Precision Medicine Program Analyzes Diverse Genetic Dataset

February 15, 2021 - Researchers from the University of Maryland School of Medicine (UMSOM) have analyzed diverse genetic datasets in an effort to advance precision medicine for minority populations.

The early analysis is part of a large-scale program funded by the National Heart, Lung, and Blood Institute (NHLBI), and examines one of the largest and most diverse datasets of high-quality whole genome sequencing – which makes up a person’s DNA.

The program aims to provide new insights into heart, lung, blood, and sleep disorders and how these conditions impact people of diverse racial and ethnic backgrounds, who are often underrepresented in genetic studies.

Called the Trans-Omics for Precision Medicine (TOPMed), the program seeks to understand the genetic variations that occur among individuals in nuclear families and populations from diverse ethnicities residing on different continents.

The ultimate goal of the project is to improve the diagnosis, treatment, and prevention of the most common conditions that lead to disability or death.

The team has identified more than 400 million genetic variations, but 97 percent of them are extremely rare and occur only in less than one percent of the population. Gene variations or variants can occur by random chance when genes get recombined or mutate.

"We have already identified some surprising new insights," said study corresponding author Timothy O'Connor, PhD, Associate Professor of Medicine & Endocrinology at the Institute for Genome Sciences (IGS) at UMSOM.

"Most of the time, these variants mean nothing, but they can provide a new understanding of mutational processes and recent human evolutionary history."

The TOPMed team includes more than 180 researchers from leading institutions in genomics around the world. These team members have been compiling huge datasets in systematic and defined ways to increase knowledge about diversity in genetic studies.

Since launching in 2014, TOPMed researchers have begun adding whole genome sequencing and “omics” analysis – which includes a study of genetic and molecular profiles like proteins – to research studies in order to better understand how variations affect different organ systems giving rise to disease.

Researchers noted that the TOPMed program aims to identify causal genetic variants and how they interact with the environment, as well as characterize disease and its molecular subtypes. The project will also seek to understand differences in disease across diverse ancestries, and establish a foundation for personalized disease prediction, prevention, diagnosis, and treatment.

The increasing diversity of the population samples will help researchers learn more about how specific diseases impact different ethnic populations around the world. The group has also established uniform standards for sequencing performed on a massive scale. The standards maximize the integrity of the data, as the group of international investigators use these standards to add other “omics” methods for analysis.

TOPMed has also enhanced the analyses of genotyped samples through a new reference panel that now includes over 97,000 individuals. The TOPMed imputation reference panel is publicly available for review and input of new genetic data by researchers.

"This is a major effort to rectify the underrepresentation of minority participants in genomic studies and tracks with a broader mission within the School of Medicine to increase diversity in clinical trials," said E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine.

"This will hopefully move the genomics field closer to extending personalized medicine for all patients."

The first stage of the data released in the study demonstrates a greater inclusion of a diversity of sampling, which will be invaluable to learn more about the diseases impacting these populations.

Because of the vast sample sizes and the longitudinal scope of many of the population samples, investigators were also able to demonstrate that the rare variants represent recent and potentially harmful changes that can impact protein function, gene expression, or other biologically important elements.

"The NHLBI's TOPMed program is a huge resource for the scientific community,” said Cashell Jaquish, PhD, an NHLBI program officer for TOPMed and a corresponding author on the Nature paper.

“We didn't really know what genomic variation looked like in diverse groups until now. This new study represents truly historic findings and we look forward to continued research studies in this area as we move toward personalized medicine."