Tobacco use remains the leading cause of preventable death in the United States and results in nearly $170 billion in direct medical care for adults and greater than $156 billion in lost productivity due to premature death and exposure to secondhand smoke (1). These costs emphasize the need to understand what genes and environments are involved in the establishment of cigarette use behavior (2). Knowing what genes and environmental risk factors impact cigarette use can help to reduce its prevalence by shaping prevention and intervention efforts. However, to date, many studies on cigarette use have focused solely on genes and environments contributing independently to risk for cigarette use and its health consequences. Fewer studies have investigated the effects of gene-environment interaction (GxE), which can be conceptualized as the difference in the contribution of genetic factors, conditional on environmental exposure (3). Since cigarette use involves both motivational and reward systems that develop through interactions between genes and the environment, studies of the joint effects of multiple genetic mutations across different environments could be useful in understanding the range of genetic susceptibility
