Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

Fachal, L. et al. (2020) Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes. Nature Genetics, 52(1), pp. 56-73. (doi: 10.1038/s41588-019-0537-1) (PMID:31911677) (PMCID:PMC6974400)

Abstract

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Paul, Mr James
• Authors: Fachal, L., Aschard, H., Beesley, J., Barnes, D. R., Allen, J., Kar, S., Pooley, K. A., Dennis, J., Michailidou, K., Turman, C., Soucy, P., Lemaçon, A., Lush, M., Tyrer, J. P., Ghoussaini, M., Moradi Marjaneh, M., Jiang, X., Agata, S., Aittomäki, K., Alonso, M. R., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Arason, A., Arndt, V., Aronson, K. J., Arun, B. K., Auber, B., Auer, P. L., Azzollini, J., Balmaña, J., Barkardottir, R. B., Barrowdale, D., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Białkowska, K., Blanco, A. M., Blomqvist, C., Blot, W., Bogdanova, N. V., Bojesen, S. E., Bolla, M. K., Bonanni, B., Borg, A., Bosse, K., Brauch, H., Brenner, H., Briceno, I., Brock, I. W., Brooks-Wilson, A., Brüning, T., Burwinkel, B., Buys, S. S., Cai, Q., Caldés, T., Caligo, M. A., Camp, N. J., Campbell, I., Canzian, F., Carroll, J. S., Carter, B. D., Castelao, J. E., Chiquette, J., Christiansen, H., Chung, W. K., Claes, K. B. M., Clarke, C. L., Collée, J. M., Cornelissen, S., Couch, F. J., Cox, A., Cross, S. S., Cybulski, C., Czene, K., Daly, M. B., de la Hoya, M., Devilee, P., Diez, O., Ding, Y. C., Dite, G. S., Domchek, S. M., Dörk, T., dos-Santos-Silva, I., Droit, A., Dubois, S., Dumont, M., Duran, M., Durcan, L., Dwek, M., Eccles, D. M., Engel, C., Eriksson, M., Evans, D. G., Fasching, P. A., Fletcher, O., Floris, G., Flyger, H., Foretova, L., Foulkes, W. D., Friedman, E., Fritschi, L., Frost, D., Gabrielson, M., Gago-Dominguez, M., Gambino, G., Ganz, P. A., Gapstur, S. M., Garber, J., García-Sáenz, J. A., Gaudet, M. M., Georgoulias, V., Giles, G. G., Glendon, G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., González-Neira, A., Tibiletti, M. G., Greene, M. H., Grip, M., Gronwald, J., Grundy, A., Guénel, P., Hahnen, E., Haiman, C. A., Håkansson, N., Hall, P., Hamann, U., Harrington, P. A., Hartikainen, J. M., Hartman, M., He, W., Healey, C. S., Heemskerk-Gerritsen, B. A. M., Heyworth, J., Hillemanns, P., Hogervorst, F. B. L., Hollestelle, A., Hooning, M. J., Hopper, J. L., Howell, A., Huang, G., Hulick, P. J., Imyanitov, E. N., Isaacs, C., Iwasaki, M., Jager, A., Jakimovska, M., Jakubowska, A., James, P. A., Janavicius, R., Jankowitz, R. C., John, E. M., Johnson, N., Jones, M. E., Jukkola-Vuorinen, A., Jung, A., Kaaks, R., Kang, D., Kapoor, P. M., Karlan, B. Y., Keeman, R., Kerin, M. J., Khusnutdinova, E., Kiiski, J. I., Kirk, J., Kitahara, C. M., Ko, Y.-D., Konstantopoulou, I., Kosma, V.-M., Koutros, S., Kubelka-Sabit, K., Kwong, A., Kyriacou, K., Laitman, Y., Lambrechts, D., Lee, E., Leslie, G., Lester, J., Lesueur, F., Lindblom, A., Lo, W.-Y., Long, J., Lophatananon, A., Loud, J. T., Lubiński, J., MacInnis, R. J., Maishman, T., Makalic, E., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M. E., Matsuo, K., Maurer, T., Mavroudis, D., Mayes, R., McGuffog, L., McLean, C., Mebirouk, N., Meindl, A., Miller, A., Miller, N., Montagna, M., Moreno, F., Muir, K., Mulligan, A. M., Muñoz-Garzon, V. M., Muranen, T. A., Narod, S. A., Nassir, R., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Neven, P., Nielsen, F. C., Nikitina-Zake, L., Norman, A., Offit, K., Olah, E., Olopade, O. I., Olsson, H., Orr, N., Osorio, A., Pankratz, V. S., Papp, J., Park, S. K., Park-Simon, T.-W., Parsons, M. T., Paul, J., Pedersen, I. S., Peissel, B., Peshkin, B., Peterlongo, P., Peto, J., Plaseska-Karanfilska, D., Prajzendanc, K., Prentice, R., Presneau, N., Prokofyeva, D., Pujana, M. A., Pylkäs, K., Radice, P., Ramus, S. J., Rantala, J., Rau-Murthy, R., Rennert, G., Risch, H. A., Robson, M., Romero, A., Rossing, M., Saloustros, E., Sánchez-Herrero, E., Sandler, D. P., Santamariña, M., Saunders, C., Sawyer, E. J., Scheuner, M. T., Schmidt, D. F., Schmutzler, R. K., Schneeweiss, A., Schoemaker, M. J., Schöttker, B., Schürmann, P., Scott, C., Scott, R. J., Senter, L., Seynaeve, C. M., Shah, M., Sharma, P., Shen, C.-Y., Shu, X.-O., Singer, C. F., Slavin, T. P., Smichkoska, S., Southey, M. C., Spinelli, J. J., Spurdle, A. B., Stone, J., Stoppa-Lyonnet, D., Sutter, C., Swerdlow, A. J., Tamimi, R. M., Tan, Y. Y., Tapper, W. J., Taylor, J. A., Teixeira, M. R., Tengström, M., Teo, S. H., Terry, M. B., Teulé, A., Thomassen, M., Thull, D. L., Tischkowitz, M., Toland, A. E., Tollenaar, R. A. E. M., Tomlinson, I., Torres, D., Torres-Mejía, G., Troester, M. A., Truong, T., Tung, N., Tzardi, M., Ulmer, H.-U., Vachon, C. M., van Asperen, C. J., van der Kolk, L. E., van Rensburg, E. J., Vega, A., Viel, A., Vijai, J., Vogel, M. J., Wang, Q., Wappenschmidt, B., Weinberg, C. R., Weitzel, J. N., Wendt, C., Wildiers, H., Winqvist, R., Wolk, A., Wu, A. H., Yannoukakos, D., Zhang, Y., Zheng, W., Hunter, D., Pharoah, P. D. P., Chang-Claude, J., García-Closas, M., Schmidt, M. K., Milne, R. L., Kristensen, V. N., French, J. D., Edwards, S. L., Antoniou, A. C., Chenevix-Trench, G., Simard, J., Easton, D. F., Kraft, P., and Dunning, A. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Genetics
• Publisher: Nature Research
• ISSN: 1061-4036
• ISSN (Online): 1546-1718
• Published Online: 07 January 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Nature Genetics 52(1): 56-73
• Publisher Policy: Reproduced in accordance with the publisher copyright policy