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

on behalf of HEBON; AOCS Investigators; on behalf of EMBRACE; GEMO Study Collaborators; KConFab Investigators; Chenjie Zeng; Xingyi Guo; Jirong Long; Karoline B. Kuchenbaecker; Arnaud Droit; Kyriaki Michailidou; Maya Ghoussaini; Siddhartha Kar; Adam Freeman; John L. Hopper; Roger L. Milne; Manjeet K. Bolla; Qin Wang; Joe Dennis; Simona Agata; Shahana Ahmed; Kristiina Aittomäki; Irene L. Andrulis; Hoda Anton-Culver; Natalia N. Antonenkova; Adalgeir Arason; Volker Arndt; Banu K. Arun; Brita Arver; Francois Bacot; Daniel Barrowdale; Caroline Baynes; Alicia Beeghly-Fadiel; Javier Benitez; Marina Bermisheva; Carl Blomqvist; William J. Blot; Natalia V. Bogdanova; Stig E. Bojesen; Bernardo Bonanni; Anne Lise Borresen-Dale; Judith S. Brand; Hiltrud Brauch; Paul Brennan; Hermann Brenner; Annegien Broeks; Thomas Brüning; Barbara Burwinkel; Saundra S. Buys; Qiuyin Cai; Trinidad Caldes; Ian Campbell; Jane Carpenter; Jenny Chang-Claude; Ji Yeob Choi; Mary Daly

doi:10.1186/s13058-016-0718-0

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

on behalf of HEBON
, AOCS Investigators
, on behalf of EMBRACE
, GEMO Study Collaborators
, KConFab Investigators
, Chenjie Zeng
, Xingyi Guo
, Jirong Long
, Karoline B. Kuchenbaecker
, Arnaud Droit
, Kyriaki Michailidou
, Maya Ghoussaini
, Siddhartha Kar
, Adam Freeman
, John L. Hopper
, Roger L. Milne
, Manjeet K. Bolla
, Qin Wang
, Joe Dennis
, Simona Agata

Shahana Ahmed, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Adalgeir Arason, Volker Arndt, Banu K. Arun, Brita Arver, Francois Bacot, Daniel Barrowdale, Caroline Baynes, Alicia Beeghly-Fadiel, Javier Benitez, Marina Bermisheva, Carl Blomqvist, William J. Blot, Natalia V. Bogdanova, Stig E. Bojesen, Bernardo Bonanni, Anne Lise Borresen-Dale, Judith S. Brand, Hiltrud Brauch, Paul Brennan, Hermann Brenner, Annegien Broeks, Thomas Brüning, Barbara Burwinkel, Saundra S. Buys, Qiuyin Cai, Trinidad Caldes, Ian Campbell, Jane Carpenter, Jenny Chang-Claude, Ji Yeob Choi, Mary Daly

Hereditary Breast and Ovarian Cancer Research Group
Netherlands Cancer Institute
University of Melbourne
University of Cambridge
UNICANCER Genetic Group
French Federation of Comprehensive Cancer Centers (UNICANCER)
Kathleen Cuningham Consortium for Research into Familial Breast Cancer
Research Department
Vanderbilt University
Université Laval
St. Vincent's Hospital Melbourne
Cancer Council Victoria
IRCCS Istituto Oncologico Veneto - Padova
University of Helsinki
Fred A. Litwin Center for Cancer Genetics
University of Toronto
University of California at Irvine
N.N. Alexandrov Research Institute of Oncology and Medical Radiology
University of Iceland
German Cancer Research Center
University of Texas MD Anderson Cancer Center
Karolinska Institutet
McGill University
Biomedical Network on Rare Diseases (CIBERER)
Centro de Investigación Biomédica en Red de Enferemdades Raras CIBERER
Russian Academy of Sciences
International Epidemiology Institute
Hannover Medical School
University of Copenhagen
IRCCS Istituto Europeo di Oncologia - Milano
University of Oslo
Robert Bosch Foundation
University of Tübingen
International Agency for Research on Cancer
Antoni van Leeuwenhoek Hospital
Ruhr University Bochum
Heidelberg University
University of Utah
Instituto de Investigación Sanitaria del Hospital Clinico San Carlos (IdISSC)
Peter Maccallum Cancer Centre
University of Sydney
University of Hamburg
Seoul National University

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

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.

Original language	English
Article number	64
Pages (from-to)	64
Journal	Breast Cancer Research
Volume	18
Issue number	1
DOIs	https://doi.org/10.1186/s13058-016-0718-0
State	Published - Jun 21 2016

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Alleles
BRCA1 Protein/genetics
Breast Neoplasms/epidemiology
Case-Control Studies
Chromosome Mapping
Chromosomes, Human, Pair 12
Computational Biology/methods
Databases, Genetic
Enhancer Elements, Genetic
Epigenesis, Genetic
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Haplotypes
Heterozygote
Humans
Mutation
Odds Ratio
Polymorphism, Single Nucleotide
Population Surveillance
Promoter Regions, Genetic
Quantitative Trait Loci
Risk
White People/genetics

Access to Document

10.1186/s13058-016-0718-0

Cite this

on behalf of HEBON, AOCS Investigators, on behalf of EMBRACE, GEMO Study Collaborators, KConFab Investigators, Zeng, C., Guo, X., Long, J., Kuchenbaecker, K. B., Droit, A., Michailidou, K., Ghoussaini, M., Kar, S., Freeman, A., Hopper, J. L., Milne, R. L., Bolla, M. K., Wang, Q., Dennis, J., ... Daly, M. (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(1), 64. Article 64. https://doi.org/10.1186/s13058-016-0718-0

@article{55166d8e32ba46a797d95d3b1974f6e2,

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

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 {\texttimes} 10-9), rs805510 (OR = 1.08, 95 \% CI = 1.04-1.12, P = 2 {\texttimes} 10-5), and rs1871152 (OR = 1.04, 95 \% CI = 1.02-1.06; P = 2 {\texttimes} 10-4) identified in the general populations, and rs113824616 (P = 7 {\texttimes} 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 = "Alleles, BRCA1 Protein/genetics, Breast Neoplasms/epidemiology, Case-Control Studies, Chromosome Mapping, Chromosomes, Human, Pair 12, Computational Biology/methods, Databases, Genetic, Enhancer Elements, Genetic, Epigenesis, Genetic, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Haplotypes, Heterozygote, Humans, Mutation, Odds Ratio, Polymorphism, Single Nucleotide, Population Surveillance, Promoter Regions, Genetic, Quantitative Trait Loci, Risk, White People/genetics",

author = "\{on behalf of HEBON\} and \{AOCS Investigators\} and \{on behalf of EMBRACE\} and \{GEMO Study Collaborators\} and \{KConFab Investigators\} and Chenjie Zeng and Xingyi Guo and Jirong Long and Kuchenbaecker, \{Karoline B.\} and Arnaud Droit and Kyriaki Michailidou and Maya Ghoussaini and Siddhartha Kar and Adam Freeman and Hopper, \{John L.\} and Milne, \{Roger L.\} and Bolla, \{Manjeet K.\} and Qin Wang and Joe Dennis and Simona Agata and Shahana Ahmed and Kristiina Aittom{\"a}ki and Andrulis, \{Irene L.\} and Hoda Anton-Culver and Antonenkova, \{Natalia N.\} and Adalgeir Arason and Volker Arndt and Arun, \{Banu K.\} and Brita Arver and Francois Bacot and Daniel Barrowdale and Caroline Baynes and Alicia Beeghly-Fadiel and Javier Benitez and Marina Bermisheva and Carl Blomqvist and Blot, \{William J.\} and Bogdanova, \{Natalia V.\} and Bojesen, \{Stig E.\} and Bernardo Bonanni and Borresen-Dale, \{Anne Lise\} and Brand, \{Judith S.\} and Hiltrud Brauch and Paul Brennan and Hermann Brenner and Annegien Broeks and Thomas Br{\"u}ning and Barbara Burwinkel and Buys, \{Saundra S.\} and Qiuyin Cai and Trinidad Caldes and Ian Campbell and Jane Carpenter and Jenny Chang-Claude and Choi, \{Ji Yeob\} and Mary Daly",

note = "Publisher Copyright: {\textcopyright} 2016 The Author(s).",

year = "2016",

month = jun,

day = "21",

doi = "10.1186/s13058-016-0718-0",

language = "English",

volume = "18",

pages = "64",

journal = "Breast Cancer Research",

issn = "1465-5411",

publisher = "BioMed Central Ltd.",

number = "1",

}

on behalf of HEBON, AOCS Investigators, on behalf of EMBRACE, GEMO Study Collaborators, KConFab Investigators, 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, AL, 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, JY & Daly, M 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, vol. 18, no. 1, 64, pp. 64. https://doi.org/10.1186/s13058-016-0718-0

TY - JOUR

T1 - Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

AU - on behalf of HEBON

AU - AOCS Investigators

AU - on behalf of EMBRACE

AU - GEMO Study Collaborators

AU - KConFab Investigators

AU - Zeng, Chenjie

AU - Guo, Xingyi

AU - Long, Jirong

AU - Kuchenbaecker, Karoline B.

AU - Droit, Arnaud

AU - Michailidou, Kyriaki

AU - Ghoussaini, Maya

AU - Kar, Siddhartha

AU - Freeman, Adam

AU - Hopper, John L.

AU - Milne, Roger L.

AU - Bolla, Manjeet K.

AU - Wang, Qin

AU - Dennis, Joe

AU - Agata, Simona

AU - Ahmed, Shahana

AU - Aittomäki, Kristiina

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Antonenkova, Natalia N.

AU - Arason, Adalgeir

AU - Arndt, Volker

AU - Arun, Banu K.

AU - Arver, Brita

AU - Bacot, Francois

AU - Barrowdale, Daniel

AU - Baynes, Caroline

AU - Beeghly-Fadiel, Alicia

AU - Benitez, Javier

AU - Bermisheva, Marina

AU - Blomqvist, Carl

AU - Blot, William J.

AU - Bogdanova, Natalia V.

AU - Bojesen, Stig E.

AU - Bonanni, Bernardo

AU - Borresen-Dale, Anne Lise

AU - Brand, Judith S.

AU - Brauch, Hiltrud

AU - Brennan, Paul

AU - Brenner, Hermann

AU - Broeks, Annegien

AU - Brüning, Thomas

AU - Burwinkel, Barbara

AU - Buys, Saundra S.

AU - Cai, Qiuyin

AU - Caldes, Trinidad

AU - Campbell, Ian

AU - Carpenter, Jane

AU - Chang-Claude, Jenny

AU - Choi, Ji Yeob

AU - Daly, Mary

PY - 2016/6/21

Y1 - 2016/6/21

N2 - 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.

AB - 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.

KW - Alleles

KW - BRCA1 Protein/genetics

KW - Breast Neoplasms/epidemiology

KW - Case-Control Studies

KW - Chromosome Mapping

KW - Chromosomes, Human, Pair 12

KW - Computational Biology/methods

KW - Databases, Genetic

KW - Enhancer Elements, Genetic

KW - Epigenesis, Genetic

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Haplotypes

KW - Heterozygote

KW - Humans

KW - Mutation

KW - Odds Ratio

KW - Polymorphism, Single Nucleotide

KW - Population Surveillance

KW - Promoter Regions, Genetic

KW - Quantitative Trait Loci

KW - Risk

KW - White People/genetics

UR - https://www.scopus.com/pages/publications/84979647977

UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000380193900001&DestLinkType=FullRecord&DestApp=WOS

U2 - 10.1186/s13058-016-0718-0

DO - 10.1186/s13058-016-0718-0

M3 - Article

C2 - 27459855

SN - 1465-5411

VL - 18

SP - 64

JO - Breast Cancer Research

JF - Breast Cancer Research

IS - 1

M1 - 64

ER -

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

Abstract

UN SDGs

Keywords

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