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

behalf of GEMO Study Collaborators

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 languageEnglish
Article number64
JournalBreast Cancer Research
Volume18
Issue number1
DOIs
Publication statusPublished - Jun 21 2016

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Breast Neoplasms
Odds Ratio
Confidence Intervals
Single Nucleotide Polymorphism
Encyclopedias
Mutation
Atlases
Genome-Wide Association Study
Genes
Chromatin
Meta-Analysis
Regression Analysis
Research Personnel
Genome
DNA
Population
Neoplasms

Keywords

  • BRAC1 mutation carriers
  • Breast cancer
  • CCDC91
  • Fine-scale mapping
  • Genetic risk factor
  • PTHLH

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus. / behalf of GEMO Study Collaborators.

In: Breast Cancer Research, Vol. 18, No. 1, 64, 21.06.2016.

Research output: Contribution to journalArticle

@article{3d452ea4c5f542f68e1504c22dd1cc1f,
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 × 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 = "BRAC1 mutation carriers, Breast cancer, CCDC91, Fine-scale mapping, Genetic risk factor, PTHLH",
author = "{behalf of GEMO Study Collaborators} 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 E. Ol{\'a}h",
year = "2016",
month = "6",
day = "21",
doi = "10.1186/s13058-016-0718-0",
language = "English",
volume = "18",
journal = "Breast Cancer Research",
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T1 - Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

AU - behalf of GEMO Study Collaborators

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 - Oláh, E.

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 - BRAC1 mutation carriers

KW - Breast cancer

KW - CCDC91

KW - Fine-scale mapping

KW - Genetic risk factor

KW - PTHLH

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U2 - 10.1186/s13058-016-0718-0

DO - 10.1186/s13058-016-0718-0

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JF - Breast Cancer Research

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