This is a revised proposal that aims to identify susceptibility genes in four genomic regions (1p31.0, 6p25.1, 7p22.3, and 17pll.2) previously identified in a genome-wide linkage analysis of two adult generations from our multiplex alcoholism families. This analysis used a Feighner Criteria and DSM-III based definition of alcoholism, similar to the definition of alcoholism used by the only other existing multiplex alcoholism study (COGA) which used a Feighner Criteria and DSM-IIIR definition, to conduct linkage analyses. Like the COGA data set, we have extensive endophenotypic (e.g., P300) and phenotypic variables collected enabling us to later refine our findings in exploratory analyses involving quantitative phenotypes. The four regions show analytic p values between 0.007 and 0.0006 GHP and SIBPAL analytic strategies. One signal (6p25.1) meets chromosome wide significance at p = 0.05. Simulations providing empirical values for previously reported LODPAL results show a need for adjustment when covariates are used. However, maximal LOD values obtained in our LODPAL analyses show convergence with GHP and SIBPAL results suggesting the importance of follow-up of all four regions. Moreover, three of the regions are within 13 Mb of COGA reported signals. Finer mapping of the four regions would include linkage analyses using STRs placed at 5cM and IcM, followed by the use of association-based methods in our family sample, and concluded by confirmation with a case/control design. An efficient SNP genotyping/analysis plan using tag SNP methodologies is proposed for the Linkage disequilibrium (LD) mapping. An attractive feature of our data set is availability of third generation 8-18 year olds for whom extensive phenotypic data are available which would allow for extension of the linkage analyses.
The second aim of our study is complete initial mapping of the third generation for whom DNA is already collected and phenotypic assessment has been done. In order to follow-up on previous linkage results, genotyping data for STRs placed at approximately 9.4 cm intervals for all three generations would be combined and linkage analyses performed using the well validated alcoholism phenotype and the well validated childhood diagnoses obtained from the K-SADS.
Showing the most recent 10 out of 24 publications
