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VA Capacity for Genomics Research Grows as Million Veteran Program Nears 750,000 Enrollees

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NEW YORK (GenomeWeb) – By the end of this week, the US Department of Veterans Affairs' Million Veteran Program will have enrolled 730,000 people into the research program, nearly three-fourths of the way to meeting its recruitment goal of 1 million military service members.

The genetic data generated within this program is fueling studies on diseases of importance to the veteran population and proving to be a rich resource for studying multi-ethnic populations. As novel findings emerge from these efforts, the VA is also contemplating how some of these learnings may be communicated to the participants.

MVP was launched in 2011 with the goal of collecting genetic, medical, lifestyle, and military exposure information from 1 million vets and using that data to improve understanding of the factors that cause conditions such as post-traumatic stress disorder, schizophrenia, and bipolar disorder. "We're hoping to reach the 750,000 enrollee mark in a couple of months," said Suma Muralidhar, MVP program director.

Samples from all enrolled patients have been sent out for genotyping, but roughly 450,000 samples have been genotyped to date and are available to researchers. "We've done imputation on that data set … with our partnership with the US Department of Energy," Muralidhar said. "That information is in the process of being returned to the VA environment, where it will be made available to current researchers."

The VA and DOE are partners in a supercomputing initiative involving information collected within MVP, electronic health records of 24 million vets, as well as data from the Department of Defense, the Centers for Medicare and Medicaid Services, and the Centers for Disease Control and Prevention’s National Death Index. The supercomputing platform will apply predictive algorithms, artificial intelligence, and deep learning. 

At the VA, the genotyping data collected to date has led to several dozen research efforts. Last year, MVP researchers described in Nature Genetics how they looked for variants associated with lipid levels among the genotyping data of nearly 300,000 veterans with at least one blood lipid measurement. They also conducted a phenome-wide association study and proposed new indications for drugs targeting PCSK9, ANGPTL4, and PDE3B, as potential treatments for abdominal aortic aneurysm, type 2 diabetes, as well as triglycerides and coronary disease, respectively. 

Although drugs targeting these genes are already available in the market for specific indications, the data from this evaluation suggest that there may be other uses for them. "We're discussing with the research teams what the next validation steps are and how to move this into real-world applications," Muralidhar said. "We're talking with our tech transfer group as well to see how this would work out."

Other publications are forthcoming from the approximately 30 MVP research projectsunderway in 2018, including studies on different cancers, cardiovascular disease, PTSD, gulf war illness, mental health conditions, substance abuse, and pharmacogenetics. For conditions of significance to veterans, such as PTSD, MVP's research is helping to not only identify associated genotypes, but also making the characterization of the phenotypes more precise.

Researchers, for example, are studying the genetic underpinnings of specific symptoms of PTSD, such as sleep deprivation and alcohol consumption. Jenny Moser, MVP's scientific program manager, highlighted that researchers will soon publish a study on novel genetic variants associated with recurring PTSD.

MVP is also starting to produce data on genetic and phenotypic associations that occur in non-European populations, for which research has been limited. Given the multiethnic nature of the MVP population, researchers have been able to explore gene-disease associations in large cohorts of African-American and Hispanic veterans, for example. A forthcoming paper on chronic kidney disease will describe some of the differences between the African-American and Caucasian population, Muralidhar noted.

Within MVP, participants are also getting their whole genomes sequenced. In the future, the samples from a small subset of participants may even undergo comprehensive omics analysis, adding, for example, proteomics and metabolomics data on top of the genotyping and WGS data. Moser noted that MVP is currently exploring metabolomics analysis in a small pilot.

However, the WGS data isn't yet available to researchers. VA's contract with Personalis for WGS currently covers analysis of nearly 80,000 samples. Approximately 10,000 participants' genomes have been sequenced to date.

"Right now, we're still working out the logistics of how we store and process this large amount of sequencing data and make the variant files available to researchers," Muralidhar said. "We are trying to pilot multiple ways to do this."

She noted that the supercomputing partnership with the DOE may be one way of handling this data. But the VA is also exploring the idea of creating a data commons through which researchers can access the data. "Security of this data is of the utmost importance, but the sheer size and volume of the data files is a big issue," Moser said. "Even if you allow researchers access to the variant files, how much do you keep in storage? And you have to pay for that storage, so it's an economic issue as well."

The VA has enough funding to get to 1 million genotypes and at least 100,000 whole genomes. But, in order to enable more in-depth analysis of WGS and other omics data, Muralidhar suspects more funds will be needed.

The VA is also enrolling veterans for the National Institutes of Health's All of Us Research Program, and has begun setting up enrollment sites. "We're expecting to enroll around 5,500 [veterans] in the first year," Muralidhar said, adding that there will be future opportunities to collaborate on research using the MVP and All of Us data sets.

The All of Us Program, which also aims to enroll 1 million participants, currently has 100,000 participants who are fully enrolled. The NIH said this week that it will pilot returning genetic test results on disease risk and drug response to 20,000 participants. 

MVP is also considering returning some results to participants. "We're conducting a couple of pilots on the return of results from MVP," Muralidhar said. "The landscape around this topic has been changing since we started."

When MVP launched there weren't any plans to return results to study participants. In the seven years that the program has been ongoing, the field of genetics has exploded and with it consumer access to genetic testing has also grown. In the civilian world, it's not uncommon for investigators to partner with consumer genomic companies to provide study participants access to some genetic test results.

Taking note of this trend, the VA is piloting how to return genetic test results within MVP among a few hundred participants, who will learn their risks for FH and metastatic prostate cancer. "Depending on [the results of] that, we'll make a decision," Muralidhar said.

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