title: A genome-wide gene-gene interaction analysis identifies an epistatic gene pair for lung cancer susceptibility in Han Chinese.
abstract: Lung cancer is the leading cause of cancer-related deaths worldwide. By now, genome-wide association studies (GWAS) have identified numerous loci associated with the risk of developing lung cancer. However, these loci account for only a small fraction of the familial lung cancer risk. We hypothesized that epistasis may contribute to the missing heritability. To test this hypothesis, we systematically evaluated the association of epistasis of genetic variants with risk of lung cancer in Han Chinese cohorts. We conducted a pairwise genetic interaction analysis of 591370 variants, using BOolean Operation-based Screening and Testing (BOOST), in an ongoing GWAS of lung cancer that includes 2331 cases and 3077 controls. Pairs of epistatic loci with P BOOST ≤ 1.00×10(-6) were further evaluated by a logistic regression model (LRM) with covariate adjustment. Four promising epistatic pairs identified at the screening stage (P LRM ≤ 2.86×10(-) (13)) were validated in two replication cohorts: the first from Beijing (1534 cases and 1489 controls) and the second from Shenyang and Guangzhou (2512 cases and 2449 controls). Using this combined analysis, we identified an interaction between rs2562796 and rs16832404 at 2p32.2 that was significantly associated with the risk of developing lung cancer (P LRM = 1.03×10(-13) in total 13 392 subjects). This study is the first investigation of epistasis for lung cancer on a genome-wide scale in Han Chinese. It addresses part of the missing heritability in lung cancer risk and provides novel insight into the multifactorial etiology of lung cancer.
authors: Department of Epidemiology and Biostatistics and Ministry of Education (MOE), Key Laboratory for Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
authors: Minjie
authors: M
authors: Chu
authors: Ruyang
authors: R
authors: Zhang
authors: Yang
authors: Y
authors: Zhao
authors: Chen
authors: C
authors: Wu
authors: Huan
authors: H
authors: Guo
authors: Baosen
authors: B
authors: Zhou
authors: Jiachun
authors: J
authors: Lu
authors: Yongyong
authors: Y
authors: Shi
authors: Juncheng
authors: J
authors: Dai
authors: Guangfu
authors: G
authors: Jin
authors: Hongxia
authors: H
authors: Ma
authors: Jing
authors: J
authors: Dong
authors: Yongyue
authors: Y
authors: Wei
authors: Cheng
authors: C
authors: Wang
authors: Jianhang
authors: J
authors: Gong
authors: Chongqi
authors: C
authors: Sun
authors: Meng
authors: M
authors: Zhu
authors: Yongyong
authors: Y
authors: Qiu
authors: Tangchun
authors: T
authors: Wu
authors: Zhibin
authors: Z
authors: Hu
authors: Dongxin
authors: D
authors: Lin
authors: Hongbing
authors: H
authors: Shen
authors: Feng
authors: F
authors: Chen
mesh_terms: D002681:China; D004843:Epistasis, Genetic; D005006:Ethnicity / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide