This study demonstrates that common, low frequency, and rare CHRNA5 coding variants independently increase risk for nicotine dependence in both European and African Americans. An important strength of our study was the large sample of African Americans, a population often under-represented in genetic studies. Differences in the genetic architecture of European and African ancestry groups indicate that distinct genetic factors differentially contribute to nicotine dependence in these populations. These differences are highlighted by the fact that the well-established coding variant in CHRNA5, rs16969968, is more common in European (MAF=0.35) than African Americans (MAF=0.06). Importantly, we identify and replicate new associations with nicotine dependence for three low frequency, nonsynonymous variants, two of which almost exclusively occur in African Americans (rs80087508 and rs79109919).
