Abstract
Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.
| Original language | English |
|---|---|
| Article number | 3043 |
| Journal | Nature Communications |
| Volume | 14 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2023 |
Bibliographical note
Publisher Copyright:© 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
Funding
Female Lung Cancer Consortium in Asia (NCI): This study was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, Culture and Technology of Japan, a Grant-in- Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry Health, Labor and Welfare of Japan, by Health and Labor Sciences Research Grants for Research on Applying Health Technology from the Ministry of Health, Labor and Welfare of Japan, by the National Cancer Center Research and Development Fund, the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (grant No. 2011-0016106), a grant of the National Project for Personalized Genomic Medicine, Ministry for Health & Welfare, Republic of Korea (A111218-11-GM04), the Program for Changjiang Scholars and Innovative Research Team in University in China (IRT_14R40 to K.C.), the National Science & Technology Pillar Program (2011BAI09B00), MOE 111 Project (B13016), the National Natural Science Foundation of China (No. 30772531, and 81272618), Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine (No. 2012A061400006), Special Fund for Research in the Public Interest from the National Health and Family Planning Commission of PRC (No. 201402031), and the Ministry of Science and Technology, Taiwan (MOST 103-2325-B-400-023 & 104-2325-B-400-012). The Japan Lung Cancer Study (JLCS) was supported in part by the Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and Development (15ck0106096h0002) and the Management Expenses Grants from the Government to the National Cancer Center (26-A-1) for Biobank. BioBank Japan was supported by the Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government. The Japan Public Health Center-based prospective Study (the JPHC Study) was supported by the National Cancer Center Research and Development Fund (23-A- 31[toku], 26-A-2, 29-A-4, and 2020-J-4) (since 2011) and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan (from 1989 to 2010). The Taiwan GELAC Study (Genetic Epidemiological Study for Lung AdenoCarcinoma) was sup- ported by grants from the National Research Program on Genomic Medicine in Taiwan (DOH99-TD-G-111-028), the National Research Program for Biopharmaceuticals in Taiwan (MOHW 103-TDUPB-211-144003, MOST 103-2325-B-400-023) and the Bioinformatics Core Facility for Translational Medicine and Biotechnology Development (MOST 104-2319-B-400-002). This work was also supported by the Jinan Science Research Project Foundation (201102051), the National Key Scientific and Technological Project (2011ZX09307-001-04), the National Natural Science Foundation of China (No.81272293), the State Key Program of National Natural Science of China (81230067), the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. NRF- 2014R1A2A2A05003665), Sookmyung Women’s University Research Grants, Korea (1-1603-2048), Agency for Science, Technology and Research (A*STAR), Singapore and the US National Institute of Health Grant (1U19CA148127-01). The overall GWAS project was supported by the intramural program of the US National Institutes of Health/National Cancer Institute. The following is a list of grants by study center: SKLCS (Y.T.K.)—National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2011-0016106). (J.C.) – This work was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health &Welfare, Republic of Korea (grant no. 0720550-2). (J.S.S)—grant number is A010250. WLCS (T.W.)—National Key Basic Research and Development Program (2011CB503800). SLCS (B.Z.)—National Nature Science Foundation of China (81102194). Liaoning Provincial Department of Education (LS2010168). China Medical Board (00726). GDS (Y.L.W.)—Foundation of Guangdong Science and Technology Department (2006B60101010, 2007A032000002, 2011A030400010). Guangzhou Science and Information Technology Bureau (2011Y2-00014). Chinese Lung Cancer Research Foundation, National Natural Science Foundation of China (81101549). Natural Science Foundation of Guangdong Province (S2011010000792). TLCS (K.C., B.Q.)—Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT), China (IRT1076). Tianjin Cancer Institute and Hospital. National Foundation for Cancer Research (US). FLCS (J.C.W., D.R., L.J.)—Ministry of Health (201002007). Ministry of Science and Technology (2011BAI09B00). National S&T Major Special Project (2011ZX09102-010-01). China National High-Tech Research and Development Program (2012AA02A517, 2012AA02A518). National Science Foundation of China (30890034). National Basic Research Program (2012CB944600). Scientific and Technological Support Plans from Jiangsu Province (BE2010715). NLCS (H.S.)—China National High-Tech Research and Development Program Grant (2009AA022705). Priority Academic Program Development of Jiangsu Higher Education Institution. National Key Basic Research Program Grant (2011CB503805). GEL-S (A.S.)—National Medical Research Council Singapore grant (NMRC/0897/2004, NMRC/1075/2006). (J.Liu)—Agency for Science, Technology and Research (A*STAR) of Singapore. GELAC (C.A.H.)—National Research Program on Genomic Medicine in Taiwan (DOH98-TDG-111-015). National Research Program for Biopharmaceuticals in Taiwan (DOH 100- TD-PB-111-TM013). National Science Council, Taiwan (NSC 100- 2319-B-400-001). YLCS (Q.L.)—Supported by the intramural pro- gram of U.S. National Institutes of Health, National Cancer Institute. SWHS (W.Z., W-H.C., N.R.)—The work was supported by a grant from the National Institutes of Health (R37 CA70867, UM1 CA182910) and the National Cancer Institute intramural research program, including NCI Intramural Research Program contract (N02 CP1101066). JLCS (K.M., T.K.)—Grants-in-Aid from the Ministry of Health, Labor, and Welfare for Research on Applying Health Technology and for the 3rd-term Comprehensive 10-year Strategy for Cancer Control; by the National Cancer Center Research and Development Fund; by Grant-in-Aid for Scientific Research on Priority Areas and on Innovative Area from the Ministry of Education, Science, Sports, Culture and—Technology of Japan. (W.P.)—NCI R01-CA121210. HKS (J.W.)—General Research Fund of Research Grant Council, Hong Kong (781511 M). The Environment and Genetics in Lung Cancer Etiology (EAGLE), Prostate, Lung, Colon, Ovary Screening Trial (PLCO), and Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) studies were supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics. ATBC was also supported by U.S. Public Health Service contracts (N01-CN-45165, N01-RC-45035, and N01-RC-37004) from the NCI. PLCO was also supported by individual contracts from the NCI to the University of Colorado Denver (NO1-CN-25514), Georgetown University (NO1-CN-25522), the Pacific Health Research Institute (NO1-CN-25515), the Henry Ford Health System (NO1-CN-25512), the University of Minnesota, (NO1-CN- 25513), Washington University (NO1-CN-25516), the University of Pittsburgh (NO1-CN-25511), the University of Utah (NO1-CN- 25524), the Marshfield Clinic Research Foundation (NO1-CN- 25518), the University of Alabama at Birmingham (NO1-CN- 75022), Westat, Inc. (NO1-CN-25476), and the University of California, Los Angeles (NO1-CN-25404). The Carotene and Retinol Efficacy Trial (CARET) is funded by the National Cancer Institute, National Institutes of Health through grants U01-CA063673, UM1-CA167462, and U01-CA167462. The Cancer Prevention Study-II (CPS-II) Nutrition Cohort was supported by the American Cancer Society. The NIH Genes, Environment and Health Initiative (GEI) partly funded DNA extraction and statis- tical analyses (HG-06-033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research. This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2020R1A2C4002236). Genotyping of the samples in NJLCS was supported by the National Natural Science of China (81820108028). The GWAS of lung cancer in European never smokers was supported by NIH R01 CA149462 (O.Y.G.). OncoArray study in Europeans: The OncoArray data and analysis from INTEGRAL-ILCCO were supported by NIH U19 CA203654, and U19 CA148127. The data harmonization for ILCCO was supported by Canadian Institute for Health Research (CIHR) Canada Research Chair to R.J.H, and CIHR FDN 167273). European never-smoking lung cancer study: C.I.A. is a Research Scholar of the Cancer Prevention Institute of Texas (CPRIT) and supported by CPRIT grant RR170048. Taiwan eQTL study: This study was supported by the Ministry of Health and Welfare grants DOH97-TD-G-111-028 (I.S.C.), DOH98-TD-G-111-017 (I.S.C.), DOH99-TD-G-111-014 (I.S.C.); DOH97-TD-G-111-026 (C.A.H.), DOH98-TD-G-111-015 (C.A.H.), DOH99-TD-G-111-028 (C.A.H.); National Health Research Institutes grants NHRI-PH-110-GP-01, NHRI-PH-110-GP-03; and the Ministry of Science and Technology grants MOST108-2314-B-400-038(C.A.H.), MOST109-2740-B-400-002(C.A.H.). N.C. is supported by NIH grant 1R01HG010480. P.Y. is supported by Mayo Clinic Foundation Research Funds, NIH-CA77118 and CA80127. G.L. is supported is supported by the Alan Brown Chair and Lusi Wong Fund of the Princess Margaret Cancer Foundation. D.C.C. is supported by U01CA209414. O.Y.G. is supported by NIH R01 CA231141. Open Access funding provided by the National Institutes of Health (NIH).
| Funders | Funder number |
|---|---|
| Agency for Science Technology and Research | |
| The Johns Hopkins University | |
| National Natural Science Foundation of China (NSFC) | 30890034 |
| National Natural Science Foundation of China (NSFC) | |
| Ministry of Health, Labor, and Welfare for Research | |
| General Research Fund of Research Grant Council | 781511 M |
| Ministry of Science, ICT and Future Planning | NRF- 2014R1A2A2A05003665 |
| Ministry of Science, ICT and Future Planning | |
| National Childhood Cancer Registry – National Cancer Institute | |
| Korean Ministry of Health and Welfare | A111218-11-GM04 |
| Korean Ministry of Health and Welfare | |
| National Natural Science Foundation of China (NSFC) | 81230067 |
| National Natural Science Foundation of China (NSFC) | |
| Henry Ford Health System | NO1-CN-25512 |
| Henry Ford Health System | |
| Japan Agency for Medical Research and Development | 26-A-1, 15ck0106096h0002 |
| Japan Agency for Medical Research and Development | |
| Chinese Lung Cancer Research Foundation | 81101549 |
| Ministry of Science, ICT and Future Planning | 81820108028, 2020R1A2C4002236 |
| Ministry of Science, ICT and Future Planning | |
| Sookmyung Women's University | 1-1603-2048 |
| Sookmyung Women's University | |
| National Institutes of Health (NIH) | 1U19CA148127-01 |
| National Institutes of Health (NIH) | |
| University of California, Los Angeles | NO1-CN-25404, U01-CA167462, U01-CA063673, UM1-CA167462 |
| University of California, Los Angeles | |
| American Cancer Society-Michigan Cancer Research Fund | |
| Agency for Science Technology and Research | |
| National Science and Technology Program during the Twelfth Five-year Plan Period | 2011BAI09B00 |
| National Science and Technology Program during the Twelfth Five-year Plan Period | |
| National Institutes of Health (NIH) | |
| U.S. Public Health Service | N01-CN-45165, N01-RC-45035, N01-RC-37004 |
| U.S. Public Health Service | |
| Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine | 2012A061400006 |
| National Health and Family Planning Commission of the People's Republic of China | 201402031 |
| National Health and Family Planning Commission of the People's Republic of China | |
| Program for Changjiang Scholars and Innovative Research Team in University | IRT_14R40 |
| Program for Changjiang Scholars and Innovative Research Team in University | |
| National Cancer Institute Division of Cancer Epidemiology and Genetics | |
| Minnesota State University-Mankato | NO1-CN- 25513 |
| Minnesota State University-Mankato | |
| State Key Laboratory of Computer Science | |
| Marshfield Clinic Research Foundation | NO1-CN- 25518 |
| Marshfield Clinic Research Foundation | |
| University of Alabama, Birmingham | NO1-CN- 75022, NO1-CN-25476 |
| University of Alabama, Birmingham | |
| PACIFIC HEALTH RESEARCH INSTITUTE | NO1-CN-25515 |
| National Institutes of Health (NIH) | UM1 CA182910, N02 CP1101066, R37 CA70867 |
| National Institutes of Health (NIH) | |
| National Natural Science Foundation of China (NSFC) | 81102194 |
| National Natural Science Foundation of China (NSFC) | |
| National Institutes of Health (NIH) | HG-06-033-NCI-01, RO1HL091172-01 |
| National Institutes of Health (NIH) | |
| Science and Technology Development Center, Ministry of Education | 2011-0016106 |
| Science and Technology Development Center, Ministry of Education | |
| National Key Scientific and Technological Project | 2011ZX09307-001-04, 81272293 |
| Georgetown University | NO1-CN-25522 |
| Georgetown University | |
| Ministry of Health, Labour and Welfare | |
| Jinan Science Research Project Foundation | 201102051 |
| Ministry of Health and Welfare, Republic of Korea | 0720550-2, A010250 |
| National Natural Science Foundation of China (NSFC) | 81272618, 30772531 |
| National Natural Science Foundation of China (NSFC) | |
| National Research Program for Biopharmaceuticals | MOHW 103-TDUPB-211-144003, MOST 103-2325-B-400-023 |
| National Research Program for Biopharmaceuticals | |
| University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh | NO1-CN-25511 |
| University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh | |
| Ministry of Science and Technology, Taiwan | 104-2325-B-400-012, 103-2325-B-400-023 |
| Ministry of Science and Technology, Taiwan | |
| University of Utah Health | NO1-CN- 25524 |
| University of Utah Health | |
| Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government | 2020-J-4, 29-A-4, 26-A-2, 23-A- 31 |
| MOE 111 Project | B13016 |
| Natural Science Foundation of Guangdong Province | S2011010000792 |
| Natural Science Foundation of Guangdong Province | |
| Ministry of Education, Culture, Sports, Science and Technology | |
| National Research Program on Genomic Medicine in Taiwan | DOH99-TD-G-111-028 |
| University of Colorado Hospital Denver | NO1-CN-25514 |
| University of Colorado Hospital Denver | |
| Ministry of Education, Culture, Sports, Science & Technology, Japan | R01-CA121210 |
| The George Washington University | NO1-CN-25516 |
| The George Washington University | |
| National Cancer Institute's Cancer Center | |
| Ministry of Health, Labour and Welfare | |
| Priority Academic Program Development of Jiangsu Higher Education Institutions | 2011CB503805 |
| Priority Academic Program Development of Jiangsu Higher Education Institutions | |
| National Medical Research Council Singapore | NMRC/0897/2004, NMRC/1075/2006 |
| Bioinformatics Core Facility for Translational Medicine and Biotechnology Development | 104-2319-B-400-002 |
| National Research Foundation of Korea | |
| Ministry of Health, Labour and Welfare | |
| National Institutes of Health (NIH) | R01 CA149462 |
| National Institutes of Health (NIH) | |
| National Institutes of Health (NIH) | U19 CA148127, U19 CA203654 |
| National Institutes of Health (NIH) | |
| Canadian Institutes of Health Research | |
| Canada Excellence Research Chairs, Government of Canada | FDN 167273 |
| Canada Excellence Research Chairs, Government of Canada | |
| Cancer Prevention and Research Institute of Texas | RR170048 |
| National Health Research Institutes Taiwan | NHRI-PH-110-GP-01, NHRI-PH-110-GP-03 |
| National Health Research Institutes Taiwan | |
| Korean Ministry of Health and Welfare | DOH97-TD-G-111-026, DOH98-TD-G-111-015, DOH99-TD-G-111-028, DOH98-TD-G-111-017, DOH97-TD-G-111-028, DOH99-TD-G-111-014 |
| Korean Ministry of Health and Welfare | |
| Ministry of Science and Technology | MOST108-2314-B-400-038, MOST109-2740-B-400-002 |
| Ministry of Science and Technology | |
| Mayo Clinic Rochester | CA80127, NIH-CA77118 |
| Mayo Clinic Rochester | |
| Princess Margaret Cancer Foundation | U01CA209414, R01 CA231141 |
| Princess Margaret Cancer Foundation | |
| National Institutes of Health (NIH) |
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy
