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Identification of Novel Loci and New Risk Variant in Known Loci for Colorectal Cancer Risk in East Asians

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Identification of Novel Loci and New Risk Variant in Known Loci for Colorectal Cancer Risk in East Asians Author Manuscript Published OnlineFirst on December 11, 2019; DOI: 10.1158/1055-9965.EPI-19-0755 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Identification of novel loci and new risk variant in known loci for colorectal cancer risk in East Asians Yingchang Lu,1 Sun-Seog Kweon,2,3 Qiuyin Cai,1 Chizu Tanikawa,4 Xiao-Ou Shu,1 Wei-Hua Jia,5 Yong-Bing Xiang,6 Jeroen R Huyghe,7 Tabitha A Harrison,7 Jeongseon Kim,8 Aesun Shin,9 Dong-Hyun Kim,10 Keitaro Matsuo,11, 12 Sun Ha Jee,13 Xingyi Guo,1 Wanqing Wen,1 Jiajun Shi,1 Bingshan Li,14 Nan Wang,15 Min-Ho Shin,16 Hong-Lan Li,6 Zefang Ren,17 Jae Hwan Oh,18 Isao Oze,10 Yoon-Ok Ahn,19 Keum Ji Jung,20 Jing Gao,6 Yu-Tang Gao,6 Zhi- Zhong Pan,5 Yoichiro Kamatani,21,22 Andrew T Chan-23,24,25,26, Andrea Gsur,27 Jochen Hampe,28 Loic Le Marchand,29 Li Li,30 Annika Lindblom,31,32 Victor Moreno,33,34,35 Polly A Newcomb,7,36 Kenneth Offit,37, 38 Paul D P Pharoah,39 Franzel JB van Duijnhoven,40 Bethany Van Guelpen,41 Pavel Erik Vodicka,42,43,44 Stephanie J Weinstein,45 Alicja Wolk,46 Anna H Wu,47 Li Hsu,7,48 Yi-Xin Zeng,5 Jirong Long,1 Ulrike Peters,7,49 Koichi Matsuda,50 and Wei Zheng 1 1, Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; 2, Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, South Korea; 3, Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, South Korea; 4, Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan; 5, State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China; 6, State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; 7, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 8, Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Gyeonggi-do, South Korea; 9, Department of Preventive Medicine, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Korea; 10, Department of Social and Preventive Medicine, Hallym University College of Medicine, Okcheon-dong, Korea; 11, Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan; 1 Downloaded from cebp.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 11, 2019; DOI: 10.1158/1055-9965.EPI-19-0755 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 12, Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan; 13, Department of Epidemiology and Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Korea; 14, Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee; 15, General Surgery Department, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China; 16, Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, South Korea; 17, School of Public Health, Sun Yat-sen University, Guangzhou, China; 18, Center for Colorectal Cancer, National Cancer Center Hospital, National Cancer Center, Gyeonggi-do, South Korea; 19, Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea; 20, Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Korea; 21, Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan; 22, Kyoto-McGill International Collaborative School in Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, JAPAN 23, Division of Gastroenterology, and Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. 24, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. 25, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. 26, Department of Epidemiology, and Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA. 27, Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria. 28, Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany. 29, University of Hawaii Cancer Center, Honolulu, Hawaii, USA. 30, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA. 31, Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. 2 Downloaded from cebp.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 11, 2019; DOI: 10.1158/1055-9965.EPI-19-0755 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 32, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. 33, Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain. 34, CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain. 35, Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain. 36, School of Public Health, University of Washington, Seattle, Washington, USA. 37, Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. 38, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. 39, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. 40, Division of Human Nutrition, Wageningen University and Research, Wageningen, The Netherlands. 41, Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden. 42, Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic. 43, Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic. 44, Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic. 45, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. 46, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 47, University of Southern California, Preventative Medicine, Los Angeles, California, USA. 48, Department of Biostatistics, University of Washington, Seattle, Washington, USA 49, Department of Epidemiology, University of Washington, Seattle, Washington, USA 50, Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan. Running title: genome-wide association study of colorectal cancer Corresponding author contact information: Wei Zheng, M.D., Ph.D. Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine 2525 West End Avenue, 8th Floor, Nashville, TN 37203-1738 3 Downloaded from cebp.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 11, 2019; DOI: 10.1158/1055-9965.EPI-19-0755 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Phone: (615) 936-0682; E-mail: [email protected] Keywords: colorectal cancer, genetic variants, GWAS, susceptibility The authors declare no potential conflicts of interest. 4 Downloaded from cebp.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 11, 2019; DOI: 10.1158/1055-9965.EPI-19-0755 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Background: Risk variants identified so far for colorectal cancer (CRC) explain only a small proportion of familial risk of this cancer, particularly in Asians. Methods: We performed a genome-wide association study (GWAS) of CRC in East Asians including 23,572 CRC cases and 48,700 controls. To identify novel risk loci, we selected sixty promising risk variants for replication using data from 58,131 CRC cases and 67,347 controls of European descent. To identify additional risk variants in known CRC loci, we performed conditional analyses in East Asians. Results: An indel variant, rs67052019 at 1p13.3, was found to be associated with CRC risk at P=3.9 x 10–8 in Asians (OR per allele deletion=1.13, 95%CI=1.08-1.18). This association was replicated in European descendants using a variant (rs2938616) in complete linkage disequilibrium with rs67052019 (P=7.7 x 10–3). Of the remaining 59 variants, 12 showed an association at P<0.05 in the European-ancestry study, including rs11108175 and rs9634162 at P<5×10-8 and two variants with an association near the genome-wide significance level (rs60911071, P=5.8×10-8; rs62558833, P=7.5×10-8) in the combined
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