Linkage of nicotine dependence and smoking behavior on 10q, 7q and 11p in twins with homogeneous genetic background

Abstract

The significant worldwide health burden introduced by tobacco smoking highlights the importance of studying the genetic determinants of smoking behavior and the key factor sustaining compulsive smoking, that is, nicotine dependence (ND). We have here addressed the genetic background of smoking in a special study sample of twins, harmonized for early life events and specifically ascertained for smoking from the nationwide twin cohort of the genetically unique population of Finland. The twins and their families were carefully examined for extensive phenotype profiles and a genomewide scan was performed to identify loci behind the smoking status, ND and the comorbid phenotype of ND and alcohol use in 505 individuals from 153 families. We replicated previous linkage findings on 10q (max logarithm of the odds (LOD) 3.12) for a smoker phenotype, and on 7q and 11p (max LOD 2.50, and 2.25, respectively) for the ND phenotype. The loci linked for ND also showed evidence for linkage for the comorbid phenotype. Our study provides confirmatory evidence for the involvement of these genome regions in the genetic etiology of smoking behavior and ND and for the first time associates drinking and smoking to a shared locus on 10q.

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

“…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.…”

“…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]. Additionally, the genes that encode the α2 and α10 nAChR subunits (CHRNA2 and CHRNA10, respectively) were found within the loci associated with nicotine dependence, suggesting that these genes may influence susceptibility to nicotine addiction [98,165].…”

“…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]. Additionally, the genes that encode the α2 and α10 nAChR subunits (CHRNA2 and CHRNA10, respectively) were found within the loci associated with nicotine dependence, suggesting that these genes may influence susceptibility to nicotine addiction [98,165]. Finally, Swan and colleagues [165] reported suggestive linkage between a region on chromosome 6 and the severity of nicotine withdrawal, and significant linkage to short term quitting (defined as quitting smoking for > 1 month but < 1 year) was found on chromosome 16.…”

“…Despite these limitations, genomewide linkage studies have provided a useful starting point for the identification of genes that may influence smoking phenotypes. Several genes that encode receptors are located within or near the regions implicated by linkage studies, including the CHRNA2 and CHRNA10 nAChR subunit genes, dopamine receptors 1 and 4 (DRD1 and DRD4, respectively), the μ 1 opioid receptor (OPRM1), and the GABA B receptor subunit 2 (GABAB2) [95,98,165,180]. Thus, numerous candidate and genome-wide gene association studies have evaluated whether variations in these genes are related to smoking phenotypes.…”

“…However, there is much that remains unknown about the role of nAChR subunit genes in nicotine addiction. To date, there are several nAChR subunit genes that have not been directly investigated, including the CHRNA2 and CHRNA10 genes which have been identified as possible candidate genes in genome-wide linkage scans [98,165]. Additionally, future research should assess the relationship between nAChR subunit genes and nicotine dependence with a more comprehensive selection of smoking phenotypes, including measures of nicotine withdrawal (e.g.…”