Polygenic Risk Score Testing for High Genetic Risk of Diseases

(GenoVA Trial)

Overseen By Jason L. Vassy, MD, MPH, SM

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Harvard Medical School

Disqualifiers: Coronary artery disease, Atrial fibrillation, Type 2 diabetes, Colorectal cancer, Breast cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the usefulness of polygenic risk score (PRS) testing for individuals who might be at high genetic risk for diseases such as heart disease, type 2 diabetes, and certain cancers. The researchers aim to determine if knowing one's risk can help delay or prevent these diseases over two years. Participants will receive their risk results either immediately or after 24 months to assess if early knowledge makes a difference. This trial targets individuals aged 50-70 who have not been diagnosed with any of these diseases. As an unphased study, it offers a unique opportunity to contribute to groundbreaking research that could improve future health outcomes.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators for more details.

What prior data suggests that polygenic risk score testing is safe?

Research has shown that polygenic risk scores (PRS) are safe to use. These scores analyze a person's DNA to predict their risk for certain diseases. No reports of harm have emerged from using PRS. The tests do not involve taking medicine or undergoing procedures; instead, they provide information about genetic risks for conditions like heart disease, diabetes, and cancer.

One study found that sharing PRS results with individuals at risk for heart disease helped them reduce their chances of major heart problems. This finding suggests that knowing one's PRS might encourage healthier choices. Since PRS involves only the analysis of genetic information, it is considered safe with no concerns. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about Polygenic Risk Score (PRS) testing because it offers a personalized approach to assessing genetic risk for diseases. Unlike standard risk assessments that might rely on family history or single genetic markers, PRS analyzes multiple genetic variations to provide a comprehensive risk profile. This method could lead to earlier and more precise interventions tailored to an individual's genetic makeup. By empowering patients and healthcare providers with detailed genetic risk information, PRS has the potential to revolutionize preventive care strategies and improve long-term health outcomes.

What evidence suggests that polygenic risk score testing could be effective for high genetic risk of diseases?

Research has shown that polygenic risk scores (PRS) can predict a person's likelihood of developing certain diseases based on their genes. These scores use genetic information to estimate the risk of conditions such as heart disease, irregular heartbeat, type 2 diabetes, and some cancers, including colorectal, breast, and prostate cancer. Studies have found that combining PRS with other health factors enhances prediction accuracy. This trial will evaluate the effectiveness of PRS in identifying individuals at high genetic risk. Participants in the PRS-high and PRS-average arms will receive their PRS results at baseline, while those in the usual care arms will receive their results after a 24-month observation period. Although PRS is promising, it remains under study and is not yet widely used in medical practice. ^{6 7 8 9 10}

Who Is on the Research Team?

Jason L. Vassy, MD, MPH, SM

Principal Investigator

Harvard Medical School (HMS and HSDM)

Are You a Good Fit for This Trial?

This trial is for individuals aged 50-70 who have a high genetic risk but no current diagnosis of coronary artery disease, atrial fibrillation, type 2 diabetes, colorectal cancer, breast cancer, or prostate cancer. Pregnant individuals, those incarcerated or institutionalized, and anyone with a known diagnosis of these diseases cannot participate.

Inclusion Criteria

I do not have a history of heart disease, irregular heartbeat, diabetes, or cancer.

I have no history of heart disease, diabetes, or certain cancers.

I am between 50 and 70 years old.

Exclusion Criteria

I have been diagnosed with one of the six specified diseases.

Pregnancy

You are currently in jail or a mental health facility.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Participants and providers receive PRS results and educational resources

1 week

1 visit (in-person)

Observation

Participants are monitored for changes in clinical management and time-to-diagnosis of diseases

24 months

Regular follow-ups as per study protocol

Follow-up

Participants are monitored for safety and effectiveness after the main observation period

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Polygenic risk score (PRS)

Trial Overview

The study is testing the effectiveness of polygenic risk score (PRS) testing in predicting the development of six different diseases over two years. It aims to see if PRS can help identify these conditions earlier among people at high genetic risk.

How Is the Trial Designed?

Group I: Polygenic risk score (PRS) - high risk stratum Experimental Treatment 1 Intervention

Patient-participants in the PRS-high arm and their providers will receive their high-PRS results at baseline, along with educational resources about the results.

Group II: Polygenic risk score (PRS) - average risk stratum Experimental Treatment 1 Intervention

Patient-participants in the PRS-average arm and their providers will receive their average-PRS results at baseline, along with educational resources about the results.

Group III: Usual care (UC) - high risk stratum Active Control 1 Intervention

Patient-participants in the UC-high arm and their providers will receive their high-PRS results after a 24-month observation period, along with educational resources about the results.

Group IV: Usual care (UC) - average risk stratum Active Control 1 Intervention

Patient-participants in the UC-average arm and their providers will receive their average-PRS results after a 24-month observation period, along with educational resources about the results..

Polygenic risk score (PRS) is already approved in United States, European Union for the following indications:

Approved in United States as Polygenic Risk Score for:

• Coronary artery disease
• Atrial fibrillation
• Type 2 diabetes mellitus
• Colorectal cancer
• Breast cancer
• Prostate cancer

Approved in European Union as Polygenic Risk Score for:

• Cardiovascular diseases
• Diabetes
• Cancer risk assessment

Who Is Running the Clinical Trial?

Harvard Medical School

Lead Sponsor

Trials

30

Recruited

40,700+

Harvard Medical School (HMS and HSDM)

Lead Sponsor

Trials

208

Recruited

1,421,000+

Boston VA Research Institute, Inc.

Lead Sponsor

Trials

24

Recruited

10,800+

VA Boston Healthcare System

Collaborator

Trials

73

Recruited

971,000+

Published Research Related to This Trial

Polygenic risk scores (PRS) can help predict genetic susceptibility to mental health disorders, but they cannot definitively diagnose these conditions on their own, as they only capture part of the genetic risk.

Combining PRS with other risk factors may enhance clinical decision-making and improve predictions for treatment responses and adverse health outcomes, but more extensive data from larger samples are needed to fully realize their potential in psychiatry.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Could Polygenic Risk Scores Be Useful in Psychiatry?: A Review. Murray, GK., Lin, T., Austin, J., et al.[2022]

Polygenic risk scores (PRS) can help estimate an individual's genetic susceptibility to complex disorders, but their effectiveness in the general population is currently low, limiting their clinical utility.

PRS may be more beneficial in specific groups with a higher likelihood of disease, such as early-stage patients, but challenges remain in applying these scores across diverse populations and translating them into actionable lifetime risk assessments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polygenic risk scores: from research tools to clinical instruments. Lewis, CM., Vassos, E.[2021]

Polygenic risk scores (PRS) can be calculated from a simple saliva or blood sample and provide insights into an individual's genetic susceptibility to various diseases, but they cannot definitively predict future diagnoses due to the complex nature of disease risk.

While PRS can aid in clinical decision-making and help stratify patients for screening programs, their effectiveness is limited and requires further research to fully understand their role in treatment choices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

From Basic Science to Clinical Application of Polygenic Risk Scores: A Primer. Wray, NR., Lin, T., Austin, J., et al.[2022]

Genotype imputation can introduce variability in polygenic risk scores (PRSs) at the individual level, but this variability is generally minor (less than 5 percentile rank change) and does not significantly affect score interpretation for most individuals.

The study suggests using deterministic imputation methods or averaging multiple stochastic imputation results to minimize fluctuations in PRS calculations, ensuring more stable and reliable genetic risk assessments for individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genotype imputation and variability in polygenic risk score estimation. Chen, SF., Dias, R., Evans, D., et al.[2022]

Polygenic Risk Scores (PRS) can help identify individuals at high risk for certain conditions, which could lead to more targeted and effective screening interventions in precision medicine.

Current PRS are primarily designed for individuals of Northern European ancestry, highlighting the need for more diverse research and ethical considerations to ensure equitable healthcare applications across different populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generalisation of genomic findings and applications of polygenic risk scores. Corpas, M., Fatumo, S.[2023]

Polygenic risk scores (PRSs) are increasingly being used in clinical settings to estimate the risk of multifactorial diseases like heart disease, diabetes, and cancer, based on genetic variations identified through genome-wide association studies (GWAS).

The effectiveness of PRSs is influenced by the methodology of the GWAS and the ethnic characteristics of the study population, highlighting the importance of combining genetic risk assessments with clinical and demographic factors for a more comprehensive understanding of disease risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The emerging field of polygenic risk scores and perspective for use in clinical care. Yanes, T., McInerney-Leo, AM., Law, MH., et al.[2021]

In a study of 4,189 Hispanic/Latino older adults, a combined Polygenic Risk Score (PRS) for Alzheimer's Disease (AD) was significantly associated with Mild Cognitive Impairment (MCI), indicating that genetic risk factors can help predict cognitive decline.

The association between the PRS and MCI was stronger when including genetic variants from the APOE region, suggesting that other APOE-related variants may play a crucial role in predicting MCI in this population, despite classic APOE alleles not being linked to MCI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A polygenic risk score for Alzheimer's disease constructed using APOE-region variants has stronger association than APOE alleles with mild cognitive impairment in Hispanic/Latino adults in the U.S. Sofer, T., Kurniansyah, N., Granot-Hershkovitz, E., et al.[2023]

Polygenic risk scores (PRSs) have advanced significantly since their inception in 2007, with many being developed to predict disease risk and drug responses based on genetic information from large-scale genome-wide association studies (GWAS).

Despite their potential for improving clinical outcomes through risk prediction and personalized medicine, PRSs have not yet been integrated into routine clinical practice due to challenges in demonstrating their clinical utility and implementing genomic technologies in healthcare systems.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polygenic risk scores: An overview from bench to bedside for personalised medicine. Cross, B., Turner, R., Pirmohamed, M.[2023]

Polygenic risk scores (PRS) are effective in predicting disease risks by quantifying genetic liability using single-nucleotide polymorphisms (SNPs) identified through genome-wide association studies (GWASs), and they can help identify high-risk groups for diseases like cancer and diabetes.

Despite their potential, PRSs face challenges in clinical application, including biases related to ethnic backgrounds and geographical differences, indicating a need for further refinement to enhance their accuracy and generalizability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Statistical genetics and polygenic risk score for precision medicine. Konuma, T., Okada, Y.[2021]

Citations

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One PRS score in a Danish case-cohort study demonstrated a 30% increased risk of receiving a diagnosis of depression before the age of 31 for each standard ...

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magazine.hms.harvard.edu/articles/what-polygenic-risk-score-can-and-cant-tell-you

What a Polygenic Risk Score Can and Can't Tell You

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Polygenic score

In genetics, a polygenic score (PGS) is a number that summarizes the estimated effect of many genetic variants on an individual's phenotype.

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ahajournals.org

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broadinstitute.org/news/depth-polygenic-risk-scoring

In depth: Polygenic risk scoring

Tests based on millions of common DNA variants reveal hidden disease risk; researchers work to bring them to the clinic.