We are searching for genetic loci that contribute to the predisposition to alcoholism and related behaviors by conducting genetic linkage and mapping analysis using over 500 highly polymorphic DNA marker loci. These loci span all of the non-sex chromosomes at an average interval less than 10 centimorgans. To date, we have completed over 300,000 locus typings, primarily on American Indians and Finns. We have performed a whole autosomal genome scan for genetic linkage to alcohol dependence in a Southwestern American Indian tribe. The best evidence for linkage is seen with D11S1984 on chromosome 11p, in close proximity to several candidate genes with neurobiological functions. These candidate genes include the DRD4 dopamine receptor gene, the tyrosine hydroxylase gene, and the tryptophan hydroxylase gene. Good evidence for linkage is also seen with D4S3242 on chromosome 4p, nearby the beta1 GABA receptor gene. The chromosome 11 findings were followed up in the past year by genotyping a high resolution map on an expanded sample of subjects from the same Southwestern Indian population. The high resolution genetic map includes polymorphisms within the DRD4 and tyrosine hydroxylase genes as well as STR markers closely linked to these candidate genes. We are also developing statistical approaches and software for identifying which specific polymorphisms from a set of closely linked loci are responsible for altering an individuals vulnerability to disease. So far, we have succeeded in identifying polymorphisms associated with disease status, but we have not identified specific variants altering vulnerability. In Finns, we have completed much of a full genome search, tested for linkage to marker loci and to candidate genes, and tested for association with DNA markers on the Y chromosome. Our genome scan has revealed three chromosomal regions that are likely to harbor genes rendering vulnerability to alcohol dependence, one on chromosome 3, another on chromosome 5, and the last on chromosome 11. In addition, we have demonstrated association between Y chromosome DNA markers and alcohol dependence and antisocial personality disorder. We find a significant association between alcoholism and 3 groups of Y- chromosomes that are closely related by their mutational histories. Interestingly, there is no association between Y chromosomes and antisocial personality disorder after the comorbid effects of alcohol dependence have been removed. However, we find evidence for genetic linkage and association between antisocial personality disorder (ASPD) comorbid with alcoholism and the chromosome 6 serotonin receptor gene HTR1B. We also find evidence for linkage and association between ASPD with alcoholism and a polymorphism in the closely linked marker locus D6S286. These findings are confirmed by multipoint linkage analyses and by independent observation in the Southwestern Indian sample. - gene mapping (human), neurosciences, drinking patterns/causes, molecular genetics - Human Subjects: Interview, Questionaires, or Surveys Only
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