Although family, twin, and adoption studies have convincingly demonstrated that genetic actors play an important role in the etiology of Alcohol Dependence (AD), the specific genomic location of genes that influence the susceptibility to AD in man remains largely unknown. While the probability of detection Of susceptibility genes for complex traits like AD is uncertain, current evidence suggests that the probability of success can be enhanced by adopting such methods as the use of selected and systematically ascertained samples of large size obtained from a population with substantial genetic and cultural homogeneity.In this application, we propose to carry out a study employing such methods. We hope to ascertain, from population-based registers in 3 counties in Ireland, 1,700 siblings from 800 multiplex sibships who meet narrow DSM-IV based criteria for AD. All siblings so ascertained will be systematically evaluated by trained mental health professionals using a personal interview that covers a detailed lifetime history for alcohol use, abuse and dependence and assesses such other risk factors as the lifetime history of psychiatric disorders (e.g. major depression, antisocial personality), the history of non-alcohol substance abuse/dependence, personality, childhood symptoms of conduct disorder and hyperactivity, and response to and attitudes towards alcohol. Personal interviews will be supplemented by information obtained from hospital records and from family informants. DNA will be sampled from all cooperative siblings and parents. This application requests support solely for data collection and """"""""phenotypic"""""""" data analysis. If it is funded, we will follow up with a request for funds to support the genotyping and linkage analysis of the data we obtain. Power simulations indicate that this sample will, under most realistic conditions, have adequate power to detect individual genes with only a modest impact on the susceptibility to AD. Phenotypic analyses of the data will focus on detecting familial resemblance for symptoms, factors and typologies of AD to be used to define putative etiologic subtypes of AD for future linkage analyses.
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