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 Twin Registry and their siblings. This IRPG component, IRPG2, focuses on the ascertainment of large Australian sibships (target N=360 sibships of average size 6.7 siblings) for a 400 marker 10cM genome scan, using a multivariate variance components linkage approach applied to quantitative indices of heavy drinking, that have been shown 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; (ii) high genetic correlation with alcohol dependence risk (0.82) as well as with nicotine dependence (0.72); (iii) a continuous and approximately normal distribution in the population; and (iv) high test-retest reliability (0.74-0.81 retest correlations). 1900 large sibships with 5 or more full siblings (range 5-15) have already been identified through surveys of the Australian twin panel 1981 and 1989 cohorts, and the spouses of the 1981 panel. The goal is to screen the largest of these, excluding sibships with deceased or uncooperative siblings, or with siblings with minimal alcohol exposure, and obtain blood samples, diagnostic interview data on lifetime history of alcohol dependence (DSM-IIIR, DSM-IV), smoking and tobacco dependence, associated psychiatric risk-factors (history of major depression, anxiety disorders, childhood conduct disorder), and quantitative indices of lifetime maximum and heaviest period alcohol consumption (target N=4000). A genome scan will be completed using the 360 most informative sibships (target N=2400 individuals). Variance components linkage methods will be used (in conjunction with IRPG3) to map genes that contribute to variation in the quantitative alcohol consumption indices and that contribute jointly to these quantitative indices as well as to alcohol (and for some loci also tobacco) dependence risk.
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