Anonymity is only part of the problem confronting the people who handle this data: In hunting for disease-linked genes in a GWAS, researchers are looking for molecular changes in the chemical bases that make up the DNA sequence – variations called single nucleotide polymorphisms (SNPs). There are millions of SNPs among the 3 billion chemical base pairs that make up human DNA, and finding the critical ones is a challenge, to say the least.

Each sample taken in at the MAVERIC lab undergoes a scan for about 765,000 SNPs of known significance, and some samples undergo closer scrutiny: a complete sequencing of the exome, the relatively small portion of the DNA that encodes for the building of proteins. Though more costly than a scan, exome sequencing is efficient: While it makes up less than 2 percent of the genome, the exome is believed to contain the majority of disease-related SNPs.

An even smaller number of MVP samples have undergone or will undergo a sequencing of the entire genome, a procedure that costs around $2,000 per sample. This deep-level analysis is typically conducted on selected sets of samples: people over 95 years of age who are exceptionally healthy, for example, or those diagnosed with a particular disease or disorder.

It’s difficult to imagine the artificial intelligence capable of finding commonalities among the billions of SNPs involved in studies of these groups. In a single study, Muralidhar said, “You’re talking about tens of thousands of cases, and other tens of thousands of controls, and to do that computation you need very high computing capacity.”

This capacity is still being developed. “Right now, we may have 25 to 50 researchers accessing the system at the same time,” said Muralidhar. “But imagine down the road, when we have hundreds or even thousands of researchers who’ve been approved and are accessing at the same time. We’re still trying to determine the capabilities and processes we’ll need to clean and curate all this data.”

 

A New Era of Genetic Study

The MVP allows teams of researchers to conduct investigations by combining secure data from GenISIS with the electronic health record data contained in another network, the VA Informatics and Computing Infrastructure (VINCI), and searching for the differences – genetic and otherwise – among those who have a certain disease and those who don’t. While the infrastructure and capabilities are still being developed to support large numbers of intensive genomic studies, several investigative teams have already begun to study parts of the MVP cohort. VA researchers Joel Gelernter, MD, and Murray Stein, MD, for example, recently launched a GWAS of PTSD. About 18 percent of the veterans enrolled in the MVP so far have a reported diagnosis of PTSD, and when enrollment reaches the 1 million mark, this will provide the research team with 180,000 veterans to study. For starters, Gelernter and Stein will focus on comparing 10,000 veterans with PTSD to a control population of 10,000.

PTSD is a difficult disorder to study. Its diagnosis isn’t as clear-cut or easily substantiated as something like diabetes or cancer, and the team expects to find several genetic variants that are relevant for all cases of PTSD – but combining genetic information with health- and service-related data allows investigators to narrow their focus to cases of combat-related PTSD. If Gelernter and Stein’s team can find evidence about genes in combat-related stress, drugs might be developed to target the underlying biology of the disease.

In the past year, several additional studies of the MVP cohort have been funded, including:

• A study of the genes that influence how obesity and lipid levels contribute to cardiovascular risk, and of whether these genetic factors differ among African-Americans and Hispanics. Farooq Amin, MD, and Peter Wilson, MD, at the Atlanta VA Medical Center, along with Kelly Cho, PhD, at the Boston VA Healthcare System, will lead the study.
• An examination of the genetic risk factors for chronic use of alcohol, tobacco, and opioids – and the dangerous use of all three together – led by Daniel Federman, MD, and Amy Justice, MD, PhD, at the VA Connecticut Healthcare System, and Henry Kranzler, MD, at the Philadelphia VA Medical Center.
• An investigation by Adriana Hung, MD, at the VA Tennessee Valley Healthcare System, of how genes affect the risk and progression of kidney disease and hypertension, including the different responses among diabetic patients (who often develop kidney problems) to the drug metformin, based on their genetic profile.
• A study, involving five VA regions and two universities, exploring the role of genetics in metabolic conditions – obesity, diabetes, and abnormal lipid levels – as drivers of heart disease. Philip Tsao, PhD, at the VA Palo Alto Health Care System and Kyong-Mi Chang, MD, at the Philadelphia VA Medical Center will lead this team of investigators.
• A study evaluating the potential genetic risk factors for Gulf War Illness (GWI), and to examine the interaction between genetic variants and Gulf War environmental exposures and susceptibility to GWI. The investigation will compare 7,500 veterans with GWI to 7,500 controls.
• An investigation of the genes that may make people susceptible to age-related macular degeneration (AMD), a retinal disorder that affects about 10 percent of older Americans. The MVP has enrolled more than 64,000 African-American veterans in this study, enabling researchers to identify susceptibility genes among a diverse population and to support an independent evaluation of susceptibility genes that have already been identified by other studies.

 

The Future of Personalized Medicine

The MVP, and the effort to develop the infrastructure and informatics necessary to make it work, have laid the groundwork for expanded initiatives that will combine the resources of different agencies to make personalized precision medicine possible for the nation. VA and the Department of Defense (DOD) have signed an agreement to open up MVP enrollment to active-duty service members before they transition to the VA. This activity will begin with DOD’s Millennium Cohort Study members. “You can imagine how powerful and rich that resource will be,” Muralidhar said. “It will allow investigators to learn about their health and illness, throughout their lives. We’ll be able to better predict things, when people are younger, and maybe even prevent certain illnesses. It will be a great contribution.”