GENE MAPPING AND LINKAGE STUDIES WITH SHORT TANDEM REPEAT (STR) MARKERS

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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 260,000 locus typings, primarily on American Indians and Finns. We have performed a whole autosomal genome scan for genetic linkage to alcohol dependence in the Southwestern American Indian tribe. Genotypes at 517 autosomal microsatellite loci and clinical evaluations were available for 152 subjects belonging to extended pedigrees and forming 172 sib-pairs. Highly suggestive evidence for linkage emerged for two genomic regions; both regions harbor neurogenetic candidate genes. The best evidence is seen with D11S1984 on chromosome 11p, in close proximity to the DRD4 dopamine receptor gene. Good evidence is seen with D4S3242 on chromosome 4p, nearby the beta1 GABA receptor gene. In Finns, we have completed over 70% of a full genome search, tested for linkage 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. The evidence for linkage in each of these regions is supported by a LOD (log odds ratio) of over 3.0. This is the generally accepted rubicon for statistical significance in linkage analysis. 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. For the candidate genes with neurobiological function, we find evidence for genetic linkage and association between antisocial personality disorder (ASPD) 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.