A Genomewide Search Finds Major Susceptibility Loci for Nicotine Dependence on Chromosome 10 in African Americans

Abstract

Epidemiological studies have demonstrated that genetic factors account for at least 50% of the liability for nicotine dependence (ND). Although several linkage studies have been conducted, all samples to date were primarily of European origin. In this study, we conducted a genomewide scan of 1,261 individuals, representing 402 nuclear families, of African American (AA) origin. We examined 385 autosomal microsatellite markers for ND, which was assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerstrom Test for ND (FTND). After performing linkage analyses using various methods implemented in the GENEHUNTER and S.A.G.E. programs, we found a region near marker D10S1432 on chromosome 10q22 that showed a significant linkage to indexed SQ, with a maximum LOD score of 4.17 at 92 cM and suggestive linkage to HSI, SQ, and log-transformed SQ. Additionally, we identified three regions that met the criteria for suggestive linkage to at least one ND measure: on chromosomes 9q31 at marker D9S1825, 11p11 between markers D11S1993 and D11S1344, and 13q13 between markers D13S325 and D13S788. Other locations on chromosomes 15p11, 17q25, and 18q12 exhibited some evidence of linkage for ND (LOD >1.44). The four regions with significant or suggestive linkage were positive for multiple ND measures by multiple statistical methods. Some of these regions have been linked to smoking behavior at nominally significant levels in other studies, which provides independent replication of the regions for ND in different cohorts. In summary, we found significant linkage on chromosome 10q22 and suggestive linkage on chromosomes 9, 11, and 13 for major genetic determinants of ND in an AA sample. Further analysis of these positive regions by fine mapping and/or association analysis is thus warranted. To our knowledge, this study represents the first genomewide linkage scan of ND in an AA sample.

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].…”

“…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.…”

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

“…39,40 The smoker phenotype yielded the highest linkage scores in this study (10q25, D10S597, NPL 3.35, LOD 3.12), less than 5 Mb apart from a previously reported linkage locus for the Fagerström Tolerance Questionnaire-(an earlier version of FTND) 41,42 based ND in 130 New Zealand families ascertained for ND, 10 and 37 Mb apart from a locus for smoking quantity recently identified in an AfricanAmerican population. 13 As the flanking markers yielded unsubstantial two-point NPL scores, the multipoint NPL curve remains flat. The definition for the smoker phenotype, assessed with a single question 'have you smoked X100 cigarettes during your lifetime?'…”

“…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.…”

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.…”