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

Abstract

Nicotine dependence is the most prevalent form of drug addiction in the US and throughout the world. Epidemiological studies demonstrate that genetics accounts for at least 50% of the liability to nicotine dependence. However, there have been very limited linkage studies providing convincing evidence of susceptibility genomic loci for this disorder. In this study, we conducted genome-wide permutation linkage analyses on the smoking data collected between 1970 and 1972 of the Framingham Heart Study (FHS) to account for the abnormality associated with the smoking quantity (defined as the number of cigarettes smoked per day). We used empirical thresholds obtained from permutation tests to determine the significance of each genomic region. The variance component method implemented in SOLAR was used for the analysis. Under the empirical genome-wide thresholds determined specifically for the FHS smoking data, we found two highly or near-highly significant linkages of nicotine dependence on chromosomes 1 and 4 (P ¼ 0.001) and eight significant linkages on chromosomes 3,7,8,9,11,16,17, and 20 (Po0.05). These findings strongly indicate that some of these regions may harbor susceptibility loci for nicotine dependence. Further analysis of these positive regions by fine mapping and/or association analysis is warranted. To our knowledge, this study presents the most convincing linkage evidence for nicotine dependence in the field.

Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

“…Using the criteria established by Lander and Kruglyak [87], suggestive linkage has been found for smoking initiation on chromosome 6 in a sample of Dutch twins [178]; other research has implicated chromosomes 16 and 20, but p values were below the criteria for suggestive linkage [120]. In addition, significant linkage to smoking quantity has been found in regions located on chromosomes 1 and 10-12, whereas chromosomes 3-5, 7-9, 13, 16, 17, 18, and 20 exhibit suggestive linkage to smoking quantity [92,96,95,120,165,182]. Several linkage studies have also evaluated nicotine dependence (defined using the Fagerström Test for Nicotine Dependence; FTND, or defined using the DSM-IV), and suggestive linkage for nicotine dependence has been found in regions of chromosomes 3-11, and 20 [50,96,95,98,165].…”

“…Four loci associated with oral nicotine consumption (located on chromosomes 1, 4, 7, and 15) were identified in F2 hybrid mice [97]. The locus found on chromosome 1 is syntenic with the human chromosome 1, and this region has also been associated with smoking quantity in humans [182]. Together, these data suggest that nAChR subunit genes play an important role in mediating sensitivity to nicotine, and reveal that some loci associated with nicotine phenotypes may be common across multiple species.…”

“…Linkage studies have evaluated several smoking phenotypes, such as smoking initiation [120,178], the number of cigarettes smoked daily (smoking quantity) [92,96,95,120,165,182], nicotine dependence [50,96,95,98,165], and withdrawal severity [165], and overall, one or more regions in nearly all chromosomes have been implicated in smoking-related behaviors. Furthermore, nAChR subunit genes have been found within some of the loci identified in linkage studies, suggesting that these genes may warrant further investigation.…”

Molecular genetics of addiction vulnerability

“…[22][23][24][25][26][27][28][29][30][31][32][33][34] Only a few of the results of these studies have converged convincingly, with the major linkage peak produced by a number of studies being poorly, if at all, supported by subsequent data (e.g., see [22][23][24][25][26] ). Indeed, assemblies of current results from at least some linkage-based genomes can produce results that cover the majority of the genome with data that derive from at least some reported linkage peak in at least one study (C Johnson, GR Uhl, unpublished observations, 2005).…”

β-Arrestins 1 and 2 are associated with nicotine dependence in European American smokers

“…2 A number of linkage and association studies have identified susceptibility genes for ND; 3,4 however, few association studies of candidate genes and/or linkage analyses for susceptibility loci have been replicated in independent samples. 3,5 Previously, we identified several chromosomal regions that are likely to harbor susceptibility loci for ND in the Framingham Heart Study (FSH) and Mid-South Tobacco Family (MSTF) samples, including one region on chromosome 11q13 and one on chromosome 17p13, 3,[6][7][8] where the two genes of interest, b-arrestins 1 and 2 (ARRB1 and ARRB2), are located, 9,10 respectively. b-arrestins are key negative regulators and scaffolds for G-protein-coupled receptor (GPCR) signaling, one of the most fundamental cellular signal transduction processes.…”