Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types

Joshua N Sampson, William A Wheeler, Meredith Yeager, Orestis Panagiotou, Zhaoming Wang, Sonja I Berndt, Qing Lan, Christian C Abnet, Laufey T Amundadottir, Jonine D Figueroa, Maria Teresa Landi, Lisa Mirabello, Sharon A Savage, Philip R Taylor, Immaculata De Vivo, Katherine A McGlynn, Mark P Purdue, Preetha Rajaraman, Hans-Olov Adami, Anders Ahlbom, Demetrius Albanes, Maria Fernanda Amary, She-Juan An, Ulrika Andersson, Gerald Andriole, Irene L Andrulis, Emanuele Angelucci, Stephen M Ansell, Cecilia Arici, Bruce K Armstrong, Alan A Arslan, Melissa A Austin, Dalsu Baris, Donald A Barkauskas, Bryan A Bassig, Nikolaus Becker, Yolanda Benavente, Simone Benhamou, Christine Berg, David Van Den Berg, Leslie Bernstein, Kimberly A Bertrand, Brenda M Birmann, Amanda Black, Heiner Boeing, Paolo Boffetta, Marie-Christine Boutron-Ruault, Paige M Bracci, Louise Brinton, Angela R Brooks-Wilson, H Bas Bueno-de-Mesquita, Laurie Burdett, Julie Buring, Mary Ann Butler, Qiuyin Cai, Geraldine Cancel-Tassin, Federico Canzian, Alfredo Carrato, Tania Carreon, Angela Carta, John K C Chan, Ellen T Chang, Gee-Chen Chang, I-Shou Chang, Jiang Chang, Jenny Chang-Claude, Chien-Jen Chen, Chih-Yi Chen, Chu Chen, Chung-Hsing Chen, Constance Chen, Hongyan Chen, Kexin Chen, Kuan-Yu Chen, Kun-Chieh Chen, Ying Chen, Ying-Hsiang Chen, Yi-Song Chen, Yuh-Min Chen, Li-Hsin Chien, María-Dolores Chirlaque, Jin Eun Choi, Yi Young Choi, Wong-Ho Chow, Charles C Chung, Jacqueline Clavel, Françoise Clavel-Chapelon, Pierluigi Cocco, Joanne S Colt, Eva Comperat, Lucia Conde, Joseph M Connors, David Conti, Victoria K Cortessis, Michelle Cotterchio, Wendy Cozen, Simon Crouch, Marta Crous-Bou, Olivier Cussenot, Faith G Davis, Ti Ding, W Ryan Diver, Miren Dorronsoro, Laure Dossus, Eric J Duell, Maria Grazia Ennas, Ralph L Erickson, Maria Feychting, Adrienne M Flanagan, Lenka Foretova, Joseph F Fraumeni, Neal D Freedman, Laura E Beane Freeman, Charles Fuchs, Manuela Gago-Dominguez, Steven Gallinger, Yu-Tang Gao, Susan M Gapstur, Montserrat Garcia-Closas, Reina García-Closas, Randy D Gascoyne, Julie Gastier-Foster, Mia M Gaudet, J Michael Gaziano, Carol Giffen, Graham G Giles, Edward Giovannucci, Bengt Glimelius, Michael Goggins, Nalan Gokgoz, Alisa M Goldstein, Richard Gorlick, Myron Gross, Robert Grubb, Jian Gu, Peng Guan, Marc Gunter, Huan Guo, Thomas M Habermann, Christopher A Haiman, Dina Halai, Goran Hallmans, Manal Hassan, Claudia Hattinger, Qincheng He, Xingzhou He, Kathy Helzlsouer, Brian Henderson, Roger Henriksson, Henrik Hjalgrim, Judith Hoffman-Bolton, Chancellor Hohensee, Theodore R Holford, Elizabeth A Holly, Yun-Chul Hong, Robert N Hoover, Pamela L Horn-Ross, G M Monawar Hosain, H Dean Hosgood, Chin-Fu Hsiao, Nan Hu, Wei Hu, Zhibin Hu, Ming-Shyan Huang, Jose-Maria Huerta, Jen-Yu Hung, Amy Hutchinson, Peter D Inskip, Rebecca D Jackson, Eric J Jacobs, Mazda Jenab, Hyo-Sung Jeon, Bu-Tian Ji, Guangfu Jin, Li Jin, Christoffer Johansen, Alison Johnson, Yoo Jin Jung, Rudolph Kaaks, Aruna Kamineni, Eleanor Kane, Chang Hyun Kang, Margaret R Karagas, Rachel S Kelly, Kay-Tee Khaw, Christopher Kim, Hee Nam Kim, Jin Hee Kim, Jun Suk Kim, Yeul Hong Kim, Young Tae Kim, Young-Chul Kim, Cari M Kitahara, Alison P Klein, Robert J Klein, Manolis Kogevinas, Takashi Kohno, Laurence N Kolonel, Charles Kooperberg, Anne Kricker, Vittorio Krogh, Hideo Kunitoh, Robert C Kurtz, Sun-Seog Kweon, Andrea LaCroix, Charles Lawrence, Fernando Lecanda, Victor Ho Fun Lee, Donghui Li, Haixin Li, Jihua Li, Yao-Jen Li, Yuqing Li, Linda M Liao, Mark Liebow, Tracy Lightfoot, Wei-Yen Lim, Chien-Chung Lin, Dongxin Lin, Sara Lindstrom, Martha S Linet, Brian K Link, Chenwei Liu, Jianjun Liu, Li Liu, Börje Ljungberg, Josep Lloreta, Simonetta Di Lollo, Daru Lu, Eiluv Lund, Nuria Malats, Satu Mannisto, Loic Le Marchand, Neyssa Marina, Giovanna Masala, Giuseppe Mastrangelo, Keitaro Matsuo, Marc Maynadie, James McKay, Roberta McKean-Cowdin, Mads Melbye, Beatrice S Melin, Dominique S Michaud, Tetsuya Mitsudomi, Alain Monnereau, Rebecca Montalvan, Lee E Moore, Lotte Maxild Mortensen, Alexandra Nieters, Kari E North, Anne J Novak, Ann L Oberg, Kenneth Offit, In-Jae Oh, Sara H Olson, Domenico Palli, William Pao, In Kyu Park, Jae Yong Park, Kyong Hwa Park, Ana Patiño-Garcia, Sofia Pavanello, Petra H M Peeters, Reury-Perng Perng, Ulrike Peters, Gloria M Petersen, Piero Picci, Malcolm C Pike, Stefano Porru, Jennifer Prescott, Ludmila Prokunina-Olsson, Biyun Qian, You-Lin Qiao, Marco Rais, Elio Riboli, Jacques Riby, Harvey A Risch, Cosmeri Rizzato, Rebecca Rodabough, Eve Roman, Morgan Roupret, Avima M Ruder, Silvia de Sanjose, Ghislaine Scelo, Alan Schned, Fredrick Schumacher, Kendra Schwartz, Molly Schwenn, Katia Scotlandi, Adeline Seow, Consol Serra, Massimo Serra, Howard D Sesso, Veronica Wendy Setiawan, Gianluca Severi, Richard K Severson, Tait D Shanafelt, Hongbing Shen, Wei Shen, Min-Ho Shin, Kouya Shiraishi, Xiao-Ou Shu, Afshan Siddiq, Luis Sierrasesúmaga, Alan Dart Loon Sihoe, Christine F Skibola, Alex Smith, Martyn T Smith, Melissa C Southey, John J Spinelli, Anthony Staines, Meir Stampfer, Marianna C Stern, Victoria L Stevens, Rachael S Stolzenberg-Solomon, Jian Su, Wu-Chou Su, Malin Sund, Jae Sook Sung, Sook Whan Sung, Wen Tan, Wei Tang, Adonina Tardón, David Thomas, Carrie A Thompson, Lesley F Tinker, Roberto Tirabosco, Anne Tjønneland, Ruth C Travis, Dimitrios Trichopoulos, Fang-Yu Tsai, Ying-Huang Tsai, Margaret Tucker, Jenny Turner, Claire M Vajdic, Roel C H Vermeulen, Danylo J Villano, Paolo Vineis, Jarmo Virtamo, Kala Visvanathan, Jean Wactawski-Wende, Chaoyu Wang, Chih-Liang Wang, Jiu-Cun Wang, Junwen Wang, Fusheng Wei, Elisabete Weiderpass, George J Weiner, Stephanie Weinstein, Nicolas Wentzensen, Emily White, Thomas E Witzig, Brian M Wolpin, Maria Pik Wong, Chen Wu, Guoping Wu, Junjie Wu, Tangchun Wu, Wei Wu, Xifeng Wu, Yi-Long Wu, Jay S Wunder, Yong-Bing Xiang, Jun Xu, Ping Xu, Pan-Chyr Yang, Tsung-Ying Yang, Yuanqing Ye, Zhihua Yin, Jun Yokota, Ho-Il Yoon, Chong-Jen Yu, Herbert Yu, Kai Yu, Jian-Min Yuan, Andrew Zelenetz, Anne Zeleniuch-Jacquotte, Xu-Chao Zhang, Yawei Zhang, Xueying Zhao, Zhenhong Zhao, Hong Zheng, Tongzhang Zheng, Wei Zheng, Baosen Zhou, Meng Zhu, Mariagrazia Zucca, Simina M Boca, James R Cerhan, Giovanni M Ferri, Patricia Hartge, Chao Agnes Hsiung, Corrado Magnani, Lucia Miligi, Lindsay M Morton, Karin E Smedby, Lauren R Teras, Joseph Vijai, Sophia S Wang, Paul Brennan, Neil E Caporaso, David J Hunter, Peter Kraft, Nathaniel Rothman, Debra T Silverman, Susan L Slager, Stephen J Chanock, Nilanjan Chatterjee

Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.