Alcohol dependence and heavy drinking are complex traits caused by genetic and environmental factors. A powerful design to study etiology would therefore address both types of factors jointly, but this has seldom been done. Polymorphisms in alcohol metabolizing genes encode liver enzymes that differ in their kinetic properties, including ADH2*2, which has a protective effect against heavy drinking and alcohol dependence. Elevated ADH2*2 prevalence in Jews facilitates its study in Jewish samples. Three large, distinct Jewish population groups in Israel offer the opportunity to study ADH2 and other alcohol metabolizing genes under different conditions. (1) Between late 1989 and 1994, many highly assimilated, urban Russian Ashkenazis migrated to Israel due to sharply increased Soviet anti-Semitism amid socially chaotic conditions. In Israel, they formed a consolidated ethnic group whose lifetime drinking histories reflect the high Russian per capita alcohol consumption. (2) Other Israeli Ashkenazis have much lower lifetime drinking histories, reflecting Israel's much lower per capita alcohol consumption. The lifetime histories of these two Ashkenazi groups allow study of ADH2*2 and other alcohol metabolizing genes under contrasting environmental conditions. (3) Israeli Sephardics offer a third important contrast. They differ from Ashkenazis in some social and genetic respects, and also have much lower lifetime drinking than the Russian immigrants. This is a unique research opportunity to study variation in gene-phenotype associations under different conditions. The relationship of ADH2 to lifetime peak alcohol consumption and lifetime DSM-IV alcohol dependence severity will be studied in 850 Russian immigrants arriving 1989-1994, 850 other Ashkenazis, and 850 Sephardics in Israel. The ADH2*2-alcohol phenotype associations are predicted to be weakest in the Russians due to Russian cultural influences promoting drinking even among those with the protective form of the gene. Gene effects are predicted to be intermediate in other Ashkenazis and strongest in Sephardics. ADH3 and promoters of ADH4 and ALDH2 will also be studied. Psychiatric comorbidity, religiosity and trauma will be assessed and controlled. Unrelated microsatellite markers will be tested for population stratification, which will be adjusted for if found. The sample will be drawn from the Israel Population Register. In-person interviews will include well-tested measures from U.S. and international studies. Genotyping will be done at Indiana and Columbia Universities. Preliminary studies support the hypotheses and feasibility of the methods. The larger significance of the study is to improve understanding of how genes relate to heavy drinking and alcohol dependence and how different environmental conditions may impact on these relationships
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