NIH Funding Bringing Genomic Risk Assessments to More Diverse Populations

By Mike Howie

The National Institutes of Health (NIH) will provide $75 million in funding over five years to support genomics research that could ultimately help healthcare providers assess, manage, and even anticipate disease risk. The funding will go to the Electronic Medical Record and Genomics (eMERGE) Genomic Risk Assessment and Management Network, a collection of hospitals and universities spread throughout the United States.

eMERGE was created in 2007 with five biobanks linked to electronic medical records systems to conduct large-scale, high-throughput genetic research to help implement genomic medicine and provide more informed medical care to patients. During the first three phases of its work, the Network used electronic phenotypic algorithms across more than 100,000 participants to electronically determine if a participant had specific diseases or traits. In this new phase of work, the Network aims to develop disease risk scores that are more comprehensive than those currently available and, importantly, applicable to a more diverse population.

Polygenic Risk Scores

While all humans have nearly identical DNA sequences, each of us has genetic variants that make us unique. In the roughly six billion letters that code the human genome, an individual will have four to five million variants, all of which may also occur in others. While some of these variants affect things like physical appearance, others influence our risk for certain diseases, making us more or less likely to get sick. By studying these variants across large populations, researchers can better understand an individual’s risk of developing a disease.

Some diseases, like cystic fibrosis, are caused by a single variant on just one chromosome. Others can be caused by hundreds or even thousands of variants across the whole genome. Coronary artery disease, for example, is linked to 60 variants. Most diseases fall somewhere on the spectrum between these single-gene and complex diseases.

By comparing the genomes of people with and without complex diseases, researchers can identify the variants associated with those diseases. They can then calculate which variants are common in groups of people with a single disease. And with statistical analysis, the researchers can create a polygenic risk score for an individual, which estimates how a person’s variants affect their relative risk for a certain disease.

A significant shortcoming, however, is that polygenic risk scores were developed and validated in studies that predominantly involved people of European descent. Because of this, the scores may not be accurate for people from other backgrounds. The scores also don’t account for other factors that play a role in disease risk, including age, environmental factors, body-mass index, and more, which similarly limits accuracy. The eMERGE Network plans to gather data in these areas to create a more accurate way of scoring risk, which they call a “genomic risk assessment” or “integrated risk score.”

"By studying these variants across large populations, researchers can better understand an individual’s risk of developing a disease."

Enhancing Diversity

Clinical sites from the eMERGE Network are now aiming to conduct and validate genomic risk assessment and management methods for common diseases, including coronary heart disease, Alzheimer’s disease, and diabetes, that can be effective in the general population. To do this, they’ll be recruiting patients from diverse populations, including racial or ethnic minority populations, underserved populations, or populations that experience poorer medical outcomes.

A portion of the Network’s new funding will go to six enhanced-diversity clinical sites. The goal for these sites — which include the University of Alabama, Icahn School of Medicine at Mount Sinai, Cincinnati Children’s Hospital Medical Center, Columbia University, Children’s Hospital of Philadelphia, and University of Washington Medical Center — is to recruit 15,000 patients, including 75% or more from diverse ancestries.

Children’s Hospital of Philadelphia (CHOP) is an asset to the Network in that it’s home to both the world’s largest pediatric biorepository and the world’s largest biorepository of samples from people of African ancestry.

"CHOP is uniquely placed to specifically address risk factors and outcomes in the African American community," said Hakon Hakonarson, MD, director of the hospital’s Center for Applied Genomics, in an interview with the Philadelphia Business Journal. "This grant addresses polygenic risk scores in minority populations, which has not been examined before."

“A key component of this effort will be to determine how to integrate clinical data, genomic risk estimates, and family history to deliver disease management recommendations,” said James Cimino, MD, professor of medicine and director of the University of Alabama at Birmingham (UAB) Informatics Institute. “We will be able to leverage UAB’s strengths in precision medicine and informatics to accomplish this goal.”

Funding will also go to the Mayo Clinic, Vanderbilt University Medical Center, Brigham and Women’s Hospital, and Northwestern University. These clinical sites will recruit about 10,000 patients, including 35% or more from diverse ancestries. Combined, the six enhanced-diversity clinical sites and four clinical sites will receive about $61 million of the funding.

"We are delighted to be part of eMERGE Network phase IV,” said Iftikhar Kullo, MD, of the Mayo Clinic. "The work has the potential to transform how we estimate disease risk in clinical practice."

Collectively, the Network will provide a genomic risk assessment to 25,000 pediatric and adult patients. The assessment will include four components: a polygenic risk score, family history, monogenic risk, and clinical risk factors. Through these assessments, they hope to identify people at unusually high risk for common diseases and test the degree to which measurable risk can aid prevention and early treatment of common complex diseases.

A Coordinated Effort

The eMERGE Network’s coordinating center at Vanderbilt will receive $13.4 million in funding. As the coordinating center, Vanderbilt will collect risk assessments from participants and process biospecimens for genotyping. They’ve also invited Duke University to become part of the coordinating center to help with this effort. Duke will use their MeTree tool to collect and interpret family history data. Vanderbilt will also be collaborating with the Broad Institute, which is developing a pipeline for a CLIA-certified polygenic risk score for each of the phenotypes the Network studies.

Vanderbilt plays a key role in bringing research from 10 health systems together. The university develops centralized data and service infrastructure that allows all the sites to communicate and deposit de-identified data into an NIH-funded discovery resource called the Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL). The coordinating center also organizes workgroups for individual aspects of the project, including interpretation of genetic results, the return-of-results process, ethical and legal implications, integration of electronic health record systems, and outcome assessment.

“We hope to be able to show that a detailed genetic assessment on each of the participants will have a meaningful impact on the participants’ preventative care,” said Josh Peterson, MD, MPH, professor of Biomedical Informatics at Vanderbilt, “either by impacting the screening and surveillance testing by their physicians, or by modifying their health habits if they are at a particularly high risk of a common complex disease.”


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