A genome-wide association study identifies two new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese

Journal name:
Nature Genetics
Volume:
43,
Pages:
792–796
Year published:
DOI:
doi:10.1038/ng.875
Received
Accepted
Published online

Lung cancer is the leading cause of cancer-related deaths worldwide. To identify genetic factors that modify the risk of lung cancer in individuals of Chinese ancestry, we performed a genome-wide association scan in 5,408 subjects (2,331 individuals with lung cancer (cases) and 3,077 controls) followed by a two-stage validation among 12,722 subjects (6,313 cases and 6,409 controls). The combined analyses identified six well-replicated SNPs with independent effects and significant lung cancer associations (P < 5.0 × 10−8) located in TP63 (rs4488809 at 3q28, P = 7.2 × 10−26), TERT-CLPTM1L (rs465498 and rs2736100 at 5p15.33, P = 1.2 × 10−20 and P = 1.0 × 10−27, respectively), MIPEP-TNFRSF19 (rs753955 at 13q12.12, P = 1.5 × 10−12) and MTMR3-HORMAD2-LIF (rs17728461 and rs36600 at 22q12.2, P = 1.1 × 10−11 and P = 6.2 × 10−13, respectively). Two of these loci (13q12.12 and 22q12.2) were newly identified in the Chinese population. These results suggest that genetic variants in 3q28, 5p15.33, 13q12.12 and 22q12.2 may contribute to the susceptibility of lung cancer in Han Chinese.

At a glance

Figures

  1. Genome-wide association results on lung cancer in Han Chinese individuals.
    Figure 1: Genome-wide association results on lung cancer in Han Chinese individuals.

    Scatter plot of P values in –log10 scale from the additive model on 591,370 SNPs (from 2,331 cases and 3,077 controls). Note that we did not include 3q13.2 rs1846594 (P = 2.71 × 10−40) or 12q13.11 rs2956467 (P = 3.77 × 10−17) in the plot. We calculated the results for the X chromosome based on 1,611 females (620 cases and 991 controls). The red line represents P = 5.0 × 10−8, and the blue line represents P = 1.0 × 10−6.

  2. Regional plot of the six identified marker SNPs (rs4488809 at 3q28, rs465498 and rs2736100 at 5p15.33, rs753955 at 13q12.12, rs17728461 at 22q12.2 and rs36600 at 22q12.2).
    Figure 2: Regional plot of the six identified marker SNPs (rs4488809 at 3q28, rs465498 and rs2736100 at 5p15.33, rs753955 at 13q12.12, rs17728461 at 22q12.2 and rs36600 at 22q12.2).

    Results (−log10 P) are shown for SNPs in the region flanking 150 kb on either side of the marker SNPs. The marker SNPs are shown in purple and the r2 values of the rest of the SNPs are indicated by different colors. The genes within the region of interest are annotated and are shown as arrows.

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Author information

  1. These authors contributed equally to this work.

    • Chen Wu,
    • Yongyong Shi,
    • Huan Guo,
    • Xueying Zhao,
    • Zhihua Yin,
    • Lei Yang,
    • Li Jin,
    • Jiachun Lu,
    • Baosen Zhou,
    • Daru Lu,
    • Tangchun Wu &
    • Dongxin Lin

Affiliations

  1. Department of Epidemiology and Biostatistics, Ministry of Education (MOE) Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.

    • Zhibin Hu,
    • Juncheng Dai,
    • Lingmin Hu,
    • Guangfu Jin,
    • Yue Jiang,
    • Hongxia Ma,
    • Jiaping Chen,
    • Mingjie Chu,
    • Feng Lu,
    • Zhengdong Zhang,
    • Feng Chen,
    • Xinru Wang &
    • Hongbing Shen
  2. Section of Clinical Epidemiology, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China.

    • Zhibin Hu,
    • Guangfu Jin,
    • Jiaping Chen &
    • Hongbing Shen
  3. State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.

    • Zhibin Hu,
    • Xinru Wang &
    • Hongbing Shen
  4. State Key Laboratory of Molecular Oncology and Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

    • Chen Wu,
    • Wen Tan,
    • Dianke Yu &
    • Dongxin Lin
  5. Bio-X Center and Affiliated Changning Mental Health Center, Ministry of Education Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai JiaoTong University, Shanghai, China.

    • Yongyong Shi,
    • Zhiqiang Li &
    • Guoquan Zhou
  6. Institute of Occupational Medicine and Ministry of Education Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

    • Huan Guo,
    • Qifei Deng &
    • Tangchun Wu
  7. State Key Laboratory of Genetic Engineering, Center for Fudan-VARI Genetic Epidemiology and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.

    • Xueying Zhao,
    • Jiucun Wang,
    • Hongyan Chen,
    • Li Jin &
    • Daru Lu
  8. Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China.

    • Zhihua Yin,
    • Wei Wu,
    • Peng Guan &
    • Baosen Zhou
  9. The Institute for Chemical Carcinogenesis, State Key Laboratory of Respiratory Disease, Guangzhou Medical College, Guangzhou, China.

    • Lei Yang &
    • Jiachun Lu
  10. Departments of Thoracic Surgery and Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

    • Yijiang Chen &
    • Yongqian Shu
  11. Department of Thoracic Surgery, Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Nanjing, China.

    • Lin Xu
  12. Department of Thoracic Surgery, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

    • Xiangyang Liu
  13. Cancer Center of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

    • Li Liu
  14. Department of Oncology, Wuhan Iron and Steel Group/Corporation Staff-Worker Hospital, Wuhan, China.

    • Ping Xu
  15. Department of Respiratory Disease, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China.

    • Baohui Han
  16. Department of Respiratory Disease, Zhongshan Hospital, Fudan University, Shanghai, China.

    • Chunxue Bai
  17. Department of Radiation Oncology, First Affiliated Hospital of China Medical University, Shenyang, China.

    • Yuxia Zhao
  18. Department of Radiotherapy, Shenyang Northern Hospital, Shenyang, China.

    • Haibo Zhang &
    • Ying Yan

Contributions

H.S. directed the study, obtained financial support and was responsible for study design, interpretation of results and manuscript writing. Z.H. performed overall project management, statistical analyses with J.D. and drafted the initial manuscript. D. Lin, T.W., Y.S., D. Lu., J.L., B.Z., X.W. and L.J. directed each participating study and jointly organized this study. L.H., Y.J., M.C., J.C. and F.L. were responsible for sample processing and managing the genotyping data. Y.C., Y.S., L.X., G.J., Z.Z. and H.M. were responsible for subject recruitment and sample preparation of Nanjing samples. X.L., C.W., W.T. and D.Y. were responsible for subject recruitment and sample preparation of Beijing samples. L.L., P.X., H.G. and Q.D. were responsible for subject recruitment and sample preparation of Wuhan samples. B.H., C.B., Z.L., X.Z., G.Z., J.W. and H.C. were responsible for subject recruitment and sample preparation of Shanghai samples. Y.Z., H.Z., Y.Y., Z.Y., W.W. and P.G. were responsible for subject recruitment and sample preparation of Shenyang samples. L.Y. was responsible for subject recruitment and sample preparation of Guangzhou samples. F.C. oversaw the statistical analyses process. All authors approved the final manuscript.

Competing financial interests

The authors declare no competing financial interests.

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