Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

Feng, H.; Gusev, A.; Pasaniuc, B.; Wu, L.; Long, J.; Abu-full, Z.; Aittomaki, K.; Andrulis, I. L.; Anton-Culver, H.; Antoniou, A. C.; Arason, A.; Arndt, V.; Aronson, K. J.; Arun, B. K.; Asseryanis, E.; Auer, P. L.; Azzollini, J.; Balmana, J.; Barkardottir, R. B.; Barnes, D. R.; Barrowdale, D.; Beckmann, M. W.; Behrens, S.; Benitez, J.; Bermisheva, M.; Bialkowska, K.; Blanco, A.; Blomqvist, C.; Boeckx, B.; Bogdanova, N. V.; Bojesen, S. E.; Bolla, M. K.; Bonanni, B.; Borg, A.; Brauch, H.; Brenner, H.; Briceno, I.; Broeks, A.; Bruning, T.; Burwinkel, B.; Cai, Q.; Caldes, T.; Caligo, M. A.; Campbell, I.; Canisius, S.; Campa, D.; Carter, B. D.; Carter, J.; Castelao, J. E.; Chang-Claude, J.; Chanock, S. J.; Christiansen, H.; Chung, W. K.; Claes, K. B. M.; Clarke, C. L.; Couch, F. J.; Cox, A.; Cross, S. S.; Cybulski, C.; Czene, K.; Daly, M. B.; de la Hoya, M.; De Leeneer, K.; Dennis, J.; Devilee, P.; Diez, O.; Domchek, S. M.; Dork, T.; dos-Santos-Silva, I.; Dunning, A. M.; Dwek, M.; Eccles, D. M.; Ejlertsen, B.; Ellberg, C.; Engel, C.; Eriksson, M.; Fasching, P. A.; Fletcher, O.; Flyger, H.; Fostira, F.; Friedman, E.; Fritschi, L.; Frost, D.; Gabrielson, M.; Ganz, P. A.; Gapstur, S. M.; Garber, J.; Garcia-Closas, M.; Garcia-Saenz, J. A.; Gaudet, M. M.; Giles, G. G.; Glendon, G.; Godwin, A. K.; Goldberg, M. S.; Goldgar, D. E.; Gonzalez-Neira, A.; Greene, M. H.; Gronwald, J.; Guenel, P.; Haiman, C. A.; Hall, P.; Hamann, U.; Hake, C.; He, W.; Heyworth, J.; Hogervorst, F. B. L.; Hollestelle, A.; Hooning, M. J.; Hoover, R. N.; Hopper, J. L.; Huang, G.; Hulick, P. J.; Humphreys, K.; Imyanitov, E. N.; Isaacs, C.; Jakimovska, M.; Jakubowska, A.; James, P.; Janavicius, R.; Jankowitz, R. C.; John, E. M.; Johnson, N.; Joseph, V.; Jung, A.; Karlan, B. Y.; Khusnutdinova, E.; Kiiski, J. I.; Konstantopoulou, I.; Kristensen, V. N.; Laitman, Y.; Lambrechts, D.; Lazaro, C.; Leroux, D.; Leslie, G.; Lester, J.; Lesueur, F.; Lindor, N.; Lindstrom, S.; W. -Y., Lo; Loud, J. T.; Lubinski, J.; Makalic, E.; Mannermaa, A.; Manoochehri, M.; Manoukian, S.; Margolin, S.; Martens, J. W. M.; Martinez, M. E.; Matricardi, L.; Maurer, T.; Mavroudis, D.; Mcguffog, L.; Meindl, A.; Menon, U.; Michailidou, K.; Kapoor, P. M.; Miller, A.; Montagna, M.; Moreno, F.; Moserle, L.; Mulligan, A. M.; Muranen, T. A.; Nathanson, K. L.; Neuhausen, S. L.; Nevanlinna, H.; Nevelsteen, I.; Nielsen, F. C.; Nikitina-Zake, L.; Offit, K.; Olah, E.; Olopade, O. I.; Olsson, H.; Osorio, A.; Papp, J.; Park-Simon, T. -W.; Parsons, M. T.; Pedersen, I. S.; Peixoto, A.; Peterlongo, P.; Peto, J.; Pharoah, P. D. P.; Phillips, K. -A.; Plaseska-Karanfilska, D.; Poppe, B.; Pradhan, N.; Prajzendanc, K.; Presneau, N.; Punie, K.; Pylkas, K.; Radice, P.; Rantala, J.; Rashid, M. U.; Rennert, G.; Risch, H. A.; Robson, M.; Romero, A.; Saloustros, E.; Sandler, D. P.; Santos, C.; Sawyer, E. J.; Schmidt, M. K.; Schmidt, D. F.; Schmutzler, R. K.; Schoemaker, M. J.; Scott, R. J.; Sharma, P.; Shu, X. -O.; Simard, J.; Singer, C. F.; Skytte, A. -B.; Soucy, P.; Southey, M. C.; Spinelli, J. J.; Spurdle, A. B.; Stone, J.; Swerdlow, A. J.; Tapper, W. J.; Taylor, J. A.; Teixeira, M. R.; Terry, M. B.; Teule, A.; Thomassen, M.; Thone, K.; Thull, D. L.; Tischkowitz, M.; Toland, A. E.; Tollenaar, R. A. E. M.; Torres, D.; Truong, T.; Tung, N.; Vachon, C. M.; van Asperen, C. J.; van den Ouweland, A. M. W.; van Rensburg, E. J.; Vega, A.; Viel, A.; Vieiro-Balo, P.; Wang, Q.; Wappenschmidt, B.; Weinberg, C. R.; Weitzel, J. N.; Wendt, C.; Winqvist, R.; Yang, X. R.; Yannoukakos, D.; Ziogas, A.; Milne, R. L.; Easton, D. F.; Chenevix-Trench, G.; Zheng, W.; Kraft, P.; Jiang, X.

doi:10.1002/gepi.22288

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.