Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity

Recently, genetic association findings for nicotine dependence,
smoking behavior, and smoking-related diseases converged to
implicate the chromosome 15q25.1 region, which includes the
CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes.
In particular, association with the nonsynonymous CHRNA5 SNP
rs16969968 and correlates has been replicated in several
independent studies. Extensive genotyping of this region has
suggested additional statistically distinct signals for nicotine
dependence, tagged by rs578776 and rs588765. One goal of the
Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP)
is to elucidate the associations among these markers and
dichotomous smoking quantity (heavy versus light smoking), lung
cancer, and chronic obstructive pulmonary disease (COPD). We
performed a meta-analysis across 34 datasets of European-ancestry
subjects, including 38,617 smokers who were assessed for
cigarettes-per-day, 7,700 lung cancer cases and 5,914
lung-cancer-free controls (all smokers), and 2,614 COPD cases and
3,568 COPD-free controls (all smokers). We demonstrate
statistically independent associations of rs16969968 and rs588765
with smoking (mutually adjusted p-values < 10(-35) and <
10(-8) respectively). Because the risk alleles at these loci are
negatively correlated, their association with smoking is stronger
in the joint model than when each SNP is analyzed alone. Rs578776
also demonstrates association with smoking after adjustment for
rs16969968 (p < 10(-6)). In models adjusting for
cigarettes-per-day, we confirm the association between rs16969968
and lung cancer (p < 10(-20)) and observe a nominally
significant association with COPD (p = 0.01); the other loci are
not significantly associated with either lung cancer or COPD after
adjusting for rs16969968. This study provides strong evidence that
multiple statistically distinct loci in this region affect smoking
behavior. This study is also the first report of association
between rs588765 (and correlates) and smoking that achieves
genome-wide significance; these SNPs have previously been
associated with mRNA levels of CHRNA5 in brain and lung tissue.