A Genome-wide Association Study Identifies New Susceptibility Loci For Age Of Smoking Initiation In African-and European-American Populations

Cigarette smoking is a risk factor for many diseases and one of the largest causes of preventable mortality worldwide.Smoking behavior is a complex phenotype determined by both genetic and environmental factors.This study was aimed to identify susceptibility loci for age at smoking initiation by performing genome-wide association(GWA)analysis.A total of 2,510 smokers of either African-American(AA)or European-American(EA)populations was genotyped and analyzed at both SNP and gene levels.After removed those SNPs with minor allele frequency<0.01,48,091 and 34,933 SNPs for AA and EA,respectively,were remained and used for subsequently analysis.The strongest signals were detected for SNP rs 17849904 in PITRM1(pitrilysin metallopeptidase 1)gene in AA sample,with a P value of 9.02×10-7,and rs34722354 in DDR2(discoidin domain receptor tyrosine kinase 2)gene,with a P-value of 9.74×10-7 in EA sample.Both SNPs remained to be significant after Bonferroni correction for number of SNPs tested.Subsequently gene-based association analysis revealed a significantly associated gene,DHRS7,in AA samples with a p value of 5.00×10-6,a gene previously implicated to play a role in nicotine metabolism.Gene-based association analysis revealed a significantly associated gene VARS2 and a significant haplotype A-A-C-G-G-A for rs1264303-rs7738138-rs2074506-rs2252760-rs2844702-rs2517449 in the VARS2 and DPCR1 in the AA sample.For Pathway analysis,AA dataset associated with the drug metabolism.In sum,our study revealed two susceptibility loci for age of smoking initiation in the two ethnic samples,with the first one in PITRM1 for AA smokers and the second one in DDR2 for EA smokers.In addition,we found DHRS7 to be a plausible candidate for ASI in the AA sample based on gene-based association analysis.Besides,the result of pathway analysis showed that the drug metabolism would play a key role in the shaping of smoking behavior.These findings provide new insights regarding genetic determinants on age of smoking initiation for the two ethnic populations.