Alcoholism and Other Addictions Research
History of the Mayo Clinic Samuel C. Johnson Genomics of Addictions Research Program
This program was established in 2004 by a generous gift from the Samuel C. Johnson Foundation aiming to identify genetic causes of alcoholism and develop individualized treatments. David Mrazek, M.D., immediate past chair of the Department of Psychiatry & Psychology and founding director of this program, formed a team with Joanna M. Biernacka, Ph.D., Doo-Sup Choi, Ph.D., Mark A. Frye, M.D., and Victor M. Karpyak, M.D., Ph.D., to achieve the goals. This program has led to the development of a new electronic database that captures key clinical characteristics of all patients with addictions at Mayo Clinic. Additionally, a DNA repository for patients with addictions was developed. New funding streams from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Mayo Center for Individualized Medicine have allowed this research to expand beyond genomics into translational science with a focus on individualized medicine.
The Mayo Clinic Program for the Individualized Treatment of Alcohol Dependence
The S.C. Johnson research team was awarded a P20 developmental center grant from the National Institute on Alcohol Abuse and Alcoholism to establish the Center for Individualized Treatment of Alcohol Dependence (CITA). The primary goal of the funded research was to develop infrastructure for an expanding research team dedicated to designing and launching systematic pharmacogenomic studies of pharmacological treatments for alcoholism, initially focused on the medication acamprosate, an FDA-approved medication for treating alcoholism.
The grant has funded the creation of an expanded multidisciplinary team of investigators who work together to design and conduct preclinical and clinical studies to identify which alcohol-dependent patients are most likely to benefit from acamprosate.
With the successful implementation of the National Institutes of Health-supported P20 Center, Mayo S.C. Johnson investigators have published approximately 40 articles, including 25 peer-reviewed research articles in major journals during the last three years in the field of addiction, neuroscience, genetics and psychiatry. In addition, the investigators have established national and international collaborations and expanded their research areas to comorbid psychiatric disorders including depression, bipolar disorders and eating disorders.
Alcohol dependence and major depressive disorder have been identified as two of the most serious public health problems. The development of depression in a patient with alcohol dependence is a major risk factor for adverse outcomes including relapse and suicide. Currently, the research team is working toward individualizing pharmacological treatment in patients with alcohol dependence and comorbid depression by the identification of pharmacogenomic and pharmacometabolomic biomarkers that predict treatment response.
Animal models also are being used to examine preclinical biomarkers and validate function of the clinical biomarkers. The long-term goal of the research program is to translate and integrate these clinical and preclinical discoveries to clinical settings to individualize treatments designed for patients based on their genomic and metabolomic profiles.
Alcoholism and Other Addictions investigators
S.C. Johnson investigators
Joanna M. Biernacka, Ph.D.
As the statistical geneticist in the Samuel C. Johnson Genomics of Addiction Program and an investigator in the NIAAA-funded Mayo Clinic Center for Individualized Treatment of Alcohol Dependence (CITA), Dr. Biernacka assists with designing studies and analyzing the resulting data. These studies are aimed at elucidating the complex relationships between particular genetic variants and traits, such as increased risk of developing alcoholism or increased likelihood of responding to a specific treatment. As these types of analyses require the application of advanced statistical techniques, Dr. Biernacka also works on the development of novel methods for the analysis of genetic data. Her research is currently focused primarily on gene-set analysis and methods for detection of gene-gene interactions.
Recently, Dr. Biernacka and her colleagues have developed novel statistical approaches to analyze data from genome-wide association studies of complex traits. These statistical approaches make use of prior information on gene function to evaluate overall evidence for the association of phenotypic trait with all measured genetic variation in a group of related genes. These gene-set analysis (or pathway analysis) methods were applied to data from a study of addiction to identify biological pathways that play a role in risk of developing alcoholism, setting the stage for further investigation.
Doo-Sup Choi, Ph.D.
Dr. Choi's research has identified several molecular and biological mechanisms underlying alcohol abuse and addiction with the goal of developing new treatment methods. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) P20 grant has enabled the establishment of an effective research program to identify biomarkers for the creation of individualized treatments for alcohol use disorders.
The program researchers have published a series of important scientific findings:
- Diminished aversion to the acute intoxicating effect of alcohol as an essential component leading to increased alcohol consumption in mice lacking a molecule that transports adenosine.
- Increased glutamate levels in a part of the brain called the ventral striatum as an important role in gene expression.
- Significant alcohol reduction in mice with increased glutamate levels using acamprosate, a medication used to treat alcoholism.
- Association of a specific variant of the ENT1 gene with a higher predisposition to alcohol withdrawal seizures in alcoholics.
Dr. Choi organized a symposium at the annual Research Society on Alcoholism meeting in 2010 and 2011. He has served as a reviewer for numerous peer-reviewed articles, as a regular member on NIH study sections, as an academic editor of several journals including PLoS One and as editor-in-chief of a new journal, Addiction Genetics.
Dr. Choi and his team continue to move toward establishing an individualized treatment center for alcohol-use disorders by examining the molecular basis of genetic variants that have pharmacological effects. Also planned is the development of neuroimaging strategies using animal models to provide a better understanding of how medications such as acamprosate decrease craving.
Mark A. Frye, M.D.
Dr. Frye has made significant advances in the understanding of the neurobiology of cravings and mood disorders comorbidity with alcohol dependence. Findings of gender differences in alcohol cravings and depressive symptoms have recently been published. Further studies of how these clinical differences relate to differential treatment response are under way.
Dr. Frye is the clinical core director of the National Institute on Alcohol Abuse and Alcoholism grant (AA017830). The grant investigates the neurobiological underpinnings of alcohol cravings in recently detoxified alcoholic subjects utilizing novel functional brain imaging. This clinical magnetic resonance spectroscopy (MRS) study will investigate whether glutamate and other brain metabolites correlate to alcohol craving severity and response to treatment with acamprosate. The study may potentially elucidate how acamprosate works and inform the development of a "spectroscopic template" for future new compounds being developed for the treatment of alcoholism.
Dr. Frye's clinical research team is exploring novel pharmacogenomic treatments for alcoholism with a focus on varenicline, a Food and Drug Administration-approved medication for smoking cessation. Because many patients with alcohol dependence are also smokers, the evaluation of varenicline for the treatment of alcohol addiction is a logical consideration. Early animal model studies have shown a reduction in alcohol intake with varenicline use.
Dr. Frye and his team continue to harvest clinically relevant data from alcohol treatment programs to help inform the research program. The main goal of the MRS project is to identify genetic components of alcoholism to improve the treatment paradigm through individualized pharmacological behavioral therapies.
The work that we have completed to date was made possible by the resources provided by the Samuel C. Johnson Program in the Genomics of Addiction.
Victor M. Karpyak, M.D., Ph.D.
Dr. Karpyak serves as the principal investigator of the pharmacogenomic probe study of acamprosate, and has been responsible for the recruitment and follow-up evaluations of more than 300 alcohol-dependent subjects. This project will allow Dr. Karpyak and his team to identify genetic predictors associated with the response to acamprosate, which can be used to guide clinical decisions.
With support from the Samuel C. Johnson Program in the Genomics of Addiction, the clinical research team has completed analyses of a polymorphic variant of the ENT1 gene and its association with alcohol withdrawal seizures. This pioneering line of research provides a better understanding of relationships between genetic variations and the physiological changes associated with severe complications.
In addition, the Samuel C. Johnson Program has allowed completion of several analyses and publications focused on the clinical aspects of alcoholism treatment.
Dr. Karpyak and his team will continue to study the MPDZ gene and its association with changes in brain metabolites indicating vitality of neural cells. This line of research may lead to the understanding of the role this gene plays in aging, as well as alcohol-related brain damage. The team also plans to extend the pharmacogenomic study of acamprosate.
See the Mayo Clinic Samuel C. Johnson Program in the Genomics of Addiction 2011 Annual Report, including a full list of publications.