Molecular Epidemiology of Alcoholism 2-Big Sibships

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DESCRIPTION (provided by applicant): This IRPG application seeks supplemental 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 focuses on the ascertainment of large Australian sibships (target N=360 sibships of average size 6.7 siblings) for a 0.5 cM 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%), 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. Currently, genomic DMA samples and 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 have been collected on over 300 families. This supplemental application requests funds to complete a single nucleotide polymorphism (snp) based genome scan using the most informative sibships (target N=1800 individuals). Variance components linkage methods will be used 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. The discovery of new genes involved in the development and course of alcoholism could have a profound impact on the development of novel pharmacological treatments for alcoholism as well as provide biomarkers for the identification of at risk individuals and the study of gene-environment interactions in the development of drinking problems.