Genomes from over 50,000 people to help bring precision medicine to all

An ambitious effort to catalog the genomes of a large, diverse pool of people recently published its first batch of results. The project, carried out in part by scientists in the UCSF School of Pharmacy, is a critical step toward making precision medicine more effective and equitable.

The study, published in Nature on February 10, identified over 400 million mutations to the human genome across about 54,000 individuals from a wide variety of ethnic backgrounds. Prior studies of the human genome have typically focused on white populations, limiting the ability of non-white individuals to benefit from advances in the field. The data is now freely available to help researchers design the most effective therapies for people from underrepresented groups.

“There is a tremendous amount that we simply don’t know about populations from [non-European] ancestry backgrounds,” said Ryan Hernandez, PhD, a senior author on the paper. “This is particularly relevant as health disparities are rampant and disproportionately affect many of our minority populations.”

The work is the fruit of the Trans-Omics for Precision Medicine (TOPMed) Program, a project of the National Heart, Lung, and Blood Institute (NHLBI), which seeks to create a database of biological information from diverse populations to improve precision medicine.

Hernandez first became interested in contributing to TOPMed in 2016 while collaborating with his colleague, Esteban Burchard, MD, MPH, on a study of Hispanic and Black children with asthma. The two scientists saw that the data from their work on asthma could easily be folded into TOPMed, and ultimately used to study other questions about human health.

Both Hernandez and Burchard are faculty members in the Department of Bioengineering and Therapeutic Sciences, a joint department of the UCSF Schools of Pharmacy and Medicine.

“TOPMed was a super forward thinking project when it began,” said Hernandez. “Esteban and I are two of over 100 investigators who contributed, and the many thousands of genomes come from dozens of studies of various diseases, spanning a variety of backgrounds and ages.”

Precision medicine, which matches effective therapies with patients based on genetics, environment, and lifestyle, relies on “reference” genomes from which researchers can tease apart relationships between human variation, disease, and drug responses. The TOPMed data enables such research to better account for the true scope of human variation and also sheds light on how modern human populations diversified.

“Only a few thousand years ago, we were a species with three orders of magnitude fewer individuals,” said Hernandez. “One of the consequences of the massive population growth that’s occurred since then is that there is way more rare variation that we might have expected from earlier studies, variation that could account, in part, for certain disparities in health care.”

In the two years since the findings were first drafted, the TOPMed program sought to make its data available to the scientific community while preserving the confidentiality of the study participants. It also continued to recruit new cohorts of people to further increase the diversity of the genome pool.

To date, approximately 155,000 genomes have been cataloged, consisting of about 41% European ancestry (European, European American), 31% African ancestry (African, African American, African Caribbean), 15% Hispanic/Latino (including Mexican, Mexican American, Central American, South American, Cuban, Dominican, Puerto Rican), 9% Asian ancestry (Chinese, Taiwanese, Asian American, Pakistani) and 4% “Other” (Samoan, Native American, multiple groups, or unknown).

Hernandez and his colleagues are now preparing the remaining 100,000 genomes for publication, and expect TOPMed to continue to grow in size and impact.

“Anybody can leverage this large scale genetic variation data to improve the power of their own studies, which on its own is going to be pretty transformative,” said Hernandez. “Every genetic study that's done in humans, that involves genotyping individuals, is probably going to account for the TOPMed data set from here on out.”

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Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program (Nature)