Using exome chip data from 12 studies containing over 10 000 heavy and 10 000 light smokers, we replicated our novel associations between low frequency CHRNA5 coding variants and smoking behaviors observed through our targeted sequencing. Our replication study design of examining phenotypic extremes of smoking quantity (heavy vs light smokers) reduces classification errors and reproduced the robust associations between common and low frequency nonsynonymous CHRNA5 variants seen in our discovery sample with nicotine dependence.
