Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus
Authors
Zeng, Chenjie
Guo, Xingyi
Long, Jirong
Kuchenbaecker, Karoline B
Droit, Arnaud
Michailidou, Kyriaki
Ghoussaini, Maya
Kar, Siddhartha
Freeman, Adam
Hopper, John L
Milne, Roger L
Bolla, Manjeet K
Agata, Simona
Ahmed, Shahana
Aittomäki, Kristiina
Andrulis, Irene L
Anton-Culver, Hoda
Antonenkova, Natalia N
Arason, Adalgeir
Arndt, Volker
Arun, Banu K
Arver, Brita
Bacot, Francois
Barrowdale, Daniel
Baynes, Caroline
Beeghly-Fadiel, Alicia
Benitez, Javier
Bermisheva, Marina
Blomqvist, Carl
Blot, William J
Bogdanova, Natalia V
Bojesen, Stig E
Bonanni, Bernardo
Borresen-Dale, Anne-Lise
Brand, Judith S
Brauch, Hiltrud
Brennan, Paul
Brenner, Hermann
Broeks, Annegien
Brüning, Thomas
Burwinkel, Barbara
Buys, Saundra S
Cai, Qiuyin
Caldes, Trinidad
Campbell, Ian
Carpenter, Jane
Chang-Claude, Jenny
Choi, Ji-Yeob
Claes, Kathleen BM
Clarke, Christine
Cox, Angela
Cross, Simon S
Czene, Kamila
Daly, Mary B
de, la Hoya Miguel
De, Leeneer Kim
Devilee, Peter
Diez, Orland
Domchek, Susan M
Doody, Michele
Dorfling, Cecilia M
Dörk, Thilo
dos-Santos-Silva, Isabel
Dumont, Martine
Dwek, Miriam
Dworniczak, Bernd
Egan, Kathleen
Eilber, Ursula
Einbeigi, Zakaria
Ejlertsen, Bent
Ellis, Steve
Frost, Debra
Lalloo, Fiona
EMBRACE2,
Fasching, Peter A
Figueroa, Jonine
Flyger, Henrik
Friedlander, Michael
Friedman, Eitan
Gambino, Gaetana
Gao, Yu-Tang
Garber, Judy
García-Closas, Montserrat
Gehrig, Andrea
Damiola, Francesca
Lesueur, Fabienne
Mazoyer, Sylvie
Stoppa-Lyonnet, Dominique
GEMO, Study
Giles, Graham G
Godwin, Andrew K
Goldgar, David E
González-Neira, Anna
Greene, Mark H
Guénel, Pascal
Haeberle, Lothar
Haiman, Christopher A
Hallberg, Emily
Hamann, Ute
Hansen, Thomas VO
Hart, Steven
Hartikainen, Jaana M
Hartman, Mikael
Hassan, Norhashimah
Healey, Sue
Hogervorst, Frans BL
Verhoef, Senno
HEBON106,
Hendricks, Carolyn B
Hillemanns, Peter
Hollestelle, Antoinette
Hulick, Peter J
Hunter, David J
Imyanitov, Evgeny N
Isaacs, Claudine
Ito, Hidemi
Jakubowska, Anna
Janavicius, Ramunas
Jaworska-Bieniek, Katarzyna
Jensen, Uffe Birk
John, Esther M
Beauparlant, Charles Joly
Jones, Michael
Kabisch, Maria
Kang, Daehee
Karlan, Beth Y
Kauppila, Saila
Kerin, Michael J
Khan, Sofia
Khusnutdinova, Elza
Knight, Julia A
Konstantopoulou, Irene
Kraft, Peter
Kwong, Ava
Laitman, Yael
Lambrechts, Diether
Lazaro, Conxi
Marchand, Loic Le
Lee, Chuen Neng
Lee, Min Hyuk
Lester, Jenny
Li, Jingmei
Liljegren, Annelie
Lindblom, Annika
Lophatananon, Artitaya
Lubinski, Jan
Mai, Phuong L
Mannermaa, Arto
Manoukian, Siranoush
Margolin, Sara
Marme, Frederik
Matsuo, Keitaro
McGuffog, Lesley
Meindl, Alfons
Menegaux, Florence
Montagna, Marco
Muir, Kenneth
Mulligan, Anna Marie
Nathanson, Katherine L
Neuhausen, Susan L
Nevanlinna, Heli
Newcomb, Polly A
Nord, Silje
Nussbaum, Robert L
Offit, Kenneth
Olah, Edith
Olopade, Olufunmilayo I
Olswold, Curtis
Osorio, Ana
Papi, Laura
Park-Simon, Tjoung-Won
Paulsson-Karlsson, Ylva
Peeters, Stephanie
Peissel, Bernard
Peterlongo, Paolo
Peto, Julian
Pfeiler, Georg
Phelan, Catherine M
Presneau, Nadege
Radice, Paolo
Rahman, Nazneen
Ramus, Susan J
Rashid, Muhammad Usman
Rennert, Gad
Rhiem, Kerstin
Rudolph, Anja
Salani, Ritu
Sangrajrang, Suleeporn
Sawyer, Elinor J
Schmidt, Marjanka K
Schmutzler, Rita K
Schoemaker, Minouk J
Schürmann, Peter
Seynaeve, Caroline
Shen, Chen-Yang
Shrubsole, Martha J
Shu, Xiao-Ou
Sigurdson, Alice
Singer, Christian F
Slager, Susan
Soucy, Penny
Southey, Melissa
Steinemann, Doris
Swerdlow, Anthony
Szabo, Csilla I
Tchatchou, Sandrine
Teixeira, Manuel R
Teo, Soo H
Terry, Mary Beth
Tessier, Daniel C
Teulé, Alex
Thomassen, Mads
Tihomirova, Laima
Toland, Amanda E
Tung, Nadine
Turnbull, Clare
van, den Ouweland Ans MW
van, Rensburg Elizabeth J
ven, den Berg David
Vijai, Joseph
Wang-Gohrke, Shan
Weitzel, Jeffrey N
Whittemore, Alice S
Winqvist, Robert
Wong, Tien Y
Wu, Anna H
Yannoukakos, Drakoulis
Yu, Jyh-Cherng
Hall, Per
Chenevix-Trench, Georgia
KConFab,
AOCS, Investigators
Simard, Jacques
Couch, Fergus J
Zheng, Wei
Publication Date
2016Journal Title
Breast Cancer Research
ISSN
1465-5411
Publisher
BioMed Central
Volume
18
Number
64
Language
English
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Zeng, C., Guo, X., Long, J., Kuchenbaecker, K. B., Droit, A., Michailidou, K., Ghoussaini, M., et al. (2016). Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus. Breast Cancer Research, 18 (64)https://doi.org/10.1186/s13058-016-0718-0
Abstract
Background
Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.
Method
We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.
Results
Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06–1.12; P = 3 × 10$^{-9}$), rs805510 (OR = 1.08, 95 % CI = 1.04–1.12, P = 2 × 10$^{-5}$), and rs1871152 (OR = 1.04, 95 % CI = 1.02–1.06; P = 2 × 10$^{-4}$) identified in the general populations, and rs113824616 (P = 7 × 10$^{-5}$) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05.
Conclusion
This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
Keywords
fine-scale mapping, genetic risk factor, PTHLH, CCDC91, breast cancer, BRAC1 mutation carriers
Sponsorship
UK funding includes Cancer Research UK and NIH.
Funder references
Cancer Research UK (10124)
Cancer Research UK (10119)
Cancer Research UK (16561)
Cancer Research UK (A11020)
Cancer Research UK (11021)
National Cancer Institute (NCI) (R01CA128978)
National Cancer Institute (NCI) (U19CA148537)
National Cancer Institute (NCI) (U19CA148065)
Cancer Research UK (CRUK-A10710)
Cancer Research UK (CRUK-A12014)
Cancer Research UK (CRUK-A10118)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1186/s13058-016-0718-0
This record's URL: https://www.repository.cam.ac.uk/handle/1810/260872
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International
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