Nature Genetics
Publication date:
2020-01-01
Volume:
52
Pages:
56 -
73
Publisher:
Nature Research
Author:
Fachal, Laura
Aschard, Hugues ; Beesley, Jonathan ; Barnes, Daniel R ; Allen, Jamie ; Kar, Siddhartha ; Pooley, Karen A ; Dennis, Joe ; Michailidou, Kyriaki ; Turman, Constance ; Soucy, Penny ; Lemacon, Audrey ; Lush, Michael ; Tyrer, Jonathan P ; Ghoussaini, Maya ; Marjaneh, Mahdi Moradi ; Jiang, Xia ; Agata, Simona ; Aittomaki, Kristiina ; Rosario Alonso, M ; Andrulis, Irene L ; Anton-Culver, Hoda ; Antonenkova, Natalia N ; Arason, Adalgeir ; Arndt, Volker ; Aronson, Kristan J ; Arun, Banu K ; Auber, Bernd ; Auer, Paul L ; Azzollini, Jacopo ; Balmana, Judith ; Barkardottir, Rosa B ; Barrowdale, Daniel ; Beeghly-Fadiel, Alicia ; Benitez, Javier ; Bermisheva, Marina ; Bialkowska, Katarzyna ; Blanco, Amie M ; Blomqvist, Carl ; Blot, William ; Bogdanova, Natalia ; Bojesen, Stig E ; Bolla, Manjeet K ; Bonanni, Bernardo ; Borg, Ake ; Bosse, Kristin ; Brauch, Hiltrud ; Brenner, Hermann ; Briceno, Ignacio ; Brock, Ian W ; Brooks-Wilson, Angela ; Bruening, Thomas ; Burwinkel, Barbara ; Buys, Saundra S ; Cai, Qiuyin ; Caldes, Trinidad ; Caligo, Maria A ; Camp, Nicola J ; Campbell, Ian ; Canzian, Federico ; Carroll, Jason S ; Carter, Brian D ; Castelao, Jose E ; Chiquette, Jocelyne ; Christiansen, Hans ; Chung, Wendy K ; Claes, Kathleen BM ; Clarke, Christine L ; Collee, J Margriet ; Cornelissen, Sten ; Couch, Fergus J ; Cox, Angela ; Cross, Simon S ; Cybulski, Cezary ; Czene, Kamila ; Daly, Mary B ; de la Hoya, Miguel ; Devilee, Peter ; Diez, Orland ; Ding, Yuan Chun ; Dite, Gillian S ; Domchek, Susan M ; Doerk, Thilo ; dos-Santos-Silva, Isabel ; Droit, Arnaud ; Dubois, Stephane ; Dumont, Martine ; Duran, Mercedes ; Durcan, Lorraine ; Dwek, Miriam ; Eccles, Diana M ; Engel, Christoph ; Eriksson, Mikael ; Evans, D Gareth ; Fasching, Peter A ; Fletcher, Olivia ; Floris, Giuseppe ; Flyger, Henrik ; Foretova, Lenka ; Foulkes, William D ; Friedman, Eitan ; Fritschi, Lin ; Frost, Debra ; Gabrielson, Marike ; Gago-Dominguez, Manuela ; Gambino, Gaetana ; Ganz, Patricia A ; Gapstur, Susan M ; Garber, Judy ; Garcia-Saenz, Jose A ; Gaudet, Mia M ; Georgoulias, Vassilios ; Giles, Graham G ; Glendon, Gord ; Godwin, Andrew K ; Goldberg, Mark S ; Goldgar, David E ; Gonzalez-Neira, Anna ; Tibiletti, Maria Grazia ; Greene, Mark H ; Grip, Mervi ; Gronwald, Jacek ; Grundy, Anne ; Guenel, Pascal ; Hahnen, Eric ; Haiman, Christopher A ; Hakansson, Niclas ; Hall, Per ; Hamann, Ute ; Harrington, Patricia A ; Hartikainen, Jaana M ; Hartman, Mikael ; He, Wei ; Healey, Catherine S ; Heemskerk-Gerritsen, Bernadette AM ; Heyworth, Jane ; Hillemanns, Peter ; Hogervorst, Frans BL ; Hollestelle, Antoinette ; Hooning, Maartje J ; Hopper, John L ; Howell, Anthony ; Huang, Guanmengqian ; Hulick, Peter J ; Imyanitov, Evgeny N ; Isaacs, Claudine ; Iwasaki, Motoki ; Jager, Agnes ; Jakimovska, Milena ; Jakubowska, Anna ; James, Paul A ; Janavicius, Ramunas ; Jankowitz, Rachel C ; John, Esther M ; Johnson, Nichola ; Jones, Michael E ; Jukkola-Vuorinen, Arja ; Jung, Audrey ; Kaaks, Rudolf ; Kang, Daehee ; Kapoor, Pooja Middha ; Karlan, Beth Y ; Keeman, Renske ; Kerin, Michael J ; Khusnutdinova, Elza ; Kiiski, Johanna ; Kirk, Judy ; Kitahara, Cari M ; Ko, Yon-Dschun ; Konstantopoulou, Irene ; Kosma, Veli-Matti ; Koutros, Stella ; Kubelka-Sabit, Katerina ; Kwong, Ava ; Kyriacou, Kyriacos ; Laitman, Yael ; Lambrechts, Diether ; Lee, Eunjung ; Leslie, Goska ; Lester, Jenny ; Lesueur, Fabienne ; Lindblom, Annika ; Lo, Wing-Yee ; Long, Jirong ; Lophatananon, Artitaya ; Loud, Jennifer T ; Lubinski, Jan ; MacInnis, Robert J ; Maishman, Tom ; Makalic, Enes ; Mannermaa, Arto ; Manoochehri, Mehdi ; Manoukian, Siranoush ; Margolin, Sara ; Martinez, Maria Elena ; Matsuo, Keitaro ; Maurer, Tabea ; Mavroudis, Dimitrios ; Mayes, Rebecca ; McGuffog, Lesley ; McLean, Catriona ; Mebirouk, Noura ; Meindl, Alfons ; Miller, Austin ; Miller, Nicola ; Montagna, Marco ; Moreno, Fernando ; Muir, Kenneth ; Mulligan, Anna Marie ; Munoz-Garzon, Victor M ; Muranen, Taru A ; Narod, Steven A ; Nassir, Rami ; Nathanson, Katherine L ; Neuhausen, Susan L ; Nevanlinna, Heli ; Neven, Patrick ; Nielsen, Finn C ; Nikitina-Zake, Liene ; Norman, Aaron ; Offit, Kenneth ; Olah, Edith ; Olopade, Olufunmilayo ; Olsson, Hakan ; Orr, Nick ; Osorio, Ana ; Pankratz, V Shane ; Papp, Janos ; Park, Sue K ; Park-Simon, Tjoung-Won ; Parsons, Michael T ; Paul, James ; Pedersen, Inge Sokilde ; Peissel, Bernard ; Peshkin, Beth ; Peterlongo, Paolo ; Peto, Julian ; Plaseska-Karanfilska, Dijana ; Prajzendanc, Karolina ; Prentice, Ross ; Presneau, Nadege ; Prokofyeva, Darya ; Angel Pujana, Miquel ; Pylkas, Katri ; Radice, Paolo ; Ramus, Susan J ; Rantala, Johanna ; Rau-Murthy, Rohini ; Rennert, Gad ; Risch, Harvey A ; Robson, Mark ; Romero, Atocha ; Rossing, Maria ; Saloustros, Emmanouil ; Sanchez-Herrero, Estela ; Sandler, Dale P ; Santamarina, Marta ; Saunders, Christobel ; Sawyer, Elinor J ; Scheuner, Maren T ; Schmidt, Daniel F ; Schmutzler, Rita K ; Schneeweiss, Andreas ; Schoemaker, Minouk J ; Schoettker, Ben ; Schuermann, Peter ; Scott, Christopher ; Scott, Rodney J ; Senter, Leigha ; Seynaeve, Caroline M ; Shah, Mitul ; Sharma, Priyanka ; Shen, Chen-Yang ; Shu, Xiao-Ou ; Singer, Christian F ; Slavin, Thomas P ; Smichkoska, Snezhana ; Southey, Melissa C ; Spinelli, John J ; Spurdle, Amanda B ; Stone, Jennifer ; Stoppa-Lyonnet, Dominique ; Sutter, Christian ; Swerdlow, Anthony J ; Tamimi, Rulla M ; Tan, Yen Yen ; Tapper, William J ; Taylor, Jack A ; Teixeira, Manuel R ; Tengstroem, Maria ; Teo, Soo Hwang ; Terry, Mary Beth ; Teul, Alex ; Thomassen, Mads ; Thull, Darcy L ; Tischkowitz, Marc ; Toland, Amanda E ; Tollenaar, Rob AEM ; Tomlinson, Ian ; Torres, Diana ; Torres-Mejia, Gabriela ; Troester, Melissa A ; Truong, Therese ; Tung, Nadine ; Tzardi, Maria ; Ulmer, Hans-Ulrich ; Vachon, Celine M ; van Asperen, Christi J ; van der Kolk, Lizet E ; van Rensburg, Elizabeth J ; Vega, Ana ; Viel, Alessandra ; Vijai, Joseph ; Vogel, Maartje J ; Wang, Qin ; Wappenschmidt, Barbara ; Weinberg, Clarice R ; Weitzel, Jeffrey N ; Wendt, Camilla ; Wildiers, Hans ; Winqvist, Robert ; Wolk, Alicja ; Wu, Anna H ; Yannoukakos, Drakoulis ; Zhang, Yan ; Zheng, Wei ; Hunter, David ; Pharoah, Paul DP ; Chang-Claude, Jenny ; Garcia-Closas, Montserrat ; Schmidt, Marjanka K ; Milne, Roger L ; Kristensen, Vessela N ; French, Juliet D ; Edwards, Stacey L ; Antoniou, Antonis C ; Chenevix-Trench, Georgia ; Simard, Jacques ; Easton, Douglas F ; Kraft, Peter ; Dunning, Alison M ; Mari, Veronique ; Berthet, Pascaline ; Castera, Laurent ; Vaur, Dominique ; Lallaoui, Hakima ; Bignon, Yves-Jean ; Uhrhammer, Nancy ; Bonadona, Valerie ; Lasset, Christine ; Revillion, Francoise ; Vennin, Paul ; Muller, Daniele ; Gomes, Denise Molina ; Ingster, Olivier ; Coupier, Isabelle ; Pujol, Pascal ; Collonge-Rame, Marie-Agnes ; Mortemousque, Isabelle ; Bera, Odile ; Rose, Mickaelle ; Baurand, Amandine ; Bertolone, Geoffrey ; Faivre, Laurence ; Dreyfus, Hlne ; Leroux, Dominique ; Venat-Bouvet, Laurence ; Bezieau, Stephane ; Delnatte, Capucine ; Chiesa, Jean ; Gilbert-Dussardier, Brigitte ; Gesta, Paul ; Prieur, Fabienne Prieur ; Bronner, Myriam ; Sokolowska, Johanna ; Coulet, Florence ; Boutry-Kryza, Nadia ; Calender, Alain ; Giraud, Sophie ; Leone, Melanie ; Fert-Ferrer, Sandra ; Jiao, Yue ; Lesueur, Fabienne Lesueur ; Barouk-Simonet, Emmanuelle ; Bubien, Virginie ; Longy, Michel ; Sevenet, Nicolas ; Gladieff, Laurence ; Toulas, Christine ; Reimineras, Audrey ; Sobol, Hagay ; Bressac-de Paillerets, Brigitte ; Cabaret, Odile ; Caron, Olivier ; Guillaud-Bataille, Marine ; Rouleau, Etienne ; Belotti, Muriel ; Buecher, Bruno ; Caputo, Sandrine ; Colas, Chrystelle ; De Pauw, Antoine ; Fourme, Emmanuelle ; Gauthier-Villars, Marion ; Golmard, Lisa ; Moncoutier, Virginie ; Saule, Claire ; Donaldson, Alan ; Murray, Alex ; Brady, Angela ; Brewer, Carole ; Pottinger, Caroline ; Miller, Clare ; Gallagher, David ; Gregory, Helen ; Cook, Jackie ; Eason, Jacqueline ; Adlard, Julian ; Barwell, Julian ; Ong, Kai-Ren ; Snape, Katie ; Walker, Lisa ; Izatt, Louise ; Side, Lucy ; Rogers, Mark T ; Porteous, Mary E ; Ahmed, Munaza ; Morrison, Patrick J ; Brennan, Paul ; Eeles, Ros ; Davidson, Rosemarie ; Sexton, Adrienne ; Christian, Alice ; Trainer, Alison ; Spigelman, Allan ; Fellows, Andrew ; Shelling, Andrew ; De Fazio, Anna ; Blackburn, Anneke ; Crook, Ashley ; Meiser, Bettina ; Patterson, Briony ; Clarke, Christine ; Hunt, Clare ; Scott, Clare ; Amor, David ; Marsh, Deb ; Edkins, Edward ; Salisbury, Elizabeth ; Haan, Eric ; Neidermayr, Eveline ; Macrea, Finlay ; Farshid, Gelareh ; Lindeman, Geoff ; Trench, Georgia ; Mann, Graham ; Giles, Graham ; Gill, Grantley ; Thorne, Heather ; Hickie, Ian ; Winship, Ingrid ; Flanagan, James ; Kollias, James ; Visvader, Jane ; Taylor, Jessica ; Burke, Jo ; Saunus, Jodi ; Forbes, John ; Hopper, John ; French, Juliet ; Tucker, Kathy ; Wu, Kathy ; Phillips, Kelly ; Lipton, Lara ; Andrews, Leslie ; Lobb, Lizz ; Walker, Logan ; Kentwell, Maira ; Spurdle, Mandy ; Cummings, Margaret ; Gleeson, Margaret ; Harris, Marion ; Jenkins, Mark ; Young, Mary Anne ; Delatycki, Martin ; Wallis, Mathew ; Burgess, Matthew ; Price, Melanie ; Brown, Melissa ; Southey, Melissa ; Bogwitz, Michael ; Field, Michael ; Friedlander, Michael ; Gattas, Michael ; Saleh, Mona ; Hayward, Nick ; Pachter, Nick ; Cohen, Paul ; Duijf, Pascal ; James, Paul ; Simpson, Pete ; Fong, Peter ; Butow, Phyllis ; Williams, Rachael ; Kefford, Rick ; Scott, Rodney ; Milne, Roger ; Balleine, Rosemary ; Dawson, SarahJane ; Lok, Sheau ; O'Connell, Shona ; Greening, Sian ; Nightingale, Sophie ; Edwards, Stacey ; Fox, Stephen ; Mclachlan, Sue-Anne ; Lakhani, Sunil ; Antill, Yoland ; Aalfs, Cora ; Meijers-Heijboer, Hanne ; van Engelen, Klaartje ; Gille, Hans ; Boere, Ingrid ; Collee, Margriet ; van Deurzen, Carolien ; Hooning, Maartje ; Obdeijn, Inge-Marie ; van den Ouweland, Ans ; Seynaeve, Caroline ; Siesling, Sabine ; Verloop, Janneke ; van Asperen, Christi ; van Cronenburg, Twiggy ; Blok, Rien ; de Boer, Maaike ; Garcia, Encarna Gomez ; Adank, Muriel ; Hogervorst, Frans ; Jenner, Denise ; van Leeuwen, Flora ; Rookus, Matti ; Russell, Nicola ; Schmidt, Marjanka ; van den Belt-Dusebout, Sandra ; Kets, Carolien ; Mensenkamp, Arjen ; de Bock, Truuske ; van Der Hout, Annemieke ; Mourits, Marian ; Oosterwijk, Jan ; Ausems, Margreet ; Koudijs, Marco ; Marsh, Deborah ; Baxter, Robert ; Yip, Desmond ; Carpenter, Jane ; Davis, Alison ; Pathmanathan, Nirmala ; Simpson, Peter ; Graham, Dinny ; Sachchithananthan, Mythily
Keywords:
Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, GENOME-WIDE ASSOCIATION, COMPREHENSIVE MOLECULAR PORTRAITS, ESTROGEN-RECEPTOR, FUNCTIONAL VARIANTS, SUSCEPTIBILITY LOCI, PROTEIN FUNCTION, CHROMATIN, ENHANCER, REVEALS, DISEASE, Bayes Theorem, Biomarkers, Tumor, Breast Neoplasms, Chromosome Mapping, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Regulatory Sequences, Nucleic Acid, Risk Factors, GEMO Study Collaborators, EMBRACE Collaborators, KConFab Investigators, HEBON Investigators, ABCTB Investigators, 06 Biological Sciences, 11 Medical and Health Sciences, Developmental Biology, 3001 Agricultural biotechnology, 3102 Bioinformatics and computational biology, 3105 Genetics
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.