Yingchang Lu1, Sun-Seog Kweon2, Chizu Tanikawa3, Wei-Hua Jia4, Yong-Bing Xiang5, Qiuyin Cai1, Chenjie Zeng1, Stephanie L Schmit6, Aesun Shin7, Keitaro Matsuo8, Sun Ha Jee9, Dong-Hyun Kim10, Jeongseon Kim11, Wanqing Wen1, Jiajun Shi1, Xingyi Guo1, Bingshan Li12, Nan Wang13, Ben Zhang14, Xinxiang Li15, Min-Ho Shin16, Hong-Lan Li5, Zefang Ren17, Jae Hwan Oh18, Isao Oze19, Yoon-Ok Ahn20, Keum Ji Jung21, David V Conti22, Fredrick R Schumacher23, Gad Rennert24, Mark A Jenkins25, Peter T Campbell26, Michael Hoffmeister27, Graham Casey28, Stephen B Gruber29, Jing Gao5, Yu-Tang Gao5, Zhi-Zhong Pan4, Yoichiro Kamatani30, Yi-Xin Zeng4, Xiao-Ou Shu1, Jirong Long1, Koichi Matsuda31, Wei Zheng32. 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; Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, South Korea. 3. Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan. 4. State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China. 5. State Key Laboratory of Oncogenes and Related Genes and Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. 6. Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. 7. Department of Preventive Medicine, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Korea. 8. Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan; Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan. 9. Department of Epidemiology and Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Korea. 10. Department of Social and Preventive Medicine, Hallym University College of Medicine, Okcheon-dong, Korea. 11. Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Gyeonggi-do, South Korea. 12. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee. 13. General Surgery Department, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. 14. Department of Epidemiology and Biostatistics First Affiliated Hospital, Army Medical University, Shapingba District, Chongqing, China. 15. Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 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. Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan. 20. Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea. 21. Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Korea. 22. Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California. 23. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio. 24. Clalit Health Services National Israeli Cancer Control Center, Haifa, Israel; Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel; Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. 25. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia. 26. Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia. 27. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. 28. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia. 29. Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California; Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California. 30. Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan; Kyoto-McGill International Collaborative School in Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. 31. Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan. 32. Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee. Electronic address: wei.zheng@vanderbilt.edu.
Abstract
BACKGROUND & AIMS: Genome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations. METHODS: We analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels. RESULTS: A meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10-8. We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%-75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci. CONCLUSIONS: We showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to β-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.
BACKGROUND & AIMS: Genome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations. METHODS: We analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels. RESULTS: A meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10-8. We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%-75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci. CONCLUSIONS: We showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to β-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.
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Authors: Juan Antonio Vizcaíno; Peter Kubiniok; Kevin A Kovalchik; Qing Ma; Jérôme D Duquette; Ian Mongrain; Eric W Deutsch; Bjoern Peters; Alessandro Sette; Isabelle Sirois; Etienne Caron Journal: Mol Cell Proteomics Date: 2019-11-19 Impact factor: 5.911
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Authors: Minta Thomas; Lori C Sakoda; Michael Hoffmeister; Elisabeth A Rosenthal; Jeffrey K Lee; Franzel J B van Duijnhoven; Elizabeth A Platz; Anna H Wu; Christopher H Dampier; Albert de la Chapelle; Alicja Wolk; Amit D Joshi; Andrea Burnett-Hartman; Andrea Gsur; Annika Lindblom; Antoni Castells; Aung Ko Win; Bahram Namjou; Bethany Van Guelpen; Catherine M Tangen; Qianchuan He; Christopher I Li; Clemens Schafmayer; Corinne E Joshu; Cornelia M Ulrich; D Timothy Bishop; Daniel D Buchanan; Daniel Schaid; David A Drew; David C Muller; David Duggan; David R Crosslin; Demetrius Albanes; Edward L Giovannucci; Eric Larson; Flora Qu; Frank Mentch; Graham G Giles; Hakon Hakonarson; Heather Hampel; Ian B Stanaway; Jane C Figueiredo; Jeroen R Huyghe; Jessica Minnier; Jenny Chang-Claude; Jochen Hampe; John B Harley; Kala Visvanathan; Keith R Curtis; Kenneth Offit; Li Li; Loic Le Marchand; Ludmila Vodickova; Marc J Gunter; Mark A Jenkins; Martha L Slattery; Mathieu Lemire; Michael O Woods; Mingyang Song; Neil Murphy; Noralane M Lindor; Ozan Dikilitas; Paul D P Pharoah; Peter T Campbell; Polly A Newcomb; Roger L Milne; Robert J MacInnis; Sergi Castellví-Bel; Shuji Ogino; Sonja I Berndt; Stéphane Bézieau; Stephen N Thibodeau; Steven J Gallinger; Syed H Zaidi; Tabitha A Harrison; Temitope O Keku; Thomas J Hudson; Veronika Vymetalkova; Victor Moreno; Vicente Martín; Volker Arndt; Wei-Qi Wei; Wendy Chung; Yu-Ru Su; Richard B Hayes; Emily White; Pavel Vodicka; Graham Casey; Stephen B Gruber; Robert E Schoen; Andrew T Chan; John D Potter; Hermann Brenner; Gail P Jarvik; Douglas A Corley; Ulrike Peters; Li Hsu Journal: Am J Hum Genet Date: 2020-08-05 Impact factor: 11.025