Smoking and Genetic Risk Variation Across Populations of European, Asian, and African American Ancestry—A Meta‐Analysis of Chromosome 15q25

Abstract

Recent meta-analyses of European ancestry subjects show strong evidence for association between smoking quantity and multiple genetic variants on chromosome 15q25. This meta-analysis extends the examination of association between distinct genes in the CHRNA5-CHRNA3-CHRNB4 region and smoking quantity to Asian and African American populations to confirm and refine specific reported associations. Association results for a dichotomized cigarettes smoked per day (CPD) phenotype in 27 datasets (European ancestry (N=14,786), Asian (N=6,889), and African American (N=10,912) for a total of 32,587 smokers) were meta-analyzed by population and results were compared across all three populations. We demonstrate association between smoking quantity and markers in the chromosome 15q25 region across all three populations, and narrow the region of association. Of the variants tested, only rs16969968 is associated with smoking (p < 0.01) in each of these three populations (OR=1.33, 95%C.I.=1.25–1.42, p=1.1×10−17 in meta-analysis across all population samples). Additional variants displayed a consistent signal in both European ancestry and Asian datasets, but not in African Americans. The observed consistent association of rs16969968 with heavy smoking across multiple populations, combined with its known biological significance, suggests rs16969968 is most likely a functional variant that alters risk for heavy smoking. We interpret additional association results that differ across populations as providing evidence for additional functional variants, but we are unable to further localize the source of this association. Using the cross-population study paradigm provides valuable insights to narrow regions of interest and inform future biological experiments.

Nicotine Dependence, Nicotine Metabolism, and the Extent of Compensation in Response to Reduced Nicotine Content Cigarettes

“…Genetic variation in the CHRNA5-A3-B4 cluster has been associated with cigarette consumption and nicotine intake, and has been suggested to a genetic marker of nicotine dependence. [16][17][18] However we found no effect of the high dependence risk variant on compensation with the caveat that the genotype groups being compared were small and would need to be tested in a much larger homogeneous population.…”

“…[13][14][15] The CHRNA5-A3-B4 gene cluster codes a5, a3, and b4 nicotinic cholinergic receptor subunits, and single nucleotide polymorphisms (SNPs) in this cluster (i.e., rs1051730) have been associated with greater cigarette consumption and higher cotinine levels. [16][17][18] The level of dependence, determined by baseline smoking behaviors, genotype and/or rate of metabolism could influence the degree of compensation after switching to reduced nicotine content cigarettes.…”

A Powerful Nonparametric Statistical Framework for Family-Based Association Analyses

“…In the empirical data application, we focused on one candidate gene, CHRNA5, which was found to be associated with various complex disorders, such as nicotine dependence (Bierut et al 2008;Chen et al 2012; Hartz et al 2012), lung cancer (Amos et al 2008;Hung et al 2008;Wang et al 2009a), chronic obstructive pulmonary disease (Pillai et al 2009), cocaine addiction , and alcohol dependence (Wang et al 2009b). In our application, none of the SNPs within the gene region was significant.…”

“…The remaining 686 pedigrees had an average of 7.2 genotyped members, including 13 pedigrees with .30 members. As an illustration of our proposed method, we focused on 24 SNPs within a genomic region between 50,000 base pairs upstream and downstream of a candidate gene, CHRNA5, which had been repeatedly reported for its association with nicotine dependence and lung cancer (Saccone et al 2010;Chen et al 2012;Hartz et al 2012). Both family-U and FBAT were applied to evaluate the association between these 24 SNPs and the quantitative phenotype, the number of cigarettes smoked per day.…”

CHRNA5 polymorphism and susceptibility to lung cancer in a Chinese population

“…Among the identified loci of lung cancer susceptibility, polymorphisms in the nicotinic acetylcholine receptor gene CHRNA5, including rs16969968 and rs503464, are closely associated with lung cancer (8)(9)(10). Indeed, these variants influence nicotine addiction and correlate with cancer risk through increased smoking (11). The rs503464 variant (T.A) appears to affect transcription of CHRNA5, offering a potential mechanism for its association with cancer (12).…”