Genome-wide linkage scan for nicotine dependence in European Americans and its converging results with African Americans in the Mid-South Tobacco Family sample

Abstract

Previously, we reported a genome-wide scan for nicotine dependence (ND) in the African American (AA) sample of the Mid-South Tobacco Family (MSTF) cohort. In this study, we conducted a genome-wide scan in 629 individuals representing 200 nuclear families of European American (EA) origin of the MSTF cohort with the goals of identifying vulnerability loci for ND in the EAs and determining converging regions across the ethnic groups. We examined 385 autosomal microsatellite markers for ND, which was assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI) and the Fagerströ m test for ND (FTND). After performing linkage analyses using various methods implemented in the GENEHUNTER and SAGE programs, we found eight regions on chromosomes 2, 4, 9-12, 17 and 18 that met the criteria for suggestive linkage to at least one ND measure in the EA sample. Of these, the region on chromosome 4 at 43 cM showed suggestive linkage to indexed SQ, the HSI and the FTND, and the region on chromosome 9 at 24 cM showed suggestive linkage to the HSI and the FTND. To increase detection power, we analyzed a combined AA and EA sample using age, gender and ethnicity as covariates and found that the region on chromosome 12 near marker D12S372 showed significant linkage to SQ. Additionally, we found six regions on chromosomes 9-11, 13 and 18 that showed suggestive linkage to at least one ND measure in the combined sample. When we compared the linkage peaks detected for ND among the two samples and a combined sample, we found that four regions on chromosomes 9 (two regions), 11 and 18 overlapped. On the other hand, we identified five regions on chromosomes 2, 4, 10, 12 and 17 that showed linkage to ND only in the EA sample, and two regions on chromosomes 10 and 13 that showed linkage to ND only in the AA sample. For those linkages identified in only one sample, we found that the combined analysis of AA plus EA samples actually decreased the linkage signal. This indicates that some chromosomal regions may be more homogenous than others across the ethnic samples. All regions except for the one on chromosome 12 have been detected at nominally significant levels in other studies, providing independent replication of ND loci in different populations.

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].…”

“…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].…”

“…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.…”

“…For example, the loci that are implicated in a given smoking-related behavior may vary as function of ethnicity or gender, and it may be difficult to detect these differences if the subject pool is heterogeneous. In support, research has identified different loci for nicotine dependence in samples with European American or African American ancestry [50,96], and combining both samples decreased the ability to detect some loci [96], which suggests that genetically heterogeneous samples may mask the detection of regions that are ethnicity-specific. Other factors that may limit the replicability of linkage studies are differences in defining phenotypes, the statistical methods used, and differences in sample size.…”

A Genomewide Linkage Scan of Cocaine Dependence and Major Depressive Episode in Two Populations

“…The resultant linkage signals remained the same within each sample, excluding the possibility that the population-specific findings were due to the use of different marker sets. Many studies have yielded different linkage signals for the same phenotype in different populations (eg, type 2 diabetes mellitus (Malhotra et al, 2009), cardiovascular-related phenotype (Lynch et al, 2005), schizophrenia (Suarez et al, 2006), and nicotine dependence (Li et al, 2008) and so on). There are several possible mechanisms that may underlie the observation of distinct linkage regions identified between populations, including genetic heterogeneity arising from random genetic drift or differences in adaption, environmental differences, differences in allele frequencies and population history, and random effects pertaining to sampling.…”