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Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

C Zeng, XY Guo, JR Long, KB Kuchenbaecker, A Droit, K Michailidou, M Ghoussaini, S Kar, A Freeman, JL Hopper, et al. (2016) BREAST CANCER RESEARCH. 18.
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 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 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.
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author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
Breast cancer, CCDC91, PTHLH, Genetic risk factor, Fine-scale mapping, BRAC1 mutation carriers, HORMONE-RELATED PROTEIN, GENOME-WIDE ASSOCIATION, BRCA2 MUTATION CARRIERS, SUSCEPTIBILITY LOCI, GENETIC MODIFIERS, OVARIAN-CANCER, LOCALIZATION, METASTASIS, EXPRESSION, ENHANCERS
journal title
BREAST CANCER RESEARCH
Breast Cancer Res.
volume
18
article number
64
pages
21 pages
Web of Science type
Article
Web of Science id
000380193900001
JCR category
ONCOLOGY
JCR impact factor
6.345 (2016)
JCR rank
27/217 (2016)
JCR quartile
1 (2016)
ISSN
1465-542X
DOI
10.1186/s13058-016-0718-0
language
English
UGent publication?
yes
classification
A1
copyright statement
Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
id
8120452
handle
http://hdl.handle.net/1854/LU-8120452
date created
2016-10-19 14:14:25
date last changed
2017-03-07 09:18:03
@article{8120452,
  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 x 10(-9)), rs805510 (OR = 1.08, 95 \% CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 \% CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 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 {\textlangle} 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 {\textlangle} 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.},
  articleno    = {64},
  author       = {Zeng, C and Guo, XY and Long, JR and Kuchenbaecker, KB and Droit, A and Michailidou, K and Ghoussaini, M and Kar, S and Freeman, A and Hopper, JL and Milne, RL and Bolla, MK and Wang, Q and Dennis, J and Agata, S and Ahmed, S and Aittomaki, K and Andrulis, IL and Anton-Culver, H and Antonenkova, NN and Arason, A and Arndt, V and Arun, BK and Arver, B and Bacot, F and Barrowdale, D and Baynes, C and Beeghly-Fadiel, A and Benitez, J and Bermisheva, M and Blomqvist, C and Blot, WJ and Bogdanova, NV and Bojesen, SE and Bonanni, B and Borresen-Dale, AL and Brand, JS and Brauch, H and Brennan, P and Brenner, H and Broeks, A and Bruning, T and Burwinkel, B and Buys, SS and Cai, QY and Caldes, T and Campbell, I and Carpenter, J and Chang-Claude, J and Choi, JY and Claes, Kathleen and Clarke, C and Cox, A and Cross, SS and Czene, K and Daly, MB and de la Hoya, M and De Leeneer, Kim and Devilee, P and Diez, O and Domchek, SM and Doody, M and Dorfling, CM and Dork, T and dos-Santos-Silva, I and Dumont, M and Dwek, M and Dworniczak, B and Egan, K and Eilber, U and Einbeigi, Z and Ejlertsen, B and Ellis, S and Frost, D and Lalloo, F and Fasching, PA and Figueroa, J and Flyger, H and Friedlander, M and Friedman, E and Gambino, G and Gao, YT and Garber, J and Garcia-Closas, M and Gehrig, A and Damiola, F and Lesueur, F and Mazoyer, S and Stoppa-Lyonnet, D and Giles, GG and Godwin, AK and Goldgar, DE and Gonzalez-Neira, A and Greene, MH and Guenel, P and Haeberle, L and Haiman, CA and Hallberg, E and Hamann, U and Hansen, TVO and Hart, S and Hartikainen, JM and Hartman, M and Hassan, N and Healey, S and Hogervorst, FBL and Verhoef, S and Hendricks, CB and Hillemanns, P and Hollestelle, A and Hulick, PJ and Hunter, DJ and Imyanitov, EN and Isaacs, C and Ito, H and Jakubowska, A and Janavicius, R and Jaworska-Bieniek, K and Jensen, UB and John, EM and Beauparlant, CJ and Jones, M and Kabisch, M and Kang, D and Karlan, BY and Kauppila, S and Kerin, MJ and Khan, S and Khusnutdinova, E and Knight, JA and Konstantopoulou, I and Kraft, P and Kwong, A and Laitman, Y and Lambrechts, D and Lazaro, C and Le Marchand, L and Lee, CN and Lee, MH and Lester, J and Li, JM and Liljegren, A and Lindblom, A and Lophatananon, A and Lubinski, J and Mai, PL and Mannermaa, A and Manoukian, S and Margolin, S and Marme, F and Matsuo, K and McGuffog, L and Meindl, A and Menegaux, F and Montagna, M and Muir, K and Mulligan, AM and Nathanson, KL and Neuhausen, SL and Nevanlinna, H and Newcomb, PA and Nord, S and Nussbaum, RL and Offit, K and Olah, E and Olopade, OI and Olswold, C and Osorio, A and Papi, L and Park-Simon, TW and Paulsson-Karlsson, Y and Peeters, S and Peissel, B and Peterlongo, P and Peto, J and Pfeiler, G and Phelan, CM and Presneau, N and Radice, P and Rahman, N and Ramus, SJ and Rashid, MU and Rennert, G and Rhiem, K and Rudolph, A and Salani, R and Sangrajrang, S and Sawyer, EJ and Schmidt, MK and Schmutzler, RK and Schoemaker, MJ and Schurmann, P and Seynaeve, C and Shen, CY and Shrubsole, MJ and Shu, XO and Sigurdson, A and Singer, CF and Slager, S and Soucy, P and Southey, M and Steinemann, D and Swerdlow, A and Szabo, CI and Tchatchou, S and Teixeira, MR and Teo, SH and Terry, MB and Tessier, DC and Teule, A and Thomassen, M and Tihomirova, L and Tischkowitz, M and Toland, AE and Tung, N and Turnbull, C and van den Ouweland, AMW and van Rensburg, EJ and ven den Berg, D and Vijai, J and Wang-Gohrke, S and Weitzel, JN and Whittemore, AS and Winqvist, R and Wong, TY and Wu, AH and Yannoukakos, D and Yu, JC and Pharoah, PDP and Hall, P and Chenevix-Trench, G and Dunning, AM and Simard, J and Couch, FJ and Antoniou, AC and Easton, DF and Zheng, W},
  issn         = {1465-542X},
  journal      = {BREAST CANCER RESEARCH},
  keyword      = {Breast cancer,CCDC91,PTHLH,Genetic risk factor,Fine-scale mapping,BRAC1 mutation carriers,HORMONE-RELATED PROTEIN,GENOME-WIDE ASSOCIATION,BRCA2 MUTATION CARRIERS,SUSCEPTIBILITY LOCI,GENETIC MODIFIERS,OVARIAN-CANCER,LOCALIZATION,METASTASIS,EXPRESSION,ENHANCERS},
  language     = {eng},
  pages        = {21},
  title        = {Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus},
  url          = {http://dx.doi.org/10.1186/s13058-016-0718-0},
  volume       = {18},
  year         = {2016},
}

Chicago
Zeng, C, XY Guo, JR Long, KB Kuchenbaecker, A Droit, K Michailidou, M Ghoussaini, 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.
APA
Zeng, C., Guo, X., Long, J., Kuchenbaecker, K., 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.
Vancouver
1.
Zeng C, Guo X, Long J, Kuchenbaecker K, Droit A, Michailidou K, et al. Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus. BREAST CANCER RESEARCH. 2016;18.
MLA
Zeng, C, XY Guo, JR Long, et al. “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 (2016): n. pag. Print.