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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 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 (odds ratio [OR] = 1.33, 95% CI = 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.
Figure 1. Top associations with heavy vs. light smoking: Bin A across three populations
Figure…
Figure 1. Top associations with heavy vs. light smoking: Bin A across three populations
Figure 1 shows all 52 SNPs in bin A, and also the only consistently associated sub-bins (p
Figure 2. Rs16969968 and heavy smoking in…
Figure 2. Rs16969968 and heavy smoking in samples of European, Asian, and African American ancestry
Figure 2. Rs16969968 and heavy smoking in samples of European, Asian, and African American ancestry
The ORs and 95% CIs are for the effect per allele using additive coding in the logistic regression with age and sex as covariates. *When rs16969968 is not available, rs1051730 and rs951266 are used as proxy SNPs in European and Asian ancestry samples.
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