Home Investigators Raymond L. White, Ph.D. Research
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Evidence from family studies indicates that alcoholism and alcohol abuse are complex, with both genetic and environmental components.  We are interested in identifying the genes’ variants responsible for these genetic components, in order to reveal underlying molecular mechanisms and proteins, which may enable development of new therapeutic medications.  Furthermore, characterization of genetic etiology may also reveal important differences among affected individuals and lead to individually-specific therapeutic approaches.  The most comprehensive approach to identifying the genetic variants carried by individuals would be to determine the complete DNA sequence of each individual.  Indeed, obtaining the complete sequence of the human genome has been a major milestone for both genetics and medicine and is virtually a prerequisite for effective approaches to the genetics of complex disease.  The next phase will explore the extent and functional consequences of variation in that sequence.  Although there is approximately 99.9% identity between the DNA sequences of two humans, there is still a great deal of variation.  Any two individuals are expected to differ at more than 3,000,000 sites.  Many of these variants may not have functional significance, occurring in the large regions between genes, or not causing changes in the amino acid sequence of a protein.  The vast majority of these variants in a population will be present at only very low (<1%) frequency, and, thus, must be detected by direct sequencing of the DNAs of affected individuals.  At present it is not economically feasible (though it may not be far off) to sequence entire human genomes, so we must be more specific in deciding which regions are most likely to carry variants that would affect an individual’s response to alcohol.
We have, therefore, initially focused on a “candidate gene” approach – genes implicated by their activities in cells and model organisms in response to alcohol or by their map locations.  150 candidate genes have been selected and sequenced in DNA samples from more than 1,000 subjects, clinically characterized with respect to their responses to an alcohol challenge and provided by our UCSD collaborator, Marc Schuckit.  The subjects include both siblings and parents from a sib-pair study.  2,500 variants, including both common and rare variants, of the candidate genes were found among these samples and are under analysis to determine whether they are associated with quantitative alcohol response traits, such as body sway and feelings of “high”.  Gene variants that show significant association in our discovery population await confirmation in a second Schuckit cohort.  This replication set was ascertained more than 25 years ago, has been followed prospectively with 5-year visits, and is, thus, able to provide not only the initial alcohol challenge phenotypic data, but also long-term outcomes, such as alcoholism.  In addition, individuals carrying variants of interest will be invited to participate in behavioral characterizations designed to reveal more completely the phenotypes associated with the variants.
Those gene/variant systems showing significant association in both the discovery and replication sample sets will be examined in in vitro systems and animal model systems to reveal the underlying molecular pathophysiology of the alcohol response.  Such studies are currently underway in the laboratory with work nearing completion on the functional characterization of a set of variants in the morphine receptor, OPRM1, we have discovered through our sequencing efforts.  Many of these relatively rare variants show functional deficiencies in our in vitro test systems.
Although we anticipate that the main body of variants with significant effects on alcohol susceptibility will be relatively rare in the population, we also expect some important variants to be common.  We have, therefore, initiated a new round of genotyping of the Schuckit samples with high density SNP chips and do expect to find novel regions and genes of interest.  In a similar spirit, we have also begun collecting, in collaboration with Nelson Freimer at UCLA, a large cohort of individuals with an alcoholism diagnosis from the Central Valley of Costa Rica.  Because this population has descended from a rather small group of founders with little in-migration, we anticipate there will be substantially less genetic variation than that found in a population resulting from a large set of founders with continuing in-migration, such as that in the U.S.  More than 500 of these subjects have been enrolled in our study and have already been characterized through genotyping with a moderate density set of SNP markers.