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Minority-Enriched Genomics Leading to More Precise Healthcare of the Future

Published on July 27, 2020 in Cornerstone Blog · Last updated 10 months 1 week ago


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Center for Applied Genomics receives NIH funding to study risk of disease in African Americans

mccannn [at] (By Nancy McCann)

Children’s Hospital of Philadelphia is among the recipients of a $75 million, five-year grant that will investigate the combination of genomic and environmental factors and their role in susceptibility to disease in diverse populations.

A group of 10 clinical sites, plus one coordinating center, located across the United States, makes up the Electronic Medical Records and Genomics (eMERGE) Genomic Risk Assessment and Management Network. This phase of the grant (eMERGE IV) focuses on minority populations.

Of the participating institutions, CHOP’s Center for Applied Genomics (CAG) is one of six “enhanced diversity” clinical sites that will recruit a higher percentage of patients from diverse ancestries. CHOP will recruit 2,500 new patients who have not been previously involved with CAG, aiming for 80 percent who are from African American families. All sites will conduct and validate genomic risk-assessment and management methods for a number of common diseases of public health importance, such as Alzheimer’s disease, asthma, diabetes, obesity, cancer, and coronary heart disease.

“This is an important area of research because the focus of the eMERGE grant is to uncover the risk that is carried in our genes for multiple complex diseases, both common and rare — our polygenetic risk score for these respective diseases,” said Hakon Hakonarson, MD, PhD, director of CAG and principal investigator for the site’s program. “By finding patients early who are at risk, you can intervene with various different measures to reduce the risk of developing the disease or intervene with therapy very early to try to prevent the disease from coming on. That is the principal goal of the program.”

Why Diversity Matters

To date, polygenic risk scores have been developed and validated in studies that almost exclusively involved people of European ancestry, but it is not clear how well the findings from these initial studies can be used for risk assessment in non-European ancestry populations.

“The genome of people in Africa has much more variation than the genome of people of European descent,” explained Dr. Hakonarson, who is also on faculty in the Perelman School of Medicine at the University of Pennsylvania. “When people moved out of Africa and migrated, 20,000 to 30,000 years ago, only a small portion of people moved out, which means there was only a small portion of the genetic variation that moved out. Therefore, the complexity of the genome in African people is much higher than in Europeans. They have much more variation. That’s why when you find a disease gene in Europeans, the variance of the gene may have no relevance to the African American person. You have to examine them separately and come up with the genetic variation in their disease gene, which is predisposing or causative for the disorder.”

CAG, one of the largest genome-research centers in academia, operates the world’s largest pediatric biorepository which stores, blood, DNA, RNA, cells, plasma, and serum from over 150,000 children. It is also the most diverse biobank in the United States with approximately 50 percent European ancestry, 40 percent African American, and smaller percentages of Asian, Latin American, and Native American people. With such a high proportion of African American samples, CHOP is the lead group within the eMERGE IV network that focuses on African American ancestry.

Researchers can use the DNA to find the mutations and genetic variants of patients. With plasma, they can measure any biomarker or protein that is altered as a consequence or result of the mutation if present in the plasma. Moreover, with the cells, the scientists can subsequently develop them into induced pluripotent stem (IPS) cells.

“We can take those stem cells and we can differentiate them into any tissue of interest which may otherwise be difficult to obtain and study,” Dr. Hakonarson said. “We can develop them into different types of neurons, heart cells, lung cells, or liver cells. Working with such brain cells, we have the tissue type that is, for example, pertinent to autism research. It would not be as informative to study blood cells in autism, but if you have cells that have been converted into brain cells and then you treat those cells and you look at the effect of the mutations you find in the brain cells, you can derive information that is much more informative. And this is one of the critical assets of the building and establishment of CAG.”

Earlier Phases of eMERGE

CAG joined the eMERGE Network in 2011, at the start of Phase II, taking part in groundbreaking genome-wide association studies (GWAS) aimed at the discovery of genes that affect common complex diseases. This method searches the genome for variations, called single nucleotide polymorphisms (SNPs), which occur more frequently in people with a particular disease than in people without the disease.

“We were working on genomic analysis of common complex diseases where the notion was that if you have 1,000 samples, you can discover a fraction of the genetic underpinnings of common complex diseases like asthma, epilepsy, anxiety, or autism,” Dr. Hakonarson said. “But if you have 10 sites that come together and all have a thousand samples, you can make a much greater impact and discover a much greater portion of the genetic variation and risk to those diseases. This has been the case because when we aligned together and meta-analyzed the data together, we made multiple additional discoveries. We have close to 140 manuscripts that we’ve published in relation with the eMERGE effort — many of them high impact manuscripts.”

This research was mostly geared to European ancestry. CAG scientists started focusing on African Americans early in the process, although it was rare finding new disease genes in the African American population at that time.

Then, with a grant supplement to look at environmental factors, CAG invented a new approach for geocoding, which allowed researchers to look at different conditions — the regions where patients come from, pollen count, exposure to diesel particles from highways, suicidal rates, and rates of different mental conditions — that could influence a patient’s risk of getting a particular disease. Researchers integrated this information into the genetic data, which led to additional publications and discoveries that were gene environment interaction related. CHOP led this effort across all eMERGE sites at the time.

The Future of Medicine

Today, CAG’s expertise in next-generation sequencing of the entire genome, which consists of six billion base pairs, provides a comprehensive analysis that can pinpoint each disease variant that the individual may have.

“So we’ve come a long way, and the focus of eMERGE IV is to take these variants — of which there are millions — that each of us have and tease out the variants that increase the risk of developing a particular disease,” Dr. Hakonarson said. “It could be Alzheimer’s later in life. It could be autoimmune disease or cancer. It could be attention-deficit/hyperactivity disorder, autism, or asthma, to name a few.”

Once the researchers of eMERGE IV have the genetic results, they will clinically validate them, inform the consenting families, and then enter the findings into the electronic health records so physicians will be aware of their patient’s risk profile.

“This is the early phase of the healthcare of the future that we are demonstrating,” Dr. Hakonarson said. “You could argue this is a pilot project to demonstrate that this is the future of medicine. It will allow for a much better precision in intervention in both diagnostic work-up and therapy and we are in a unique position at CHOP to be able to prioritize this effort in highly diverse minority populations with emphasis on patients of African American ancestry.”

The National Human Genome Research Institute part of the National Institutes of Health supports eMERGE IV, “Utilizing Polygenic Risk To Understand And Improve Outcomes: A Model For Overturning Health Disparities Through Minority-Enriched Genomics Healthcare.”