This IRPG application seeks support for a research program to localize genes that contribute to variation in heavy drinking and alcohol (and associated tobacco) dependence risk, using epidemiologically informative samples ascertained from general population surveys of the Australian and U.S. Vietnam-Era Twin Registers and their family members. This IRPG component, IRPG3, proposes a 400 marker 10cM genome scan using an EDAC (extreme-discordant and concordant) approach on a targeted N=600 Australian sibships, for an expected total of 2400 individuals. Sibships will be selected on a quantitative index of heavy drinking that has been show in this society to exhibit (i) high heritability (45-52 percent), throughout the range of alcohol consumption levels, that is not accounted for by inherited psychiatric, sociodemographic, body-mass index or other risk factors; high genetic correlation with alcohol dependence risk (0.82) as well as with nicotine dependence (0.72); a continuous and approximately normal distribution in the population; high test-retest reliability (0.74-0.81 retest correlations). Informative sibships will be identified via diagnostic interviews with full siblings of probands with either a history of alcohol dependence, or with scores above the 85 percentile on a quantitative index of alcohol consumption. The targeted 600 sibships: (i) will each contain two sibs who are either discordant (one below the 30th percentile and one above the 85th percentile) or high-concordant (both in the upper 85th percentile); (ii) will include data on additional siblings; and (iii) will include all available biological parents. We will obtain blood samples, diagnostic interview data on lifetime history of alcohol dependence, smoking and tobacco dependence, and associated psychiatric risk-factors (history of major depression, anxiety disorders, childhood conduct disorder) and quantitative indices of lifetime maximum and heaviest period alcohol consumption. Data from the targeted 600 IRPG3 sibships, plus additional informative sibships selected from among approximately 600 sib pairs concordant for heavy smoking for whom genome scan will be available from an already funded study (many of whom will therefore be concordant for heavy alcohol consumption) will be analyzed using robust, model-free multipoint linkage analysis techniques, and in joint linkage analysis of binary alcohol (or nicotine) dependence and quantitative alcohol consumption phenotypes.
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