Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Kyriaki Michailidou; Jonathan Beesley; Sara Lindstrom; Sander Canisius; Joe Dennis; Michael J Lush; Mel J Maranian; Manjeet K Bolla; Qin Wang; Mitul Shah; Barbara J Perkins; Kamila Czene; Mikael Eriksson; Hatef Darabi; Judith S Brand; Stig E Bojesen; Børge G Nordestgaard; Henrik Flyger; Sune F Nielsen; Nazneen Rahman; Clare Turnbull; Olivia Fletcher; Julian Peto; Lorna Gibson; Isabel dos-Santos-Silva; Jenny Chang-Claude; Dieter Flesch-Janys; Anja Rudolph; Ursula Eilber; Sabine Behrens; Heli Nevanlinna; Taru A Muranen; Kristiina Aittomäki; Carl Blomqvist; Sofia Khan; Kirsimari Aaltonen; Habibul Ahsan; Muhammad G Kibriya; Alice S Whittemore; Esther M John; Kathleen E Malone; Marilie D Gammon; Regina M Santella; Giske Ursin; Enes Makalic; Daniel F Schmidt; Graham Casey; David J Hunter; Wei Zheng; BOCS; Zofia Helena Miedzybrodzka

doi:10.1038/ng.3242

Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Kyriaki Michailidou, Jonathan Beesley, Sara Lindstrom, Sander Canisius, Joe Dennis, Michael J Lush, Mel J Maranian, Manjeet K Bolla, Qin Wang, Mitul Shah, Barbara J Perkins, Kamila Czene, Mikael Eriksson, Hatef Darabi, Judith S Brand, Stig E Bojesen, Børge G Nordestgaard, Henrik Flyger, Sune F Nielsen, Nazneen RahmanClare Turnbull, Olivia Fletcher, Julian Peto, Lorna Gibson, Isabel dos-Santos-Silva, Jenny Chang-Claude, Dieter Flesch-Janys, Anja Rudolph, Ursula Eilber, Sabine Behrens, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Sofia Khan, Kirsimari Aaltonen, Habibul Ahsan, Muhammad G Kibriya, Alice S Whittemore, Esther M John, Kathleen E Malone, Marilie D Gammon, Regina M Santella, Giske Ursin, Enes Makalic, Daniel F Schmidt, Graham Casey, David J Hunter, Wei Zheng, BOCS, Zofia Helena Miedzybrodzka

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Abstract

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.

Original language	English
Pages (from-to)	373-380
Number of pages	8
Journal	Nature Genetics
Volume	47
Issue number	4
Early online date	9 Mar 2015
DOIs	https://doi.org/10.1038/ng.3242
Publication status	Published - Apr 2015

Keywords

Breast Neoplasms
Case-Control Studies
Cohort Studies
Female
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Meta-Analysis as Topic
Microarray Analysis
Polymorphism, Single Nucleotide

UN SDGs

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

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Michailidou, K., Beesley, J., Lindstrom, S., Canisius, S., Dennis, J., Lush, M. J., Maranian, M. J., Bolla, M. K., Wang, Q., Shah, M., Perkins, B. J., Czene, K., Eriksson, M., Darabi, H., Brand, J. S., Bojesen, S. E., Nordestgaard, B. G., Flyger, H., Nielsen, S. F., ... Miedzybrodzka, Z. H. (2015). Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer. Nature Genetics, 47(4), 373-380. https://doi.org/10.1038/ng.3242

Michailidou, K, Beesley, J, Lindstrom, S, Canisius, S, Dennis, J, Lush, MJ, Maranian, MJ, Bolla, MK, Wang, Q, Shah, M, Perkins, BJ, Czene, K, Eriksson, M, Darabi, H, Brand, JS, Bojesen, SE, Nordestgaard, BG, Flyger, H, Nielsen, SF, Rahman, N, Turnbull, C, Fletcher, O, Peto, J, Gibson, L, dos-Santos-Silva, I, Chang-Claude, J, Flesch-Janys, D, Rudolph, A, Eilber, U, Behrens, S, Nevanlinna, H, Muranen, TA, Aittomäki, K, Blomqvist, C, Khan, S, Aaltonen, K, Ahsan, H, Kibriya, MG, Whittemore, AS, John, EM, Malone, KE, Gammon, MD, Santella, RM, Ursin, G, Makalic, E, Schmidt, DF, Casey, G, Hunter, DJ, Zheng, W, BOCS & Miedzybrodzka, ZH 2015, 'Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer', Nature Genetics, vol. 47, no. 4, pp. 373-380. https://doi.org/10.1038/ng.3242

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title = "Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer",

abstract = "Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.",

keywords = "Breast Neoplasms, Case-Control Studies, Cohort Studies, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Meta-Analysis as Topic, Microarray Analysis, Polymorphism, Single Nucleotide",

author = "Kyriaki Michailidou and Jonathan Beesley and Sara Lindstrom and Sander Canisius and Joe Dennis and Lush, {Michael J} and Maranian, {Mel J} and Bolla, {Manjeet K} and Qin Wang and Mitul Shah and Perkins, {Barbara J} and Kamila Czene and Mikael Eriksson and Hatef Darabi and Brand, {Judith S} and Bojesen, {Stig E} and Nordestgaard, {B{\o}rge G} and Henrik Flyger and Nielsen, {Sune F} and Nazneen Rahman and Clare Turnbull and Olivia Fletcher and Julian Peto and Lorna Gibson and Isabel dos-Santos-Silva and Jenny Chang-Claude and Dieter Flesch-Janys and Anja Rudolph and Ursula Eilber and Sabine Behrens and Heli Nevanlinna and Muranen, {Taru A} and Kristiina Aittom{\"a}ki and Carl Blomqvist and Sofia Khan and Kirsimari Aaltonen and Habibul Ahsan and Kibriya, {Muhammad G} and Whittemore, {Alice S} and John, {Esther M} and Malone, {Kathleen E} and Gammon, {Marilie D} and Santella, {Regina M} and Giske Ursin and Enes Makalic and Schmidt, {Daniel F} and Graham Casey and Hunter, {David J} and Wei Zheng and BOCS and Miedzybrodzka, {Zofia Helena}",

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doi = "10.1038/ng.3242",

language = "English",

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journal = "Nature Genetics",

issn = "1061-4036",

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AU - Michailidou, Kyriaki

AU - Beesley, Jonathan

AU - Lindstrom, Sara

AU - Canisius, Sander

AU - Dennis, Joe

AU - Lush, Michael J

AU - Maranian, Mel J

AU - Bolla, Manjeet K

AU - Wang, Qin

AU - Shah, Mitul

AU - Perkins, Barbara J

AU - Czene, Kamila

AU - Eriksson, Mikael

AU - Darabi, Hatef

AU - Brand, Judith S

AU - Bojesen, Stig E

AU - Nordestgaard, Børge G

AU - Flyger, Henrik

AU - Nielsen, Sune F

AU - Rahman, Nazneen

AU - Turnbull, Clare

AU - Fletcher, Olivia

AU - Peto, Julian

AU - Gibson, Lorna

AU - dos-Santos-Silva, Isabel

AU - Chang-Claude, Jenny

AU - Flesch-Janys, Dieter

AU - Rudolph, Anja

AU - Eilber, Ursula

AU - Behrens, Sabine

AU - Nevanlinna, Heli

AU - Muranen, Taru A

AU - Aittomäki, Kristiina

AU - Blomqvist, Carl

AU - Khan, Sofia

AU - Aaltonen, Kirsimari

AU - Ahsan, Habibul

AU - Kibriya, Muhammad G

AU - Whittemore, Alice S

AU - John, Esther M

AU - Malone, Kathleen E

AU - Gammon, Marilie D

AU - Santella, Regina M

AU - Ursin, Giske

AU - Makalic, Enes

AU - Schmidt, Daniel F

AU - Casey, Graham

AU - Hunter, David J

AU - Zheng, Wei

AU - BOCS

AU - Miedzybrodzka, Zofia Helena

PY - 2015/4

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N2 - Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.

AB - Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.

KW - Breast Neoplasms

KW - Case-Control Studies

KW - Cohort Studies

KW - Female

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Meta-Analysis as Topic

KW - Microarray Analysis

KW - Polymorphism, Single Nucleotide

U2 - 10.1038/ng.3242

DO - 10.1038/ng.3242

M3 - Letter

C2 - 25751625

SN - 1061-4036

VL - 47

SP - 373

EP - 380

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Abstract

Keywords

UN SDGs

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