Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.
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Date
2020-01-07Author
Fachal, L
Aschard, H
Beesley, J
Barnes, DR
Allen, J
Kar, S
Pooley, KA
Dennis, J
Michailidou, K
Turman, C
Soucy, P
Lemaçon, A
Lush, M
Tyrer, JP
Ghoussaini, M
Moradi Marjaneh, M
Jiang, X
Agata, S
Aittomäki, K
Alonso, MR
Andrulis, IL
Anton-Culver, H
Antonenkova, NN
Arason, A
Arndt, V
Aronson, KJ
Arun, BK
Auber, B
Auer, PL
Azzollini, J
Balmaña, J
Barkardottir, RB
Barrowdale, D
Beeghly-Fadiel, A
Benitez, J
Bermisheva, M
Białkowska, K
Blanco, AM
Blomqvist, C
Blot, W
Bogdanova, NV
Bojesen, SE
Bolla, MK
Bonanni, B
Borg, A
Bosse, K
Brauch, H
Brenner, H
Briceno, I
Brock, IW
Brooks-Wilson, A
Brüning, T
Burwinkel, B
Buys, SS
Cai, Q
Caldés, T
Caligo, MA
Camp, NJ
Campbell, I
Canzian, F
Carroll, JS
Carter, BD
Castelao, JE
Chiquette, J
Christiansen, H
Chung, WK
Claes, KBM
Clarke, CL
GEMO Study Collaborators,
EMBRACE Collaborators,
Collée, JM
Cornelissen, S
Couch, FJ
Cox, A
Cross, SS
Cybulski, C
Czene, K
Daly, MB
de la Hoya, M
Devilee, P
Diez, O
Ding, YC
Dite, GS
Domchek, SM
Dörk, T
Dos-Santos-Silva, I
Droit, A
Dubois, S
Dumont, M
Duran, M
Durcan, L
Dwek, M
Eccles, DM
Engel, C
Eriksson, M
Evans, DG
Fasching, PA
Fletcher, O
Floris, G
Flyger, H
Foretova, L
Foulkes, WD
Friedman, E
Fritschi, L
Frost, D
Gabrielson, M
Gago-Dominguez, M
Gambino, G
Ganz, PA
Gapstur, SM
Garber, J
García-Sáenz, JA
Gaudet, MM
Georgoulias, V
Giles, GG
Glendon, G
Godwin, AK
Goldberg, MS
Goldgar, DE
González-Neira, A
Tibiletti, MG
Greene, MH
Grip, M
Gronwald, J
Grundy, A
Guénel, P
Hahnen, E
Haiman, CA
Håkansson, N
Hall, P
Hamann, U
Harrington, PA
Hartikainen, JM
Hartman, M
He, W
Healey, CS
Heemskerk-Gerritsen, BAM
Heyworth, J
Hillemanns, P
Hogervorst, FBL
Hollestelle, A
Hooning, MJ
Hopper, JL
Howell, A
Huang, G
Hulick, PJ
Imyanitov, EN
KConFab Investigators,
HEBON Investigators,
ABCTB Investigators,
Isaacs, C
Iwasaki, M
Jager, A
Jakimovska, M
Jakubowska, A
James, PA
Janavicius, R
Jankowitz, RC
John, EM
Johnson, N
Jones, ME
Jukkola-Vuorinen, A
Jung, A
Kaaks, R
Kang, D
Kapoor, PM
Karlan, BY
Keeman, R
Kerin, MJ
Khusnutdinova, E
Kiiski, JI
Kirk, J
Kitahara, CM
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, JT
Lubiński, J
MacInnis, RJ
Maishman, T
Makalic, E
Mannermaa, A
Manoochehri, M
Manoukian, S
Margolin, S
Martinez, ME
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, AM
Muñoz-Garzon, VM
Muranen, TA
Narod, SA
Nassir, R
Nathanson, KL
Neuhausen, SL
Nevanlinna, H
Neven, P
Nielsen, FC
Nikitina-Zake, L
Norman, A
Offit, K
Olah, E
Olopade, OI
Olsson, H
Orr, N
Osorio, A
Pankratz, VS
Papp, J
Park, SK
Park-Simon, T-W
Parsons, MT
Paul, J
Pedersen, IS
Peissel, B
Peshkin, B
Peterlongo, P
Peto, J
Plaseska-Karanfilska, D
Prajzendanc, K
Prentice, R
Presneau, N
Prokofyeva, D
Pujana, MA
Pylkäs, K
Radice, P
Ramus, SJ
Rantala, J
Rau-Murthy, R
Rennert, G
Risch, HA
Robson, M
Romero, A
Rossing, M
Saloustros, E
Sánchez-Herrero, E
Sandler, DP
Santamariña, M
Saunders, C
Sawyer, EJ
Scheuner, MT
Schmidt, DF
Schmutzler, RK
Schneeweiss, A
Schoemaker, MJ
Schöttker, B
Schürmann, P
Scott, C
Scott, RJ
Senter, L
Seynaeve, CM
Shah, M
Sharma, P
Shen, C-Y
Shu, X-O
Singer, CF
Slavin, TP
Smichkoska, S
Southey, MC
Spinelli, JJ
Spurdle, AB
Stone, J
Stoppa-Lyonnet, D
Sutter, C
Swerdlow, AJ
Tamimi, RM
Tan, YY
Tapper, WJ
Taylor, JA
Teixeira, MR
Tengström, M
Teo, SH
Terry, MB
Teulé, A
Thomassen, M
Thull, DL
Tischkowitz, M
Toland, AE
Tollenaar, RAEM
Tomlinson, I
Torres, D
Torres-Mejía, G
Troester, MA
Truong, T
Tung, N
Tzardi, M
Ulmer, H-U
Vachon, CM
van Asperen, CJ
van der Kolk, LE
van Rensburg, EJ
Vega, A
Viel, A
Vijai, J
Vogel, MJ
Wang, Q
Wappenschmidt, B
Weinberg, CR
Weitzel, JN
Wendt, C
Wildiers, H
Winqvist, R
Wolk, A
Wu, AH
Yannoukakos, D
Zhang, Y
Zheng, W
Hunter, D
Pharoah, PDP
Chang-Claude, J
García-Closas, M
Schmidt, MK
Milne, RL
Kristensen, VN
French, JD
Edwards, SL
Antoniou, AC
Chenevix-Trench, G
Simard, J
Easton, DF
Kraft, P
Dunning, AM
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Subject
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
Research team
Complex Trait Genetics
Functional Genetic Epidemiology
Aetiological Epidemiology
Oncogenetics
Language
eng
Date accepted
2019-10-24
License start date
2020-01-07
Citation
Nature genetics, 2020, 52 (1), pp. 56 - 73
Publisher
NATURE PORTFOLIO
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