Using VA’s Million Veteran Program to identify genetic risk factors for alcohol, tobacco, and opioid use

With funding from VA, our research team has begun to use data from the VA’s Million Veteran Program (MVP) to identify genetic variants that contribute to the risk of multisubstance use and what it could mean for Veterans.

To date, well over 550,000 Veterans have been enrolled in MVP, which enables researchers to link their genetic, clinical and lifestyle information for research on a variety of health conditions that affect Veterans. An important component of MVP is the use of existing medical records to identify DNA sequence differences in study participants based on the presence or absence of any of a number of health conditions. Findings from this effort can yield insights into the causes of the conditions that affect health and identify targets for the development of medications to treat these problems.

Our research group (Drs. Daniel Federman and Amy Justice from the VA Connecticut Healthcare System, and Dr. Henry Kranzler from the Corporal Michael J. Crescenz VA Medical Center in Philadelphia) is examining the genetic risk factors for chronic use of alcohol, tobacco, and opioids—and the use of all three together. Most people who smoke or use drugs also drink alcohol, and changes in one behavior are likely to be associated with changes in the others.

These observations suggest that there is shared genetic risk for multiple substance use behaviors. To date, however, studies in this area have been limited by the small size of the available samples. MVP provides a unique opportunity to analyze longitudinal electronic health record data on alcohol, tobacco, and opioid use to support gene discovery in what will ultimately include a million Veterans.

The broad goal of this effort is to identify genetic variants contributing to sustained harmful substance use, which can provide opportunities for prevention and treatment. For example, it may be possible to reduce or stop the use of multiple harmful substances simultaneously by treating Veterans with one or more medications.

The first target in this ambitious effort is heavy drinking, which adversely affects a large number of Veterans. To accomplish this, we are using the AUDIT-C, a self-report questionnaire that quantifies recent drinking. The AUDIT-C is administered annually to all Veterans. To inform the analyses in the large MVP dataset, we have analyzed data from the Veterans Aging Cohort Study (VACS), a smaller, more manageable project, to identify the best use of the AUDIT-C data for genetic analyses. Findings from an initial study showed that a trajectory analysis, which takes advantage of multiple AUDIT-C scores for each participant, is the best approach to categorizing individuals’ drinking levels.

The findings, which were recently published in the journal Alcoholism: Clinical and Experimental Research, have paved the way for the analysis of AUDIT-C scores in the MVP sample, which is currently underway. Once the initial findings are validated, the AUDIT-C trajectory grouping will be combined with the genotype information obtained by MVP to identify novel genetic predictors of heavy drinking.

We have also begun to use a similar approach to study chronic opioid use and smoking in the VACS and MVP samples. The ultimate goal will be to integrate all of the findings to yield genetic profiles for multi-substance use.

About the authors:

Daniel G. Federman, M.D., is a professor of medicine at the Yale University School of Medicine and associate chief of medicine of the VA Connecticut Health Care System. In addition to providing clinical care to Veterans, he has published extensively on quality of care, cancer screening, venous disease, and peripheral arterial disease.

Amy C. Justice, M.D., Ph.D., is a professor of medicine and public health at Yale University and a staff physician at VA Connecticut Healthcare System. She has been using electronic health record data to study clinical outcomes among Veterans for the last 25 years.

Henry R. Kranzler, M.D., is professor and director of the Center for Studies of Addiction at the University of Pennsylvania Perelman School of Medicine. He is also a staff physician at the Michael J. Crescenz VAMC in Philadelphia. For the past 30 years he has studied the genetics and pharmacological treatment of alcohol and drug dependence, including genetic predictors of medication response.