UNC Genetics - Faculty - Kirk Wilhelmsen, PhD

Research Interests
Key words: genetic mapping, neurodegenerative diseases

Summary of Dr. Wilhelmsen’s Research Focus
Dr. Wilhelmsen’s laboratory is engaged in the genetic mapping of susceptibility loci for complex traits and the positional cloning of genes responsible for neurodegenerative disorders. They are mapping susceptibility loci for simple neurobehavioral traits associated with alcoholism. Dr. Wilhelmsen’s original identification of linkage of the syndrome disinhibition-dementia-parkinsonism-amyotrophy complex to 17q21-22 has been an important development in neurogenetics. He and his collaborators have identified eight named neurodegenerative syndromes that appear to be due to different mutations in the same locus. Dr. Wilhelmsen was a co-organizer of a NIH sponsored conference on this subject. Subsequently mutations in the tau gene were shown to be responsible for some of these conditions. Dr. Wilhelmsen's current research activity in this area is devoted to determining how tau mutations produce disease and what role tau plays in other neurodegenenerative conditions.
Dr. Wilhelmsen’s long term interest is in the genetic dissection of complex traits. Since coming to UCSF he has established a clinical and laboratory program to identify alcoholism susceptibility genes. There are few conditions where there is a genetic susceptibility that shows more complex interactions between genes and the environment than alcoholism. Using genetic epidemiology it has been possible to show a heritable component to alcoholism. These studies do not, however, allow us to infer how many genes are involved, how these genes interact with each other, or how they are affected by the environment. Epidemiological studies have also suggested that the pattern and quantity of alcohol consumption have a major heritable component. It is likely that there are fewer genetic and environmental factors that contribute to these more easily definable traits compared to the more global diagnosis of alcoholism. The mapping of the genes for these simpler traits may be more tractable and could lead to the development of a more etiologically based framework for the definition of alcoholism.
Dr. Wilhelmsen, with Drs. Cassandra Vieten and Cheryl Jay, established a clinical program to recruit subjects for the alcoholism study. During subject recruitment the clinical staff are using instruments that diagnose alcoholism and determine the age of onset of problem drinking; frequency and quantity of alcohol consumption; and measures of physiologic dependence. Each of these items will be analyzed as a separate trait in parametric and nonparametric linkage analysis. When linkage to a specific chromosome location is detected for any item, we will attempt to determine which of the other items is expressed in a pattern that segregates with the same chromosome location.
To enable continuous throughput for genotype determination and linkage analysis in all his studies, Dr. Wilhelmsen’s laboratory has invested heavily in automation that enables large scale genotype determination, which is the currency of genetic analysis and data processing. They are have developed a system that will determine the genotypes of 815 evenly spaced markers (3 cM average spacing) for 10 people per day. Data collection is nearly complete for two large family studies related to addiction and analysis is underway. Data collection is complete for the half way point of a large family of Mission Indians and for a family based young adult alcohol challenge experiment, manuscripts have been submitted or are in preparation based on the interim analysis. As data accumulates, this will enable parametric and nonparametric linkage analysis of large numbers of traits at regular intervals for the entire genome. This high throughput genotyping project is the foundation for a powerful human neurogenetics program.

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