To identify alcoholism vulnerability and protective genes, we collected and tested for linkage and pattern of genetic transmission families from American Indian populations. Such populations are relatively homogeneous genetically and environmentally. This report addresses an American Indian tribe in which alcoholism is highly prevalent. A total of 582 subjects from a large family genealogy were psychiatrically interviewed (SADS-L), blind rated for diagnosis and genotyped. An analysis (J. Long) of the familiality of alcoholism revealed a significant increase in relative risk in first- degree relatives of alcoholics. In females, the risk was highest in first-degree relatives, still significant at the 3rd degree of genetic relationship and compatible with a heritability of about 40%. Binge drinking in American Indians was found to be a behavior which is not, as has been alleged, benign or beneficial, but associated with dramatic increases in problems in multiple domains: social, violence/lawlessness, work and medical. A whole autosome genetic linkage analysis on a subset of the sample utilized 517 short tandem repeat markers. By sib-pair analysis, strong evidence for linkage to alcohol dependence [DSM-III-R] was found near the chromosome 11p telomere [near the DRD4 dopamine receptor locus] and the centromeric region of chromosome 4p [near the GABA receptor cluster]. A more modest linkage signal was also detected on chromosome 4q [at the location of the alcohol dehydrogenase gene cluster]. Simulation analyses confirmed that these linkage signals were statistically highly significant. The 11p finding could, on a conservative basis, have been randomly expected in about one in six whole genome linkage analyses.
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