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 & 31 others 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

Research output: Contribution to journalLetter

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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 languageEnglish
Pages (from-to)373-380
Number of pages8
JournalNature Genetics
Volume47
Issue number4
Early online date9 Mar 2015
DOIs
Publication statusPublished - Apr 2015

Fingerprint

Genome-Wide Association Study
Breast Neoplasms
Chromatin
Amino Acid Substitution
Single Nucleotide Polymorphism
Meta-Analysis
Breast
Genotype
Genome
Cell Line
Genes

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

Cite this

Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer. / Michailidou, Kyriaki; Beesley, Jonathan; Lindstrom, Sara; Canisius, Sander; Dennis, Joe; Lush, Michael J; Maranian, Mel J; Bolla, Manjeet K; Wang, Qin; Shah, Mitul; Perkins, Barbara J; Czene, Kamila; Eriksson, Mikael; Darabi, Hatef; Brand, Judith S; Bojesen, Stig E; Nordestgaard, Børge G; Flyger, Henrik; Nielsen, Sune F; Rahman, Nazneen; Turnbull, Clare; Fletcher, Olivia; Peto, Julian; Gibson, Lorna; dos-Santos-Silva, Isabel; Chang-Claude, Jenny; Flesch-Janys, Dieter; Rudolph, Anja; Eilber, Ursula; Behrens, Sabine; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Khan, Sofia; Aaltonen, Kirsimari; Ahsan, Habibul; Kibriya, Muhammad G; Whittemore, Alice S; John, Esther M; Malone, Kathleen E; Gammon, Marilie D; Santella, Regina M; Ursin, Giske; Makalic, Enes; Schmidt, Daniel F; Casey, Graham; Hunter, David J; Zheng, Wei; BOCS ; Miedzybrodzka, Zofia Helena.

In: Nature Genetics, Vol. 47, No. 4, 04.2015, p. 373-380.

Research output: Contribution to journalLetter

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
Michailidou, Kyriaki ; Beesley, Jonathan ; Lindstrom, Sara ; Canisius, Sander ; Dennis, Joe ; Lush, Michael J ; Maranian, Mel J ; Bolla, Manjeet K ; Wang, Qin ; Shah, Mitul ; Perkins, Barbara J ; Czene, Kamila ; Eriksson, Mikael ; Darabi, Hatef ; Brand, Judith S ; Bojesen, Stig E ; Nordestgaard, Børge G ; Flyger, Henrik ; Nielsen, Sune F ; Rahman, Nazneen ; Turnbull, Clare ; Fletcher, Olivia ; Peto, Julian ; Gibson, Lorna ; dos-Santos-Silva, Isabel ; Chang-Claude, Jenny ; Flesch-Janys, Dieter ; Rudolph, Anja ; Eilber, Ursula ; Behrens, Sabine ; Nevanlinna, Heli ; Muranen, Taru A ; Aittomäki, Kristiina ; Blomqvist, Carl ; Khan, Sofia ; Aaltonen, Kirsimari ; Ahsan, Habibul ; Kibriya, Muhammad G ; Whittemore, Alice S ; John, Esther M ; Malone, Kathleen E ; Gammon, Marilie D ; Santella, Regina M ; Ursin, Giske ; Makalic, Enes ; Schmidt, Daniel F ; Casey, Graham ; Hunter, David J ; Zheng, Wei ; BOCS ; Miedzybrodzka, Zofia Helena. / Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer. In: Nature Genetics. 2015 ; Vol. 47, No. 4. pp. 373-380.
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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

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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

VL - 47

SP - 373

EP - 380

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

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