Polygenic Risk Scores: From Discovery to Implementation

Background

Recent advancements in genome-wide association studies (GWAS) and whole-genome sequencing (WGS) identified novel genetic variants for many common disorders, including those specific to the heart, lung, and blood diseases. While the relative disease risk caused by a single genetic variant is usually low, when multiple genetic variants are considered together, along with environmental factors, the cumulative effect on disease risk can be quite large. Polygenic risk scores (PRS) quantify the additive effect of numerous genes to predict risks for complex diseases, including hypertension, coronary artery diseases, Type 2 diabetes, etc. PRS are especially important for high-risk individuals, as timely intervention can significantly reduce or eliminate disease development or disease-associated morbidity and mortality. Therefore, PRS have the potential to guide risk-based population stratification and personalized medicine approaches to target prevention, screening, and treatment strategies.

Purpose and Objectives

The objectives of this workshop were: 1) To identify current gaps in knowledge and evaluate the science of using polygenic risk scores for population and clinical based prevention, 2) To develop a research agenda for evaluating the clinical utility of PRS for prediction of cardiovascular diseases, and 3) To develop strategies for implementing proven effective PRS applications into clinical practice and public health prevention efforts.

Scientific Opportunities

Scientific opportunities from the NHLBI PRS workshop fell into several categories: Research Gaps; Clinical Trials; Implementation Research; Consensus Building and Standardization; and Understanding Stakeholders’ Perspectives.

Research Gaps: Specific research needs include a thorough understanding of PRS and its application, i.e., larger sample sizes in non-Caucasian populations to adequately capture genetic variation and methods to integrate traditional and genetic risk factors for more accurate estimation of participant risk. It was also recommended to use PRS to define subtypes of disease and severity of disease outcomes.

Clinical Trials Research: Understanding what the outcome for a trial would be, short term versus long term outcomes, and whether to design a trial for one specific disease outcome or multiple diseases/outcomes. Additionally, attendees suggested trial designs to assess PRS utility for risk stratification and prevention. The added value of PRS over current risk assessments could be investigated using a “non-inferiority” trial design as opposed to a superiority trial.

Implementation Research: Research to determine what strategies, tools, and resources is needed to improve the adoption of PRS scores in clinical and public health practice. Identifying circumstances where PRS would have high clinical utility, and methods to best communicate PRS results to patients are dissemination and implementation research opportunities.

Consensus Building and Standardization: There is a need for consensus and standardization to facilitate comparisons across studies and validation/replication. One important area that needs standardization is to clearly define outcome measures and the minimal clinically important effect size. Creating clear guidelines for analytic and clinical validity, and utility, and developing professional guideline are also critical.

Understand Patients’, and Other Stakeholders’ Perspective: The Patients’/Participants’/Stakeholders’ Perspectives discussion focused on multidisciplinary efforts to be inclusive and collaborate with all stakeholders to understand the impact of PRS in the clinic. A clearer understanding of what participants do with genomic information is also needed.

Leveraging Existing Resources: Use existing studies that have GWAS, WGS, deep phenotyping, and other omics, such as the Trans-Omics for Precision Medicine (TOPMed) program that also have substantial representation of non-European ancestries, to conduct basic PRS research and implementation science.

Caveats: Workshop participants addressed the concern that the clinical use of current PRS has the potential to exacerbate health disparities. This concern stems from the fact that currently available PRS are several times more accurate in individuals of European ancestry than other ancestries because they were developed from predominantly Eurocentric GWAS. This caveat highlights the importance of prioritizing ancestral diversity in genomic studies and resources.

Publication Plans

The meeting participants will develop a workshop report, highlighting the main objectives of the meeting and scientific opportunities identified. The report will be published in a -peer-reviewed journal.

NHLBI Contact

Cashell E. Jaquish, Ph.D.
Division of Cardiovascular Sciences
National Heart, Lung, and Blood Institute
NIH

Working Group Participants

Organizing Committee

• Bishow Adhikari, Ph.D., DCVS, NHLBI
• Whitney L. Barfield, Ph.D., CTRIS, NHLBI
• Jazmin Bustillo, B.A., CTRIS, NHLBI
• Sean Coady, M.A., DCVSDCVS, NHLBI
• Jennifer Curry, M.P.H., CTRIS, NHLBI
• Yi-Ping Fu, Ph.D., DCVS, NHLBI
• Weiniu Gan, Ph.D., DLD, NHLBI
• Cashell E. Jaquish, Ph.D., DCVS, NHLBI
• Muin Khoury, M.D., Ph.D., CDC
• Mollie Minear, Ph.D., DCVS, NHLBI
• George J. Papanicolaou, Ph.D., DCVS, NHLBI
• Nicole Redmond, M.D., Ph.D., M.P.H., DCVS, NHLBI

Presenters, Moderators, and Discussants

• Whitney Barfield, Ph.D., CTRIS, NHLBI
• Eric Boerwinkle, Ph.D., UTHSC Houston
• Nilanjan Chatterjee, Ph.D., Johns Hopkins School of Medicine
• Katherine Donigan, Ph.D., FDA
• Weiniu Gan, Ph.D., DLD, NHLBI
• Cashell E. Jaquish, Ph.D., DCVS, NHLBI
• Sekar Kathiresan, M.D., Broad Institute, MGH, Workshop Co-Chair
• Muin Khoury, M.D., Ph.D., CDC
• Bertram Koelsch, Ph.D., 23andMe
• Iftikhar J. Kullo, M.D., Mayo Clinic
• Latrice Landry, M.S., Ph.D., M.Sc., Harvard Medical School
• Karen Meagher, Ph.D., Mayo Clinic
• George A. Mensah, M.D., FACC, CTRIS, NHLBI
• Mollie Minear, Ph.D., DCVS, NHLBI
• George Papanicolaou, Ph.D., DCVS, NHLBI
• Daniel Rader, M.D., University of Pennsylvania
• Dan Roden, M.D.C.M., Vanderbilt University Medicine Center
• Edwin Silverman, M.D., Ph.D., Harvard School of Medicine
• Murat Sincan, M.D., Sanford Imagenetics
• Amy Sturm, M.S., L.G.C, Geisinger, Workshop Co-Chair
• Ali Torkamani, Ph.D., Scripps Research Institute
• Brenda Wilson, MBChB, MSc, MRCP, FFPH, Memorial University of Newfoundland
• Alicia Zhou, Ph.D., Color Genomics

NIH Staff Attendees

• Bishow Adhikari, Ph.D., DCVS, NHLBI
• Whitney Barfield, Ph.D., CTRIS, NHLBI
• Joy Boyer, Ph.D., DGS, NHGRI
• Lawrence Brody, Ph.D., DGS, NHGRI
• Jazmin Bustillo, B.A., CTRIS, NHLBI
• Sean Coady, M.A., DCVSDCVS, NHLBI
• Jennifer Curry, M.P.H., CTRIS, NHLBI
• Yi-Ping Fu, Ph.D., DCVS, NHLBI
• Weiniu Gan, Ph.D., DLD, NHLBI
• Elizabeth Gillanders, Ph.D., GEB, NCI
• Emily Harris, Ph.D., M.P.H., DCCP, NCI
• Lucia Hindorff, Ph.D., M.P.H., DGM, NHGRI
• Cashell E. Jaquish, Ph.D., DCVS, NHLBI
• Nicole Lockhart, Ph.D., DGS, NHGRI
• Teri Manolio, M.D., Ph.D., DGM, NHGRI
• Leah E. Mechanic, Ph.D., M.P.H., GEB, NCI
• George A. Mensah, M.D., FACC, CTRIS, NHLBI
• Mollie Minear, Ph.D., DCVS, NHLBI
• George Papanicolaou, Ph.D., DCVS, NHLBI
• Erin Ramos, Ph.D., M.P.H., DGM, NHGRI
• Nicole Redmond, M.D., Ph.D., M.P.H., DCVS, NHLBI
• Robb Rowley, Ph.D., DGM, NHGRI