U01HG011719

Enabling Improved Applicability and Transferability of Polygenic Scores Across Diverse Populations - A Focus on South Asians

Polygenic scores, which quantify inherited risk by integrating information from many common sites of DNA variation, hold considerable promise for enabling a tailored approach to clinical medicine. However, alongside considerable (and warranted) enthusiasm, we and others have highlighted a crucial equity issue - current polygenic scores have diminished predictive power in non-European ancestries.

By assembling a team with deep expertise in statistical genetics, clinical informatics, data sharing, and genomic medicine, we outline the Functional and Fine-Mapping Approach to Improve Responsible Risk-Modeling of Polygenic Risk Scores (‘FFAIRR-PRS’) approach to systematically address the key factors driving diminished performance.

To enable analysis by the NHGRI Consortium within the AnVIL ecosystem, we will contribute genetic and rich phenotype data from >57,136 individuals of South Asian ancestry from the Genes & Health and UK Biobank studies, and whole genome sequencing data from 5,734 South Asians from the GenomeAsia Phase 2 to serve as an ancestry-matched reference panel.

South Asian individuals are prioritized based on marked under-representation in genome-wide association studies - accounting for 23% of the global population but only 1.2% of individuals studied - and polygenic prediction efforts to date, as well as a key public health need for enhanced risk stratification.

Individual-level data in AnVIL will be paired with summary association statistics of >100,000 South Asians and >1 million individuals of other ancestries, which will enable enhanced fine-mapping, score weighting, and transe-thnic benchmarking activities.

Our study site aims to:
1. Aggregate and harmonize genotyping and phenotype data and deliver a sharable and scalable end-to-end analytic pipeline that starts with genotyping array data and a phenotype file and enables automated output of polygenic score benchmarking parameters.
2. Develop and share the new 'FFAIRR-PRS' statistical genetics framework, leveraging: (i) fine-mapping to assign causal probabilities based on >180 functional genomic annotations; (ii) incorporating correlations between effect sizes across traits; and (iii) integration of South Asian and non-South Asian GWAS data.
3. Benchmark FFAIRR-PRS scores for 27 important phenotypes in the South Asian datasets and develop risk models that integrate genetic and non-genetic factors. Performance will be benchmarked in accordance with ClinGen Complex Disease Working Group recommendations and compared against individuals of European and other major ancestry groups.

Beyond enhanced polygenic scores - aware of an ultimate aim of clinical implementation - we will develop a framework for integrated absolute risk models calibrated to the U.S. population that account for rare monogenic variants of large effect, family history, lifestyle, and clinical risk factors by adapting the Individualized Coherent Absolute Risk Estimator (ICARE) tool developed by Co-I Chatterjee.

The General Hospital Corporation

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]

Boston, Massachusetts 021142790 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 396% from $999,998 to $4,959,712.