Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 x 10-5. Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 x 10-6), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 x 10-9. Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis. ; Lin, Wei-Yu Camp, Nicola J Ghoussaini, Maya Beesley, Jonathan Michailidou, Kyriaki Hopper, John L Apicella, Carmel Southey, Melissa C Stone, Jennifer Schmidt, Marjanka K Broeks, Annegien Van't Veer, Laura J Th Rutgers, Emiel J Muir, Kenneth Lophatananon, Artitaya Stewart-Brown, Sarah Siriwanarangsan, Pornthep Fasching, Peter A Haeberle, Lothar Ekici, Arif B Beckmann, Matthias W Peto, Julian Dos-Santos-Silva, Isabel Fletcher, Olivia Johnson, Nichola Bolla, Manjeet K Wang, Qin Dennis, Joe Sawyer, Elinor J Cheng, Timothy Tomlinson, Ian Kerin, Michael J Miller, Nicola Marme, Frederik Surowy, Harald M Burwinkel, Barbara Guenel, Pascal Truong, Therese Menegaux, Florence Mulot, Claire Bojesen, Stig E Nordestgaard, Borge G Nielsen, Sune F Flyger, Henrik Benitez, Javier Zamora, M Pilar Arias Perez, Jose Ignacio Menendez, Primitiva Gonzalez-Neira, Anna Pita, Guillermo Alonso, M Rosario Alvarez, Nuria Herrero, Daniel Anton-Culver, Hoda Brenner, Hermann Dieffenbach, Aida Karina Arndt, Volker Stegmaier, Christa Meindl, Alfons Lichtner, Peter Schmutzler, Rita K Muller-Myhsok, Bertram Brauch, Hiltrud Bruning, Thomas Ko, Yon-Dschun The GENICA Network Tessier, Daniel C Vincent, Daniel Bacot, Francois Nevanlinna, Heli Aittomaki, Kristiina Blomqvist, Carl Khan, Sofia Matsuo, Keitaro Ito, Hidemi Iwata, Hiroji Horio, Akiyo Bogdanova, Natalia V Antonenkova, Natalia N Dork, Thilo Lindblom, Annika Margolin, Sara Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M kConFab Investigators Australian Ovarian Cancer Study Group Wu, Anna H Tseng, Chiu-Chen Van Den Berg, David Stram, Daniel O Neven, Patrick Wauters, Els Wildiers, Hans Lambrechts, Diether Chang-Claude, Jenny Rudolph, Anja Seibold, Petra Flesch-Janys, Dieter Radice, Paolo Peterlongo, Paolo Manoukian, Siranoush Bonanni, Bernardo Couch, Fergus J Wang, Xianshu Vachon, Celine Purrington, Kristen Giles, Graham G Milne, Roger L Mclean, Catriona Haiman, Christopher A Henderson, Brian E Schumacher, Fredrick Le Marchand, Loic Simard, Jacques Goldberg, Mark S Labreche, France Dumont, Martine Teo, Soo Hwang Yip, Cheng Har Hassan, Norhashimah Vithana, Eranga Nishanthie Kristensen, Vessela Zheng, Wei Deming-Halverson, Sandra Shrubsole, Martha J Long, Jirong Winqvist, Robert Pylkas, Katri Jukkola-Vuorinen, Arja Kauppila, Saila Andrulis, Irene L Knight, Julia A Glendon, Gord Tchatchou, Sandrine Devilee, Peter Tollenaar, Robert A E M Seynaeve, Caroline Van Asperen, Christi J Garcia-Closas, Montserrat Figueroa, Jonine Lissowska, Jolanta Brinton, Louise Czene, Kamila Darabi, Hatef Eriksson, Mikael Brand, Judith S Hooning, Maartje J Hollestelle, Antoinette Van Den Ouweland, Ans M W Jager, Agnes Li, Jingmei Liu, Jianjun Humphreys, Keith Shu, Xiao-Ou Lu, Wei Gao, Yu-Tang Cai, Hui Cross, Simon S Reed, Malcolm W R Blot, William Signorello, Lisa B Cai, Qiuyin Pharoah, Paul D P Perkins, Barbara Shah, Mitul Blows, Fiona M Kang, Daehee Yoo, Keun-Young Noh, Dong-Young Hartman, Mikael Miao, Hui Chia, Kee Seng Putti, Thomas Choudary Hamann, Ute Luccarini, Craig Baynes, Caroline Ahmed, Shahana Maranian, Mel Healey, Catherine S Jakubowska, Anna Lubinski, Jan Jaworska-Bieniek, Katarzyna Durda, Katarzyna Sangrajrang, Suleeporn Gaborieau, Valerie Brennan, Paul Mckay, James Slager, Susan Toland, Amanda E Yannoukakos, Drakoulis Shen, Chen-Yang Hsiung, Chia-Ni Wu, Pei-Ei Ding, Shian-Ling Ashworth, Alan Jones, Michael Orr, Nick Swerdlow, Anthony J Tsimiklis, Helen Makalic, Enes Schmidt, Daniel F Bui, Quang M Chanock, Stephen J Hunter, David J Hein, Rebecca Dahmen, Norbert Beckmann, Lars Aaltonen, Kirsimari Muranen, Taru A Heikkinen, Tuomas Irwanto, Astrid Rahman, Nazneen Turnbull, Clare A The Breast and Ovarian Cancer Susceptibility (BOCS) Study Waisfisz, Quinten Meijers-Heijboer, Hanne E J Adank, Muriel A Van Der Luijt, Rob B Hall, Per Chenevix-Trench, Georgia Dunning, Alison Easton, Douglas F Cox, Angela 16561/Cancer Research UK/United Kingdom P50 CA116201/CA/NCI NIH HHS/United States R01 CA128978/CA/NCI NIH HHS/United States Human molecular genetics Hum Mol Genet. 2014 Aug 28. pii: ddu431.