An exome-wide association study identifies new susceptibility loci for age of smoking initiation in African- and European-American populations.

Introduction: Cigarette smoking is one of the largest causes of preventable death worldwide. This study aimed to identify susceptibility loci for age at smoking initiation (ASI) by performing exome-wide association analysis.

Methods: A total of 2,510 smokers of either African-American (AA) or European-American (EA) origin were genotyped and analyzed at both the single nucleotide polymorphism (SNP) and gene levels. After removal of those SNPs with minor allele frequency (<0.01), 48,091 and 34,933 SNPs for AAs and EAs, respectively, were used to conduct single nucleotide polymorphism (SNP)-based association analysis. Gene-based analyses were then performed for all SNPs examined within each gene. Further, we estimated the proportion of variance explained by all common SNPs included in the analysis.

Results: The strongest signals were detected for SNPs rs17849904 in the pitrilysin metallopeptidase 1 gene (PITRM1) in the AA sample (P=9.02×10-7) and rs34722354 in the discoidin domain of the receptor tyrosine kinase 2 gene (DDR2) in the EA sample (P = 9.74 × 10-7). Both SNPs remained significant after Bonferroni correction for the number of SNPs tested. Subsequently, gene-based association analysis revealed a significantly associated gene, DHRS7, in the AA sample (P = 5.00 × 10-6), a gene previously implicated in nicotine metabolism.

Conclusions: Our study revealed two susceptibility loci for age of smoking initiation in the two ethnic samples, with the first being PITRM1 for AA smokers and the second DDR2 for EA smokers. In addition, we found DHRS7 to be a plausible candidate for ASI in the AA sample from our gene-based association analysis.

Implications: PITRM1 and DHRS7 for African American smokers and DDR2 for European American smokers are new candidate genes for smoking initiation. These genes represent new additions to smoking initiation, an important but less studied phenotype in nicotine dependence research.