Background: Nicotine withdrawal symptoms are related to smoking cessation. A Rasch model has been used to develop a unidimensional sensitivity score representing multiple correlated measures of nicotine withdrawal. A previous autosome-wide screen identified a nonparametric linkage (NPL) log-likelihood ratio (LOD) score of 2.7 on chromosome 6q26 for the sum of nine withdrawal symptoms. Methods: The objectives of these analyses were to (a) assess the influence of nicotine withdrawal sensitivity on relapse, (b) conduct autosome-wide NPL analysis of nicotine withdrawal sensitivity among 158 pedigrees with 432 individuals with microsatellite genotypes and nicotine withdrawal scores, and (c) explore familybased association of single nucleotide polymorphism (SNP) at the mu opioid receptor candidate gene (OPRM1) with nicotine withdrawal sensitivity in 172 nuclear pedigrees with 419 individuals with both SNP genotypes and nicotine withdrawal scores. 1esults: An increased risk for relapse was associated with nicotine withdrawal sensitivity score (odds ratio, 1.25; 95% confidence interval, 1.10-1.42). A maximal NPL LOD score of 3.15, suggestive of significant linkage, was identified at chr6q26 for nicotine withdrawal sensitivity. Evaluation of 18 OPRM1 SNPs via the family-based association test with the nicotine withdrawal sensitivity score identified eight tagging SNPs with global P values <0.05 and false discovery rate Q values <0.06. Conclusion: An increased risk of relapse, suggestive linkage at chr6q26, and nominally significant association with multiple OPRM1 SNPs were found with Rasch-modeled nicotine withdrawal sensitivity scores in a multiplex smoking pedigree sample. Future studies should attempt to replicate these findings and investigate the relationship between nicotine withdrawal symptoms and variation at OPRM1.
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