Abstract
A thorough genetic mapping study was performed to identify predisposing genes for alcoholism dependence using the Collaborative Study on the Genetics of Alcoholism (COGA) data. The procedure comprised whole-genome linkage and confirmation analyses, single locus and haplotype fine mapping analyses, and gene × environment haplotype regression. Stratified analysis was considered to reduce the ethnic heterogeneity and simultaneously family-based and case-control study designs were applied to detect potential genetic signals. By using different methods and markers, we found high linkage signals at D1S225 (253.7 cM), D1S547 (279.2 cM), D2S1356 (64.6 cM), and D7S2846 (56.8 cM) with nonparametric linkage scores of 3.92, 4.10, 4.44, and 3.55, respectively. We also conducted haplotype and odds ratio analyses, where the response was the dichotomous status of alcohol dependence, explanatory variables were the inferred individual haplotypes and the three statistically significant covariates were age, gender, and max drink (the maximum number of drinks consumed in a 24-hr period). The final model identified important AD-related haplotypes within a candidate region of NRXN1 at 2p21 and a few others in the inter-gene regions. The relative magnitude of risks to the identified risky/protective haplotypes was elucidated.
Highlights
Alcohol dependence (AD) is a complex disorder accompanying familial aggregation and etiological heterogeneity.The development of AD involves genetic and environmental components as well as gene × gene and gene ×environmental interactions
The genetic map was provided by the Genetic
Whole-genome linkage mapping with short tandem repeat polymorphisms (STRPs) markers was applied to these two subpopulations and yielded rather different results compared with the whole population
Summary
Alcohol dependence (AD) is a complex disorder accompanying familial aggregation and etiological heterogeneity.The development of AD involves genetic and environmental components as well as gene × gene and gene ×environmental interactions. Alcohol dependence (AD) is a complex disorder accompanying familial aggregation and etiological heterogeneity. The development of AD involves genetic and environmental components as well as gene × gene and gene ×. Due to these factors, results from different studies often diverge [1]. STRP and SNP markers were integrated and a five-stage procedure was designed to identify the putative AD loci and to elucidate the genotype-phenotype-covariate relationship. Different methodologies (linkage analysis, association fine mapping, haplotype inference, and regression model) were considered for statistical analyses, different populations (whole, non-Black, and non-White populations) for heterogeneity issues, different types of markers (STRPs and SNPs) for linkage mapping, different densities of SNPs (Illumina and Affymetrix) for association study, and different data structures (family data and case-control data) for study design to yield reliable conclusions
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