorts with diabetes traits across the life-span and genomics for development, training, and testing PRS for diverse ancestries;

(2) Development of methods to improve PRS prediction in non-European populations by using Bayesian approaches that allow integration of linkage disequilibrium and summary statistics from several ancestries.

(3) Development, testing, and comparing performance of PRS for each trait, development of risk prediction tools that integrate clinical and genetic risk factors, and assessment of scenarios where PRS improve the prediction.

Accomplishing the aims of this proposal will demonstrate how genomic data can inform more efficient and targeted preventive strategies within healthcare systems and across ethnically diverse populations. Findings are expected to advance precision care of patients with diabetes and related conditions in people of diverse ancestral background and serve as a paradigm for many other complex diseases.

The Broad Institute

NHGRI SUPPORTS THE DEVELOPMENT OF RESOURCES AND TECHNOLOGIES THAT WILL ACCELERATE GENOME RESEARCH AND ITS APPLICATION TO HUMAN HEALTH AND GENOMIC MEDICINE. A CRITICAL PART OF THE NHGRI MISSION CONTINUES TO BE THE STUDY OF THE ETHICAL, LEGAL AND SOCIAL IMPLICATIONS (ELSI) OF GENOME RESEARCH. NHGRI ALSO SUPPORTS THE TRAINING AND CAREER DEVELOPMENT OF INVESTIGATORS AND THE DISSEMINATION OF GENOME INFORMATION TO THE PUBLIC AND TO HEALTH PROFESSIONALS. THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM IS USED TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM IS USED TO FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.172 - Human Genome Research

National Human Genome Research Institute (NHGRI) [HHS - NIH]

Cambridge, Massachusetts 021421027 United States

Single Zip Code

Polygenic Risk Score (PRS) Methods and Analysis for Populations of Diverse Ancestry Centers (U01 Clinical Trial Not Allowed) (RFA-HG-20-001)

Amendment Since initial award the total obligations have increased 392% from $986,883 to $4,851,908.