Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.
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Date
2016-06-21Author
Zeng, C
Guo, X
Long, J
Kuchenbaecker, KB
Droit, A
Michailidou, K
Ghoussaini, M
Kar, S
Freeman, A
Hopper, JL
Milne, RL
Bolla, MK
Wang, Q
Dennis, J
Agata, S
Ahmed, S
Aittomäki, K
Andrulis, IL
Anton-Culver, H
Antonenkova, NN
Arason, A
Arndt, V
Arun, BK
Arver, B
Bacot, F
Barrowdale, D
Baynes, C
Beeghly-Fadiel, A
Benitez, J
Bermisheva, M
Blomqvist, C
Blot, WJ
Bogdanova, NV
Bojesen, SE
Bonanni, B
Borresen-Dale, A-L
Brand, JS
Brauch, H
Brennan, P
Brenner, H
Broeks, A
Brüning, T
Burwinkel, B
Buys, SS
Cai, Q
Caldes, T
Campbell, I
Carpenter, J
Chang-Claude, J
Choi, J-Y
Claes, KBM
Clarke, C
Cox, A
Cross, SS
Czene, K
Daly, MB
de la Hoya, M
De Leeneer, K
Devilee, P
Diez, O
Domchek, SM
Doody, M
Dorfling, CM
Dörk, T
Dos-Santos-Silva, I
Dumont, M
Dwek, M
Dworniczak, B
Egan, K
Eilber, U
Einbeigi, Z
Ejlertsen, B
Ellis, S
Frost, D
Lalloo, F
EMBRACE,
Fasching, PA
Figueroa, J
Flyger, H
Friedlander, M
Friedman, E
Gambino, G
Gao, Y-T
Garber, J
García-Closas, M
Gehrig, A
Damiola, F
Lesueur, F
Mazoyer, S
Stoppa-Lyonnet, D
behalf of GEMO Study Collaborators,
Giles, GG
Godwin, AK
Goldgar, DE
González-Neira, A
Greene, MH
Guénel, P
Haeberle, L
Haiman, CA
Hallberg, E
Hamann, U
Hansen, TVO
Hart, S
Hartikainen, JM
Hartman, M
Hassan, N
Healey, S
Hogervorst, FBL
Verhoef, S
HEBON,
Hendricks, CB
Hillemanns, P
Hollestelle, A
Hulick, PJ
Hunter, DJ
Imyanitov, EN
Isaacs, C
Ito, H
Jakubowska, A
Janavicius, R
Jaworska-Bieniek, K
Jensen, UB
John, EM
Joly Beauparlant, C
Jones, M
Kabisch, M
Kang, D
Karlan, BY
Kauppila, S
Kerin, MJ
Khan, S
Khusnutdinova, E
Knight, JA
Konstantopoulou, I
Kraft, P
Kwong, A
Laitman, Y
Lambrechts, D
Lazaro, C
Le Marchand, L
Lee, CN
Lee, MH
Lester, J
Li, J
Liljegren, A
Lindblom, A
Lophatananon, A
Lubinski, J
Mai, PL
Mannermaa, A
Manoukian, S
Margolin, S
Marme, F
Matsuo, K
McGuffog, L
Meindl, A
Menegaux, F
Montagna, M
Muir, K
Mulligan, AM
Nathanson, KL
Neuhausen, SL
Nevanlinna, H
Newcomb, PA
Nord, S
Nussbaum, RL
Offit, K
Olah, E
Olopade, OI
Olswold, C
Osorio, A
Papi, L
Park-Simon, T-W
Paulsson-Karlsson, Y
Peeters, S
Peissel, B
Peterlongo, P
Peto, J
Pfeiler, G
Phelan, CM
Presneau, N
Radice, P
Rahman, N
Ramus, SJ
Rashid, MU
Rennert, G
Rhiem, K
Rudolph, A
Salani, R
Sangrajrang, S
Sawyer, EJ
Schmidt, MK
Schmutzler, RK
Schoemaker, MJ
Schürmann, P
Seynaeve, C
Shen, C-Y
Shrubsole, MJ
Shu, X-O
Sigurdson, A
Singer, CF
Slager, S
Soucy, P
Southey, M
Steinemann, D
Swerdlow, A
Szabo, CI
Tchatchou, S
Teixeira, MR
Teo, SH
Terry, MB
Tessier, DC
Teulé, A
Thomassen, M
Tihomirova, L
Tischkowitz, M
Toland, AE
Tung, N
Turnbull, C
van den Ouweland, AMW
van Rensburg, EJ
Ven den Berg, D
Vijai, J
Wang-Gohrke, S
Weitzel, JN
Whittemore, AS
Winqvist, R
Wong, TY
Wu, AH
Yannoukakos, D
Yu, J-C
Pharoah, PDP
Hall, P
Chenevix-Trench, G
KConFab,
AOCS Investigators,
Dunning, AM
Simard, J
Couch, FJ
Antoniou, AC
Easton, DF
Zheng, W
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
EMBRACE
behalf of GEMO Study Collaborators
HEBON
KConFab
AOCS Investigators
Chromosomes, Human, Pair 12
Humans
Breast Neoplasms
Genetic Predisposition to Disease
BRCA1 Protein
Population Surveillance
Odds Ratio
Risk
Case-Control Studies
Chromosome Mapping
Computational Biology
Epigenesis, Genetic
Genotype
Haplotypes
Heterozygote
Mutation
Polymorphism, Single Nucleotide
Alleles
Quantitative Trait Loci
Databases, Genetic
European Continental Ancestry Group
Female
Enhancer Elements, Genetic
Promoter Regions, Genetic
Genome-Wide Association Study
Research team
Aetiological Epidemiology
Language
eng
Date accepted
2016-05-18
License start date
2016-06-21
Citation
Breast cancer research : BCR, 2016, 18 (1), pp. 64 - ?
Publisher
BMC
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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