Linkage analysis of smoking initiation and quantity in Dutch sibling pairs

Abstract

The heritability of smoking initiation (SI) and number of cigarettes smoked (NC) was determined in 3657 Dutch twin pairs. For SI a heritability of 36% was found and for NC of 51%. Both SI and NC were also significantly influenced by environmental factors shared by family members. The etiological factors that influence these traits partly overlap. Linkage analyses were performed on data of 536 DZ twins and siblings from 192 families, forming 592 sibling pairs. Results suggested QTLs on chromosome 6 (LOD ¼ 3.05) and chromosome 14 (LOD ¼ 1.66) for SI and on chromosome 3 (LOD ¼ 1.98) for NC. Strikingly, on chromosome 10 a peak was found in the same region for both SI (LOD ¼ INTRODUCTIONLarge-scale population-based twin and family studies have shown that genetic factors contribute to individual differences in smoking behavior. 1-4 Several different, possibly correlated, dimensions of smoking behavior can be distinguished: smoking initiation (SI), number of cigarettes smoked per day and nicotine dependence (ND). 5 Koopmans et al 6 investigated the heritability of SI and the number of cigarettes smoked per day (NC) in adolescent Dutch twins by considering a single liability model, an independent liability model and a combined model. The combined model best described the data and showed that 39% of the variance in SI and 86% of the variance in NC was explained by genetic influences. Kendler et al 7 found that liabilities to SI and ND were substantially correlated but not identical, and that heritable factors played an important role in both SI and in ND.The next step after obtaining evidence for significant heritability is to identify chromosomal regions involved in smoking behavior, either by linkage or association approaches. 8 Both human and animal studies have explored candidate genes for smoking behavior. Association studies point to dopamine receptor genes, dopamine transporter genes, cytochrome P450 and serotonergic genes. 9,10 Association studies have relatively high statistical power, and can detect quantitative trait loci (QTLs) with only small effects. A possible disadvantage of the candidate gene approach is that the focus is on known pathways, which may lead us to overlook genes that are etiologically important, because of our ignorance of other biological systems involved. In contrast, linkage analysis will identify chromosomal regions that harbor known and

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

“…Although the prevalence of smoking has decreased significantly in many countries, particularly among men, the number of highly dependent smokers has not declined correspondingly. 28 In previous linkage analyses, smoking behavior as a phenotype has been defined in several different ways: average 7,15 or maximum 29,30 number of cigarettes smoked per day, ever smoking, 31 habitual smoking 17,18 and total number of cigarette packs per day for 1 year. 14 Similarly, ND can be defined in various ways, the most commonly used definitions being based on the DSM-IV 32 and the FTND.…”

“…Twin and family studies have suggested a high heritability (56-75%) for ND; [3][4][5][6][7] clearly, social, psychological and other environmental factors as well as comorbidities, such as alcohol use and depression, contribute as well. 8,9 Several genome-wide scans have been performed suggesting loci linked to smoking behavior and ND.…”

“…However, ascertainment criteria as well as study samples have been diverse, and not surprisingly, only a few findings seem consistent across studies. Depending on the study population and the phenotype criteria used, some evidence of linkage (logarithm of the odds (LOD)/Z scores X2) for ND has been reported on chromosomes 2, 6, 7, 8, 10, 11 and 18, [10][11][12][13] linkage for smoking rate on chromosomes 3, 4, 5, 10, 11 and 17, 7,[12][13][14][15][16] and linkage for ever smoking, habitual smoking or smoking initiation on chromosomes 6, 9 and 11. 7,[16][17][18] Thus, suggestive findings for smoking-related loci exist for most 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).…”

“…[12][13][14][15][16][17][18][19][20] This may be due, at least in part, to the broadness of this phenotype which encompasses those who have only tried cigarettes once to regular heavy smokers. Once smoking is initiated, the heritability for persistence to regular smoking has been estimated at 28-84%, 12,[15][16][17][19][20][21] for number of cigarettes smoked at 45-86% [21][22][23][24][25][26] and for diagnosed ND at 31-75%. 19,21,27 A genetic influence on nicotine withdrawal symptoms and smoking cessation has also been identified with heritability estimated at 26-48 and 50-58%, respectively.…”