Targeted sequencing of chromosome 15q25 identified novel variants associated with risk of lung cancer and smoking behavior in Chinese

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Previous genome-wide association studies (GWAS) in populations of European descent identified a lung cancer susceptibility locus at 15q25 that was biologically associated with nicotine addiction. However, the allele frequency of susceptibility variants identified in this region varied dramatically across European and Asian populations, suggesting that additional risk single nucleotide polymorphism (SNPs) in Asians need to be identified. Thus, we conducted a fine-mapping study of chromosome 15q25 using targeted resequencing of 200 lung cancer cases and 300 controls of Chinese descent. An approximate conditional and joint analysis of the discovery data revealed two novel SNPs with independent effects (rs6495304: OR = 1.79, <span style="font-style:italic;">P</span> = 9.37 × 10⁻⁴; and rs74733525: OR = 1.68, <span style="font-style:italic;">P =</span> 8.05 × 10⁻³). Both variants were common in Asians but rare or monomorphic in Whites. These results were further supported by <span style="font-style:italic;">in silico</span> validation including 8047 cases and 8898 controls from multiethnic lung cancer genome-wide association studies (GWASs) (rs6495304: OR = 1.32, <span style="font-style:italic;">P</span> = 1.21 × 10^–11; and rs74733525: OR = 1.29, <span style="font-style:italic;">P</span> = 4.29 × 10⁻⁴); however, rs6495304 demonstrated significant effects only in ever-smokers (<span style="font-style:italic;">P</span> = 0.004 for heterogeneity test of smoking). Mediation analysis indicated that smoking behavior may mediate the effect of rs6495304 on lung cancer risk. Furthermore, expression quantitative trait loci analysis showed the risk allele (A) of rs6495304 was significantly associated with lower mRNA expression of <span style="font-style:italic;">CHRNA3</span> (<span style="font-style:italic;">P</span> = 0.029) in 81 hypothalamic tissue samples. This finding provides new insights into the association between lung cancer susceptibility and the 15q25 locus.</span>

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