Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33

Zhaoming Wang, Bin Zhu, Mingfeng Zhang, Hemang Parikh, Jinping Jia, Charles C. Chung, Joshua N. Sampson, Jason W. Hoskins, Amy Hutchinson, Laurie Burdette, Abdisamad Ibrahim, Christopher Hautman, Preethi S. Raj, Christian C. Abnet, Andrew A. Adjei, Anders Ahlbom, Demetrius Albanes, Naomi E. Allen, Christine B. Ambrosone, Melinda AldrichPilar Amiano, Christopher Amos, Ulrika Andersson, Gerald Andriole, Irene L. Andrulis, Cecilia Arici, Alan A. Arslan, Melissa A. Austin, Dalsu Baris, Donald A. Barkauskas, Bryan A. Bassig, Laura E. Beane Freeman, Christine D. Berg, Sonja I. Berndt, Pier Alberto Bertazzi, Richard B. Biritwum, Amanda Black, William Blot, Heiner Boeing, Paolo Boffetta, Kelly Bolton, Marie-Christine Boutron-Ruault, Paige M. Bracci, Paul Brennan, Louise A. Brinton, Michelle Brotzman, H. Bas Bueno-de-Mesquita, Julie E. Buring, Mary Ann Butler, Qiuyin Cai, Geraldine Cancel-Tassin, Federico Canzian, Guangwen Cao, Neil E. Caporaso, Alfredo Carrato, Tania Carreon, Angela Carta, Gee-Chen Chang, I-Shou Chang, Jenny Chang-Claude, Xu Che, Chien-Jen Chen, Chih-Yi Chen, Chung-Hsing Chen, Constance Chen, Kuan-Yu Chen, Yuh-Min Chen, Anand P. Chokkalingam, Lisa W. Chu, Francoise Clavel-Chapelon, Graham A. Colditz, Joanne S. Colt, David Conti, Michael B. Cook, Victoria K. Cortessis, E. David Crawford, Olivier Cussenot, Faith G. Davis, Immaculata De Vivo, Xiang Deng, Ti Ding, Colin P. Dinney, Anna Luisa Di Stefano, W. Ryan Diver, Eric J. Duell, Joanne W. Elena, Jin-Hu Fan, Heather Spencer Feigelson, Maria Feychting, Jonine D. Figueroa, Adrienne M. Flanagan, Joseph F. Fraumeni, Neal D. Freedman, Brooke L. Fridley, Charles S. Fuchs, Manuela Gago-Dominguez, Steven Gallinger, Yu-Tang Gao, Susan M. Gapstur, Montserrat Garcia-Closas, Reina Garcia-Closas, Julie M. Gastier-Foster, J. Michael Gaziano, Daniela S. Gerhard, Carol A. Giffen, Graham G. Giles, Elizabeth M. Gillanders, Edward L. Giovannucci, Michael Goggins, Nalan Gokgoz, Alisa M. Goldstein, Carlos Gonzalez, Richard Gorlick, Mark H. Greene, Myron Gross, H. Barton Grossman, Robert Grubb, Jian Gu, Peng Guan, Christopher A. Haiman, Goran Hallmans, Susan E. Hankinson, Curtis C. Harris, Patricia Hartge, Claudia Hattinger, Richard B. Hayes, Qincheng He, Lee Helman, Brian E. Henderson, Roger Henriksson, Judith Hoffman-Bolton, Chancellor Hohensee, Elizabeth A. Holly, Yun-Chul Hong, Robert N. Hoover, H. Dean Hosgood, Chin-Fu Hsiao, Ann W. Hsing, Chao Agnes Hsiung, Nan Hu, Wei Hu, Zhibin Hu, Ming-Shyan Huang, David J. Hunter, Peter D. Inskip, Hidemi Ito, Eric J. Jacobs, Kevin B. Jacobs, Mazda Jenab, Bu-Tian Ji, Christoffer Johansen, Mattias Johansson, Alison Johnson, Rudolf Kaaks, Ashish M. Kamat, Aruna Kamineni, Margaret Karagas, Chand Khanna, Kay-Tee Khaw, Christopher Kim, In-Sam Kim, Jin Hee Kim, Yeul Hong Kim, Young-Chul Kim, Young Tae Kim, Chang Hyun Kang, Yoo Jin Jung, Cari M. Kitahara, Alison P. Klein, Robert Klein, Manolis Kogevinas, Woon-Puay Koh, Takashi Kohno, Laurence N. Kolonel, Charles Kooperberg, Christian P. Kratz, Vittorio Krogh, Hideo Kunitoh, Robert C. Kurtz, Nilgun Kurucu, Qing Lan, Mark Lathrop, Ching C. Lau, Fernando Lecanda, Kyoung-Mu Lee, Maxwell P. Lee, Loic Le Marchand, Seth P. Lerner, Donghui Li, Linda M. Liao, Wei-Yen Lim, Dongxin Lin, Jie Lin, Sara Lindstrom, Martha S. Linet, Jolanta Lissowska, Jianjun Liu, Börje Ljungberg, Josep Lloreta, Daru Lu, Jing Ma, Nuria Malats, Satu Mannisto, Neyssa Marina, Giuseppe Mastrangelo, Keitaro Matsuo, Katherine A. McGlynn, Roberta McKean-Cowdin, Lorna H. McNeill, Robert R. McWilliams, Beatrice S. Melin, Paul S. Meltzer, James E. Mensah, Xiaoping Miao, Dominique S. Michaud, Alison M. Mondul, Lee E. Moore, Kenneth Muir, Shelley Niwa, Sara H. Olson, Nick Orr, Salvatore Panico, Jae Yong Park, Alpa V. Patel, Ana Patino-Garcia, Sofia Pavanello, Petra H. M. Peeters, Beata Peplonska, Ulrike Peters, Gloria M. Petersen, Piero Picci, Malcolm C. Pike, Stefano Porru, Jennifer Prescott, Xia Pu, Mark P. Purdue, You-Lin Qiao, Preetha Rajaraman, Elio Riboli, Harvey A. Risch, Rebecca J. Rodabough, Nathaniel Rothman, Avima M. Ruder, Jeong-Seon Ryu, Marc Sanson, Alan Schned, Fredrick R. Schumacher, Ann G. Schwartz, Kendra L. Schwartz, Molly Schwenn, Katia Scotlandi, Adeline Seow, Consol Serra, Massimo Serra, Howard D. Sesso, Gianluca Severi, Hongbing Shen, Min Shen, Sanjay Shete, Kouya Shiraishi, Xiao-Ou Shu, Afshan Siddiq, Luis Sierrasesumaga, Sabina Sierri, Alan Dart Loon Sihoe, Debra T. Silverman, Matthias Simon, Melissa C. Southey, Logan Spector, Margaret Spitz, Meir Stampfer, Par Stattin, Mariana C. Stern, Victoria L. Stevens, Rachael Z. Stolzenberg-Solomon, Daniel O. Stram, Sara S. Strom, Wu-Chou Su, Malin Sund, Sook Whan Sung, Anthony Swerdlow, Wen Tan, Hideo Tanaka, Wei Tang, Ze-Zhang Tang, Adonina Tardon, Evelyn Tay, Philip R. Taylor, Yao Tettey, David M. Thomas, Roberto Tirabosco, Anne Tjonneland, Geoffrey S. Tobias, Jorge R. Toro, Ruth C. Travis, Dimitrios Trichopoulos, Rebecca Troisi, Ann Truelove, Ying-Huang Tsai, Margaret A. Tucker, Rosario Tumino, David Van Den Berg, Stephen K. Van Den Eeden, Roel Vermeulen, Paolo Vineis, Kala Visvanathan, Ulla Birgitte Vogel, Chaoyu Wang, Chengfeng Wang, Junwen Wang, Sophia S. Wang, Elisabete Weiderpass, Stephanie J. Weinstein, Nicolas Wentzensen, William Wheeler, Emily White, John K. Wiencke, Alicja Wolk, Brian M. Wolpin, Maria Pik Wong, Margaret Wrensch, Chen Wu, Tangchun Wu, Xifeng Wu, Yi-Long Wu, Jay S. Wunder, Yong-Bing Xiang, Jun Xu, Hannah P. Yang, Pan-Chyr Yang, Yasushi Yatabe, Yuanqing Ye, Edward D. Yeboah, Zhihua Yin, Chen Ying, Chong-Jen Yu, Kai Yu, Jian-Min Yuan, Krista A. Zanetti, Anne Zeleniuch-Jacquotte, Wei Zheng, Baosen Zhou, Lisa Mirabello, Sharon A. Savage, Peter Kraft, Stephen J. Chanock, Meredith Yeager, Maria Terese Landi, Jianxin Shi, Nilanjan Chatterjee, Laufey T. Amundadottir

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10−39; Region 3: rs2853677, P = 3.30 × 10−36 and PConditional = 2.36 × 10−8; Region 4: rs2736098, P = 3.87 × 10−12 and PConditional = 5.19 × 10−6, Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10−6; and Region 6: rs10069690, P = 7.49 × 10−15 and PConditional = 5.35 × 10−7) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10−18 and PConditional = 7.06 × 10−16). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
Original languageEnglish
JournalHuman Molecular Genetics
Volume23
Issue number24
Pages (from-to)6616-6633
Number of pages18
ISSN0964-6906
DOIs
Publication statusPublished - 2014

Cite this

Wang, Z., Zhu, B., Zhang, M., Parikh, H., Jia, J., Chung, C. C., Sampson, J. N., Hoskins, J. W., Hutchinson, A., Burdette, L., Ibrahim, A., Hautman, C., Raj, P. S., Abnet, C. C., Adjei, A. A., Ahlbom, A., Albanes, D., Allen, N. E., Ambrosone, C. B., ... Amundadottir, L. T. (2014). Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33. Human Molecular Genetics, 23(24), 6616-6633. https://doi.org/10.1093/hmg/ddu363