Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.
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Authors
Beesley, Jonathan
Kar, Siddhartha
Turman, Constance
Soucy, Penny
Lush, Michael
Ghoussaini, Maya
Moradi Marjaneh, Mahdi
Jiang, Xia
Agata, Simona
Aittomäki, Kristiina
Alonso, M Rosario
Anton-Culver, Hoda
Antonenkova, Natalia N
Aronson, Kristan J
Arun, Banu K
Auer, Paul L
Balmaña, Judith
Barkardottir, Rosa B
Barrowdale, Daniel
Beeghly-Fadiel, Alicia
Benitez, Javier
Bermisheva, Marina
Białkowska, Katarzyna
Blanco, Amie M
Blomqvist, Carl
Blot, William
Bogdanova, Natalia V
Bolla, Manjeet K
Borg, Ake
Bosse, Kristin
Brenner, Hermann
Briceno, Ignacio
Brock, Ian W
Brooks-Wilson, Angela
Brüning, Thomas
Burwinkel, Barbara
Buys, Saundra S
Cai, Qiuyin
Caldés, Trinidad
Caligo, Maria A
Camp, Nicola J
Canzian, Federico
Carter, Brian D
Castelao, Jose E
Chiquette, Jocelyne
Christiansen, Hans
Chung, Wendy K
Clarke, Christine L
GEMO Study Collaborators
EMBRACE Collaborators
Cornelissen, Sten
Couch, Fergus J
Cox, Angela
Cross, Simon S
Cybulski, Cezary
Czene, Kamila
Daly, Mary B
de la Hoya, Miguel
Diez, Orland
Ding, Yuan Chun
Dite, Gillian S
Domchek, Susan M
Dos-Santos-Silva, Isabel
Droit, Arnaud
Dubois, Stéphane
Dumont, Martine
Duran, Mercedes
Durcan, Lorraine
Eccles, Diana M
Engel, Christoph
Eriksson, Mikael
Evans, D Gareth
Fasching, Peter A
Flyger, Henrik
Foretova, Lenka
Friedman, Eitan
Fritschi, Lin
Frost, Debra
Gabrielson, Marike
Gago-Dominguez, Manuela
Gambino, Gaetana
Ganz, Patricia A
Gapstur, Susan M
Garber, Judy
Gaudet, Mia M
Georgoulias, Vassilios
Giles, Graham G
Glendon, Gord
Godwin, Andrew K
Goldberg, Mark S
Goldgar, David E
González-Neira, Anna
Tibiletti, Maria Grazia
Grip, Mervi
Gronwald, Jacek
Grundy, Anne
Hahnen, Eric
Haiman, Christopher A
Håkansson, Niclas
Hall, Per
Hamann, Ute
Harrington, Patricia A
Hartikainen, Jaana M
Hartman, Mikael
He, Wei
Healey, Catherine S
Heyworth, Jane
Hillemanns, Peter
Hogervorst, Frans BL
Hooning, Maartje J
Hopper, John L
Howell, Anthony
Huang, Guanmengqian
Imyanitov, Evgeny N
KConFab Investigators
HEBON Investigators
ABCTB Investigators
Isaacs, Claudine
Iwasaki, Motoki
Jager, Agnes
Janavicius, Ramunas
Jankowitz, Rachel C
John, Esther M
Johnson, Nichola
Jukkola-Vuorinen, Arja
Jung, Audrey
Kaaks, Rudolf
Kang, Daehee
Karlan, Beth Y
Kerin, Michael J
Khusnutdinova, Elza
Kiiski, Johanna I
Kirk, Judy
Kitahara, Cari M
Ko, Yon-Dschun
Kosma, Veli-Matti
Koutros, Stella
Kubelka-Sabit, Katerina
Kwong, Ava
Kyriacou, Kyriacos
Laitman, Yael
Lambrechts, Diether
Lee, Eunjung
Lester, Jenny
Lindblom, Annika
Lo, Wing-Yee
Long, Jirong
Lophatananon, Artitaya
Loud, Jennifer T
Lubiński, Jan
MacInnis, Robert J
Maishman, Tom
Makalic, Enes
Mannermaa, Arto
Manoochehri, Mehdi
Manoukian, Siranoush
Margolin, Sara
Martinez, Maria Elena
Maurer, Tabea
Mavroudis, Dimitrios
Mayes, Rebecca
McGuffog, Lesley
Mebirouk, Noura
Meindl, Alfons
Miller, Nicola
Montagna, Marco
Moreno, Fernando
Mulligan, Anna Marie
Muñoz-Garzon, Victor M
Narod, Steven A
Nassir, Rami
Neuhausen, Susan L
Neven, Patrick
Nielsen, Finn C
Nikitina-Zake, Liene
Norman, Aaron
Offit, Kenneth
Olah, Edith
Olsson, Håkan
Osorio, Ana
Papp, Janos
Park, Sue K
Park-Simon, Tjoung-Won
Pedersen, Inge Sokilde
Peissel, Bernard
Prajzendanc, Karolina
Prentice, Ross
Presneau, Nadege
Prokofyeva, Darya
Pujana, Miquel Angel
Ramus, Susan J
Rantala, Johanna
Rau-Murthy, Rohini
Risch, Harvey A
Rossing, Maria
Sánchez-Herrero, Estela
Sandler, Dale P
Santamariña, Marta
Saunders, Christobel
Sawyer, Elinor J
Scheuner, Maren T
Schmidt, Daniel F
Schmutzler, Rita K
Schneeweiss, Andreas
Schoemaker, Minouk J
Schöttker, Ben
Schürmann, Peter
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
Stoppa-Lyonnet, Dominique
Swerdlow, Anthony J
Tamimi, Rulla M
Tapper, William J
Taylor, Jack A
Tengström, Maria
Teo, Soo Hwang
Terry, Mary Beth
Teulé, Alex
Thomassen, Mads
Thull, Darcy L
Tollenaar, Rob AEM
Torres, Diana
Torres-Mejía, Gabriela
Troester, Melissa A
Truong, Thérèse
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
Vogel, Maartje J
Wang, Qin
Wappenschmidt, Barbara
Weinberg, Clarice R
Weitzel, Jeffrey N
Wendt, Camilla
Wildiers, Hans
Winqvist, Robert
Wu, Anna H
Zhang, Yan
Zheng, Wei
Hunter, David
Chang-Claude, Jenny
García-Closas, Montserrat
Kristensen, Vessela N
French, Juliet D
Chenevix-Trench, Georgia
Publication Date
2020-01Journal Title
Nat Genet
ISSN
1061-4036
Publisher
Springer Science and Business Media LLC
Volume
52
Issue
1
Pages
56-73
Language
eng
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Fachal Vilar, L., Aschard, H., Beesley, J., Barnes, D., Allen, J., Kar, S., Pooley, K., et al. (2020). Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.. Nat Genet, 52 (1), 56-73. https://doi.org/10.1038/s41588-019-0537-1
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.
Keywords
GEMO Study Collaborators, EMBRACE Collaborators, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Bayes Theorem, Risk Factors, Chromosome Mapping, Regulatory Sequences, Nucleic Acid, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Female, Genome-Wide Association Study, Biomarkers, Tumor
Sponsorship
Includes CRUK, FP7 and H2020
Funder references
Cancer Research Uk (None)
European Commission Horizon 2020 (H2020) Societal Challenges (634935)
European Commission Horizon 2020 (H2020) Societal Challenges (633784)
European Commission (223175)
National Cancer Institute (U19CA148065)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (656144)
Cancer Research UK (A10710)
Cancer Research UK (A16563)
Cancer Research UK (A10118)
Wellcome Trust (203477/Z/16/Z)
Identifiers
External DOI: https://doi.org/10.1038/s41588-019-0537-1
This record's URL: https://www.repository.cam.ac.uk/handle/1810/298712
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