An Exome-Wide Association Study Identifies New Susceptibility Loci for the Risk of Nicotine Dependence in European-American Populations

Cigarette smoking is one of the largest causes of preventable death worldwide. Smoking behaviors, including age at smoking initiation (ASI), smoking dependence (SD), and smoking cessation (SC), are all complex phenotypes determined by both genetic and environmental factors as well as their interactions. To identify susceptibility loci for each smoking phenotype, numerous studies have been conducted, with approaches including genome-wide linkage scans, candidate gene-based association analysis, and genome-wide association study (GWAS). Therefore, we conducted an exome-wide association study to identify new susceptibility loci for the risk of nicotine dependence in European-American populations. To reveal the molecular mechanism underling each smoking phenotype, we used high-throughput approaches such as exome-based association study to identify genetic variants that contribute to nicotine dependence and other smoking-related phenotypes. First, we evaluated each common variant individually with a univariate statistic; i.e., logistic and linear regression models. Second, rare variants were grouped by genomic regions and analysed using burden tests, i.e., the Weighted Sum Statistic (WSS). Third, we tested for combined effects of rare and common variants with a unified statistical test that allows both types of variants to contribute fully to the overall test statistic.