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Veterans' DNA study finds diversity defines overall outcomes | STAT

Veterans' DNA study finds diversity defines overall outcomes | STAT

 


aA wide range of new studies provide clear evidence that sequencing the genomes of diverse populations can provide new insights into how DNA influences health.

A team of researchers working on an ongoing project led by the US Department of Veterans Affairs analyzed data from about 636,000 veterans, looking for genetic variants associated with more than 2,000 traits, including height, blood sugar levels and the presence or absence of certain cancers. The scientists found about 26,000 associations between variants and traits, most of which were detectable regardless of the participants' ancestry.

But the roughly 3,500 associations only became apparent when people of non-European ancestry were included in the analysis. The team also found that including non-European populations could help determine which genetic variants were actually responsible for the associations. Cause Indicates an increased risk of a certain characteristic.

“On the one hand, we're empirically showing that the genetics are roughly the same, and on the other hand, we're showing that including individuals from non-European populations tells us a lot and gives us a lot of population-specific knowledge,” said Scott Damrauer, one of the study's senior authors and a vascular surgeon at the Corporal Michael J. Crescenz Veterans Affairs Hospital in Philadelphia and the University of Pennsylvania. “The only way to do genetics unbiased is to have participants from diverse populations.”

According to the survey results, Published In Thursday's Science magazine, out of V.A. Million Veterans ProgramA national research project launched in 2011 to investigate how genes, lifestyle and other factors affect the health of veterans, with the hope that its findings could be applied to the general population. Data from the effort has already been used in more than 350 scientific publications, including studies of cancer, diabetes and post-traumatic stress disorder.

In the new study, the researchers explored associations between genes and traits in different populations. To do so, they compared the subjects' genes to sequences from the 1000 Genomes Project, a global standard for human genetic variation, and classified the subjects into one of four broad groups: African, East Asian, European, and mixed American, which includes Hispanic populations. Dammrauer acknowledged that these categories don't fully capture human genetic variation, but they did give the researchers some way to compare populations based on genetic similarities rather than self-reported race or ethnicity.

The researchers then conducted more than 4,000 genome-wide association studies (GWAS) to identify variants associated with specific health traits in these four populations. Performing this analysis of 44 million DNA variants would take computers about 250 years using traditional methods, but the Department of Energy provided supercomputers and expertise that allowed the team to crunch the data in a matter of weeks.

Only 8 percent of participants were women, and the average age of the subjects was 62, roughly matching the demographics of the current veteran population. About 29 percent of the study's participants were of non-European ancestry, compared with an average of 13 percent in other GWAS studies. That's one reason why Anurag Verma, the study's lead author, expected to see more differences in the association of genetic variants between populations than he ultimately found.

“It was surprising,” says Verma, a VA staff scientist and assistant professor at the University of Pennsylvania who studies the genetics of complex traits, “but when you think about it from a biology perspective and actually think about the pathophysiology of the disease, it makes sense.”

But the team also found clear evidence of the value of diversity in genetic research. In some cases, associations between mutations and traits were seen in one population but not in another. Often, this is because the mutation or trait was so rare in the population that scientists could not see a clear association. For example, the researchers found mutations associated with an increased risk of prostate cancer and mutations associated with keloid scarring, a response to injury that causes skin to regrow as bumpy, raised scars. Both discoveries were sparked by working with people of African descent.

In total, the authors found more than 800 variant-trait associations that would have been missed if they had only included individuals whose DNA was similar to the European reference sequence.

“This collaboration has the potential to accelerate scientific discoveries across hundreds of health conditions and diseases and help address gaps in participation in health research around the world,” Carolyn Clancy, VA's assistant secretary of health for discovery, education and related networks, said in a statement to STAT.

Scientists have leveraged diversity to understand which variants are most important. Genetic association studies often find that an entire set of variants next to each other in the genome is associated with a particular trait. However, many of these variants don't affect the trait; they are simply located next to variants that do. By increasing the diversity of study populations, scientists can pinpoint variants that are important. Researchers identified 6,318 variants that could be causally responsible for influencing 613 traits.

“This study sets a new standard for polyancestry analysis and marks a major step toward greater diversity representation in the genomic literature,” said Euan Ashley, a cardiologist at Stanford University who was not involved in the study. Rapid diagnosis patient.

“A more diverse cohort gives you much greater power of discovery, as this study uncovered many previously undiscovered associations,” he told STAT in an email, “but it also allows us to quantify the effects, perhaps for the first time, and certainly for the first time at this scale and resolution.”

As of last year, a million Many of the veterans volunteered to participate in the Million Veterans program, and Damrauer said researchers will continue to study the relationship between the variants and traits as they gain access to more data. The effort is one of a growing number of large-scale studies seeking to collect and analyze large amounts of genetic and health data from volunteers, and parallel efforts include: UK Biobank National Institutes of Health “All of Us” Project.

The findings could one day be used to create risk scores that more accurately sum up the incremental contributions of genetic variants and help doctors assess patients' risk for certain diseases. Earlier this year, researchers used All of Us data to show These polygenic risk scores are currently not very accurate for populations of non-European descent, but Damrauer hopes that this may change by using more diverse populations to find disease-associated variants.

The most impactful application of this recent study may not come from any of its authors: the team has taken the main results of their genetic association study and applied it to dbGaPis a repository of NIH's human genome data, allowing other researchers to learn from and build on its findings.

“To me, the most exciting next step is seeing what other people come up with with the data,” Damrauer said. “I'm hopeful that this will really advance the overall effort to understand human genetics.”

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