Genetic analysis of maximum cigarette-use phenotypes

Abstract

BackgroundUsing the Framingham Heart Study data set provided for Genetic Analysis Workshop 13, we defined the cigarette-use phenotype M for smokers to be the maximum number of cigarettes-per-day (MAXCIG) reported over the longitudinal course of the study. Adjustments were made for the significant covariates of gender and year of birth, and sib-pair based linkage analysis was performed.ResultsThe primary analyses, in which individuals with MAXCIG = 0 were considered to have missing phenotype, resulted in modest linkage evidence, with LOD scores over 1 on chromosomes 5, 9, 13, 14, and 22.ConclusionsWhile the results reported here do not indicate definitive evidence for linkage to specific chromosomal regions, future studies may find it useful to include direct assessments of maximum and quantitative cigarette use. In defining and analyzing quantitative or "maximum use" phenotypes, the choice of how to handle individuals with MAXCIG = 0, or alternatively, individuals who are substance-naive, is a crucial one for genetic studies of nicotine and other substance use. In this study, the linkage results vary greatly depending on whether or not these "unexposed" individuals are included in the analyses.

Mapping and verification of susceptibility loci for smoking quantity using permutation linkage analysis

“…Of these 10 significant or highly significant linkages for smoking quantity, eight of them located on chromosomes 1, 4, 7, 8, 11, 16, 17, and 20 were also reported by one or more research groups [22][23][24][25] previously with the FHS smoking data at a nominal significance level, with a P-value of around 0.05 or LOD score between 1.0 and 2.0, except for the results reported by our group 25 in which we found significant evidence for linkage on chromosome 11 (pointwise Pvalue ¼ 10 À6 ) and suggestive evidence on chromosomes 4, 7, and 17 with a pointwise P-value of less than 0.0017. Nevertheless, our study does not represent a simple replication of those early works.…”

“…3 Recently, several research groups have performed linkage analyses with the smoking data of the FHS that were made available through the Genetic Analysis Workshop (GAW) 13. [22][23][24][25] In aggregate, these studies reported approximately 29 potential linkage regions for the smoking behavior. These potential linkage regions were located on most of the 22 autosomal chromosomes except chromosomes 3, 10, 18, and 19 (no genotypic data were available on the sex chromosomes).…”

Overview of the pharmacogenomics of cigarette smoking

“…39 Loci identified with other smoking phenotypes also contain some biologically interesting candidates, such as a region on chromosome 5q located near the dopamine receptor (D 1 ) gene, which has been reported in several studies. 32,40,41 Regions on chromosomes 6, 9 and 11 26,32,33,[40][41][42][43][44][45][46] are also promising as several studies have replicated the linkage and these regions contain some potential biologically relevant candidate genes (Table 1).…”

“…82 There is modest evidence for a role of DRD1, DRD3 or DRD5 in smoking behaviors. A region near DRD1 on chromosome 5 has shown significant linkage to cigarette consumption and age of smoking initiation in genome-wide scans (Table 1); 32,40,41 one study found an association of the DdeI polymorphism in DRD1 with current smoking. 83 D 3 receptors are selectively expressed in the nucleus accumbens and they may be important in the reactivity to drugassociated stimuli.…”

“…Dopamine b-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine, and its locus on chromosome 9q34 has been implicated with cigarette consumption 40 and habitual smoking 71 in genome-wide linkage analyses (Table 1). Polymorphisms in DBH (1368 G4A) and monoamine oxidase A (MAO-A 1460 C4T), which is also involved in dopamine metabolism, have been associated with cigarette consumption, 103 but these results were not repeated in a larger sample of the same cohort.…”