Three low frequency, nonsynonymous CHRNA5 variants were identified. In the primary Multivariate Model Set 1, this aggregate low frequency term provided modest evidence for association in both populations (European: OR=1.8, p=0.06; African: OR=1.4, p=0.07) (Table 2). Results from the replication studies demonstrated a significant effect of the aggregated three low frequency variants on heaviness of smoking. The overall meta-analysis combining the primary and replication samples yielded an OR=1.3 in European Americans (p=0.005) and OR=1.4 in African Americans (p=0.0006) for the aggregate low frequency term.