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Volume 19, Number 4, December 2008

“It’s no wonder he’s a drinker; alcoholism runs in his family.” This statement could as easily have been made a hundred years ago as it could be made today. That a person’s heritage influences his susceptibility to alcoholism and other addictions has been recognized by both scientists and lay people for centuries. The importance of genetic factors in alcoholism is supported by the finding of higher risk of alcoholism among relatives of an alcoholic than among the general population, as well as a higher risk among genetically identical twins than among fraternal twins or non-twin siblings (who are genetically similar but not identical). The evidence that children of alcoholics who are adopted and raised by their non-alcoholic parents are at heightened risk of alcohol dependence also reflects a significant genetic contribution to alcoholism. Indeed, family and twin studies suggest that a person’s genetic make-up explains approximately 40% to 60% of the risk for alcoholism.

While the conclusion that there is a genetic contribution to alcoholism and addiction is inescapable, success in identifying genes that play a major role in alcohol addiction has been limited. Anticipating that the effect of genes on alcohol use behavior would be complex, several investigators have been focusing on developing strategies to dissect complex genetic systems. Dr. Kirk Wilhelmsen, Distinguished Scholar and Associate Professor in the Departments of Genetics and Neurology and the Bowles Center for Alcohol Studies at UNC, is at the forefront of these efforts. Wilhelmsen is famous in neurology circles for his discovery a decade ago of the role of genetic mutations in a protein known as tau in neurodegenerative diseases such as frontal-lobe dementia and Parkinson’s. While he continues to study the role of genetic mutations in neurodegeneration, Wilhelmsen has developed a twin interest in the genetic determinants of addiction, including alcohol and nicotine dependence. “I can think of few conditions that involve more complex interactions between genes and the environment than addiction,” says Wilhelmsen. “Gaining insight into addiction, which is medically important, will also tell us important things about how the brain works. Addiction is the subversion of biologic processes that affect learning and these processes drive behavior.”

Wilhelmsen Lab (Left to Right): Scott Chasse, Ph.D., Kirk Wilhelmsen, M.D., Ph.D., Gabi Cameron, B.S., Amy Webb, B.S., Jackie Ellis, B.S., and Ian Gizer, Ph.D.

Dr. Wilhelmsen believes the principal reason that genetic analysis of alcoholism has had such limited success is that a change in approach is needed. Geneticists have learned that without correctly defining a trait that gene mapping will usually fail. Dr. Wilhelmsen’s group has focused on determining the attributes of alcohol use behavior that are linked to the chromosomes they implicate in alcoholism. This approach has produced much stronger evidence for the location of genes that affect alcoholism than the conventional approach. The unique aspects of this approach are that it could find genetic subtypes of alcoholism and/or genetic linkage to characteristics that overlap with other mental diseases like anxiety. This novel approach of careful behavioral phenotyping and genotyping to the specific phenotypes may uncover strong associations not previously recognized.

Wilhelmsen began his study of addiction at the Gallo Clinic and Research Center and the University of California at San Francisco, where he established clinical and laboratory programs to identify addiction susceptibility genes. At the Gallo Center, Wilhelmsen was the only geneticist among clinical and animal researchers who studied the physiological and behavioral effects of alcohol, and he was charged with establishing, from the ground up, the incredibly complex computing and databasing infrastructure required for genetic analysis. He moved to UNC in the fall of 2004 in part to take advantage of the university’s network of investigators with interest in human genetics, neurobiology, and complex traits. UNC has benefited from Wilhelmsen’s vast experience in creating the infrastructure necessary for genetic analysis.

At UNC, Wilhelmsen has developed large-scale, highly automated systems for genotyping, which is the process of determining the genetic makeup of an individual by using biological assays. The data derived from these systems enable analysis of large numbers of traits for the entire human genome. Two types of analysis—linkage analysis and association analysis—are performed. Linkage analysis involves sequencing portions of chromosomes to search for genetic markers of disease. Association analysis involves comparing the genotypes, or genetic makeups, of a population of individuals with a disease to those of a control population without the disease to identify genetic variations responsible for a trait.

Wilhelmsen’s lab has completed the laboratory analysis for four large-scale, family-based projects and has identified several chromosome locations for behavioral traits related to alcohol addiction. They found that chromosome locations implicated in alcoholism and other forms of drug dependence are also related to consumption behavior in general. Furthermore, they determined that body mass index was strongly linked to the same chromosome region. By a systematic exploration of alcoholism trait definition, the Wilhelmsen group has been able to integrate the evidence supporting the gene mapping data from many studies. Such consistency between studies is rare in behavioral genetics, suggesting that proper trait definition matters and will lead to success in the identification of alcohol addiction genes.

Wilhelmsen’s expertise in genetic analysis and infrastructure has led to collaborations across institutions. Wilhelmsen is integrally involved in the Renaissance Computing Institute (RENCI), a collaborative, multidisciplinary organization that involves government, industry, and academic institutions including UNC, Duke University, and North Carolina State University. Supported by the state of North Carolina, RENCI was launched in 2004 to bring world-class computing and technology resources to bear on addressing research questions and identifying solutions to scientific and medical problems affecting North Carolina, the nation, and the world. Many of the RENCI initiatives are directed at identifying means of improving healthcare and people’s overall health.

Wilhelmsen is co-principal investigator of a large new multidisciplinary initiative called Carolina Center for Exploratory Genetic Analysis (CCEGA). This project brings geneticists, statisticians, and computer scientists together to develop the technological infrastructure needed to identify the genetic determinants of human diseases. An important focus of CCEGA’s is developing the tools to support the genetic analysis of complex traits like alcohol addiction. Funded by the National Institutes of Health, CCEGA has developed tools to analyze the relationships between genotypes and physical and behavioral traits in three contexts: (1) family linkage studies, which examine the relationships between genotypes and susceptibility to alcoholism; (2) gene expression profile studies, which identify genetic and cellular patterns or signatures associated with disease; and (3) public health studies, which identify risk factors in specific communities. Conducting these studies requires analysis of a vast quantity of genetic data at a rate fast enough to provide information meaningful to the scientists interpreting it. Wilhelmsen is a leader in these efforts.

The increasingly sophisticated genetic tools, developed by Wilhelmsen, could con-tribute to enormous advances in the treatment of alcoholism and other addictions. Two of these tools which the Wilhelmsen Group has developed, called Convergent Haplotype Association Tagging and Genometric Linkage Analysis, require supercomputing capability. Together with computer scientists at RENCI, the Wilhelmsen group is developing web portals so that these tools can be used by the wider genetics community. One potential future application of genetic data is prediction of risk or susceptibility for alcoholism. Genetic information on risk combined with information on family history of alcoholism and personal history of alcohol consumption could improve the ability to predict risk of becoming an alcoholic. Armed with knowledge of their genetic risk, individuals could modify their behavior to minimize the chance that they will become alcohol dependent. Another potential application of genetic data is the ability to tailor medicine to the genetic make-up of an individual. One day, it may be possible to select pharmacotherapy for alcoholism based on a person’s genotype in order to maximize the efficacy of therapy. Some progress in this area has already been realized: the efficacy of naltrexone in the treatment of alcohol dependence has been found to depend partly on a polymorphism (i.e., a genetic variant) in a specific type of receptor on nerve cells (the mu opioid receptor).

“People who drink excessively do so because environmental influences and inherited biological factors interact in complex ways,” says Wilhelmsen. “Human genetic analysis has allowed disease-causing genes to be identified for many conditions, and I am confident that we will one day identify key genes for alcoholism. Identifying these genes will improve our understanding of the biological causes of excessive drinking and eventually lead to biologically based individualized therapies.”