The largest study to date of genetic contributions to African Americans’ smoking behaviors confirms the importance of the region 15q25.1, on chromosome 15. The meta-analysis of data from 13 genome-wide association studies (GWAS) also tentatively revealed a role for variation within a gene, called SPOCK2, which has previously not been reported in relation to smoking in any group.
Previous studies have implicated 15q25.1 in multiple aspects of smoking among European Americans. The new findings strengthen evidence from smaller studies that have suggested a role for this region among African Americans as well.
GWAS of the smoking behaviors of individuals with African ancestry are important, because this group has greater genetic diversity than individuals of European ancestry, and their smoking patterns differ. On average, compared to European Americans, African Americans start smoking later in life, smoke fewer cigarettes per day, and have more trouble quitting. Their risk for smoking-related lung cancer is higher.
The Study of Tobacco Use in Minority Populations (STOMP) Genetics Consortium, co-led by Dr. Sean P. David of Stanford University School of Medicine, analyzed data from 32,389 African American participants in the 13 studies. The researchers looked for associations between genomic point variations (single nucleotide polymorphisms, or SNPs) and whether participants had ever smoked regularly, the number of cigarettes smoked per day, the age of smoking initiation, and smoking cessation.
The only SNP that correlated with any smoking behavior to a degree that reached genome-wide statistical significance was situated in 15q25.1 (see Figure). The researchers estimated that each copy of the A allele of this SNP (rs2036527) increased a study participant’s smoking quantity, on average, by slightly less than one cigarette smoked per day. In other studies with populations of European and African ancestry, variation in the 15q25.1 region has likewise been associated with smoking intensity, and also with nicotine dependence, smoking cessation, and lung cancer.
The location of rs2036527 is upstream of the gene that codes for the α5 subunit of the nicotinic acetylcholine receptor (CHRNA5). Imaging studies and studies with knockout mice have suggested that changes in the expression of this gene influence the reinforcing and the withdrawal effects of nicotine.
The STOMP meta-analysis also found correlations between three SNPs in the SPOCK2 gene and the age at which study participants initiated smoking. The researchers believe that theirs is the first study to associate SNPs in this gene, which encodes a protein that is part of the extracellular matrix, with smoking behaviors. However, the SPOCK2-smoking initiation correlations fell short of genome-wide significance and require confirmation in other studies.
The researchers note that genetic variation at 15q25.1 accounted for only a small portion—0.20 percent—of the variance in smoking quantity among the study participants. They say that still larger GWAS with more sensitive technologies are needed to detect potentially hundreds of genetic variations, each of which makes a small contribution to smoking patterns, and all of which in concert shape these complex behaviors.
Figure. A Genetic Variant Influences Smoking Quantity Among African Americans Each copy of the A allele of a single nucleotide polymorphism (rs2036527; circled) situated in region 15q25.1 increased study participants’ smoking by an estimated average of slightly less than one cigarette per day.Source: Courtesy of Translational Psychiatry, an open-access journal published by Nature Publishing Group.
*The red line near the top of the figure indicates the statistical threshold for genome-wide significance (P<5x10-8).
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The y-axis in this figure indicates the likelihood that the cigarettes-smoked-per-day trait is associated with a particular single-nucleotide polymorphism (SNP). The x-axis locates each SNP to one of 22 chromosomes. On each chromosome, a very large number of SNPs is present, and their vertical position indicates their statistically determined likelihood of being associated with the cigarette-smoking trait. On the y-axis, a horizontal line is drawn at 7.2, units being -Log10P. This is the experimental threshold for statistical significance for this study. Of the hundreds of SNPs displayed in this figure, only one, rs2036527, rises above this statistical threshold, indicating its significant association with cigarette smoking.
This study was supported by NIH grants CA015704 and CA058223.
Source:
David, S.P. et al. Genome-wide meta-analyses of smoking behaviors in African Americans. Translational Psychiatry 2012 May; 2(5): e119. Full Text