This study is motivated by the recent controversy of an association over alcoholism and a restriction fragment length polymorphism (RFLP) allele at the Dopamine D2 Receptor locus (DRD2). Though many are interpreting the association as indicative of causation, we feel that a population stratification artifact has NOT been excluded and is a priori the more likely explanation. It is our opinion that resolution of that controversy requires better control samples and better estimates of population allele frequencies. Therefore, we propose to provide such a better understanding of normal population variation at the DRD2 locus. For several populations distributed around the world we will determine the frequencies, not just of the TaqI RFLP that was used in the studies reported so far, but also of multisite haplotypes at the DRD2 locus. This global survey of diversity will utilize the large collection of cell lines we have already assembled on human populations representing all major ethnic groups. That collection will be augmented by collecting new samples of specific Caucasian populations to allow a proper assessment of frequency variation among Caucasian populations, a critical unknown in, assessing association studies of alcoholism and alleles of DRD2. Most important will be Middle Eastern populations, some of which have shown the lowest known frequency of the Al allele (7%) in small preliminary samples. The CEPH families and numerous reference families will be used to identify haplotypes by segregation. A variety of molecular techniques that allow direct haplotyping will be used as necessary in the population samples. Modified gene counting (a maximum likelihood procedure) will be used to estimate the haplotype frequencies. We will study all of the six described DNA polymorphisms and search for and characterize additional polymorphisms using PCR, denaturing gradient gel electrophoresis (DGE), and coupled amplification and sequencing (CAS). Finally, depending on the results for these polymorphisms at DRD2, we will either attempt to identify functionally relevant sequence variation at DRD2 or will use the population samples accumulated to investigate in a similar manner normal genetic variation at other loci possibly relevant to alcoholism. Such other loci include the other known dopamine receptor genes (DRD1, DRD3, DRD4, DRD5) among many other possibilities.
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