Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population

• Published in: Nature communications Vol. 14; no. 1; pp. 3043 - 17
• Main Authors: Choi, Jiyeon, Matsuo, Keitaro, Dai, Juncheng, Hung, Rayjean J., Shu, Xiao-Ou, Lin, Dongxin, Yin, Zhihua, Song, Lei, Chang, I-Shou, Cai, Qiuyin, Wu, Yi-Long, Blechter, Batel, Wong, Jason Y. Y., Chung, Lap Ping, Zheng, Hong, Yatabe, Yasushi, Zhang, Xu-Chao, Caporaso, Neil E., Ho, James Chung Man, Kubo, Michiaki, Daigo, Yataro, Kamatani, Yoichiro, Kunitoh, Hideo, Patel, Harsh, Watanabe, Shun-ichi, Miyagi, Yohei, Matsumoto, Shingo, Horinouchi, Hidehito, Hamamoto, Ryuji, Goto, Koichi, Ohe, Yuichiro, Takahashi, Atsushi, Minamiya, Yoshihiro, Hara, Megumi, Murakami, Yoshinori, Saito, Motonobu, Ohtaki, Yoichi, Su, Jian, Kim, Yeul Hong, Lee, Victor Ho Fun, Chang, Gee-Chen, Tsai, Ying-Huang, Chen, Kuan-Yu, Huang, Ming-Shyan, Su, Wu-Chou, Chen, Yuh-Min, Park, Jae Yong, Gao, Yu-Tang, Qian, Biyun, Lu, Daru, Houlston, Richard, Spitz, Margaret R., Lam, Stephen, Chen, Chu, Bojesen, Stig E., Johansson, Mattias, Bickeböller, Heike, Christiani, David C., Rennert, Gadi, Field, John K., Le Marchand, Loic, Andrew, Angeline, Kiemeney, Lambertus A., Grankvist, Kjell, Johansson, Mikael, Taylor, Fiona, Schabath, Matthew B., Jeon, Hyo-Sung, Jung, Yoo Jin, Berndt, Sonja I., Wu, Wei, Park, Kyong Hwa, Kang, Chang Hyun, Wang, Wen-Chang, Xu, Jun, Yu, Chong-Jen, Yang, Gong, Sihoe, Alan Dart Loon, Kim, Jun Suk, Park, In Kyu, Vermeulen, Roel C. H., Wu, Junjie, Lim, Wei-Yen, Li, Jihua, Chen, Hongyan, Jin, Li, Liu, Jie, Yamaji, Taiki, Ma, Hongxia, Li, Xuelian, Ren, Yangwu, Zhu, Junjie, Jiang, Gening, Fei, Ke, Wu, Guoping, Yu, Jinming, Fraumeni, Joseph F., Chatterjee, Nilanjan, Hsiung, Chao Agnes, Amos, Christopher I.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.05.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 38/43; 631/208/205/2138; 631/67/2324; Adenocarcinoma; Adenocarcinoma of Lung - genetics; Asia, Eastern - epidemiology; Cancer; Chromosome 11; Chromosome 2; Gene loci; Gene mapping; Genetic Predisposition to Disease; Genome-wide association studies; Genome-Wide Association Study; Genomes; Heritability; Humanities and Social Sciences; Humans; Lung cancer; Lung Neoplasms - epidemiology; Lung Neoplasms - genetics; multidisciplinary; Polygenic inheritance; Polymorphism, Single Nucleotide; Population studies; Populations; Quantitative trait loci; Risk; Science; Science (multidisciplinary); Smoking; Transcriptomes; Asia, Eastern; East Asia
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-38196-z

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 (P interaction  = 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. Genome-wide association studies (GWAS) have improved our understanding of the genetic basis of lung adenocarcinoma but known susceptibility variants explain only a small fraction of the familial risk. Here, the authors perform a two-stage GWAS and report 12 novel genetic loci associated with lung adenocarcinoma in East Asians.