Genome-wide association analysis identifies three new breast cancer susceptibility loci

Maya Ghoussaini; Olivia Fletcher; Kyriaki Michailidou; Clare Turnbull; Marjanka K Schmidt; Ed Dicks; Joe Dennis; Qin Wang; Manjeet K Humphreys; Craig Luccarini; Caroline Baynes; Don Conroy; Melanie Maranian; Shahana Ahmed; Kristy Driver; Nichola Johnson; Nicholas Orr; Isabel dos Santos Silva; Quinten Waisfisz; Hanne Meijers-Heijboer; Andre G Uitterlinden; Fernando Rivadeneira; Per Hall; Kamila Czene; Astrid Irwanto; Jianjun Liu; Heli Nevanlinna; Kristiina Aittomäki; Carl Blomqvist; Alfons Meindl; Rita K Schmutzler; Bertram Müller-Myhsok; Peter Lichtner; Jenny Chang-Claude; Rebecca Hein; Stefan Nickels; Dieter Flesch-Janys; Helen Tsimiklis; Enes Makalic; Daniel Schmidt; Minh Bui; John L Hopper; Carmel Apicella; Daniel J Park; Melissa Southey; David J Hunter; Stig E Bojesen; Børge G Nordestgaard; Sune F Nielsen; Henrik Flyger; Netherlands Collaborative Group on Hereditary Breast and Ovarian Cancer (HEBON)

doi:10.1038/ng.1049

Genome-wide association analysis identifies three new breast cancer susceptibility loci

Maya Ghoussaini, Olivia Fletcher, Kyriaki Michailidou, Clare Turnbull, Marjanka K Schmidt, Ed Dicks, Joe Dennis, Qin Wang, Manjeet K Humphreys, Craig Luccarini, Caroline Baynes, Don Conroy, Melanie Maranian, Shahana Ahmed, Kristy Driver, Nichola Johnson, Nicholas Orr, Isabel dos Santos Silva, Quinten Waisfisz, Hanne Meijers-HeijboerAndre G Uitterlinden, Fernando Rivadeneira, Per Hall, Kamila Czene, Astrid Irwanto, Jianjun Liu, Heli Nevanlinna, Kristiina Aittomäki, Carl Blomqvist, Alfons Meindl, Rita K Schmutzler, Bertram Müller-Myhsok, Peter Lichtner, Jenny Chang-Claude, Rebecca Hein, Stefan Nickels, Dieter Flesch-Janys, Helen Tsimiklis, Enes Makalic, Daniel Schmidt, Minh Bui, John L Hopper, Carmel Apicella, Daniel J Park, Melissa Southey, David J Hunter, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Netherlands Collaborative Group on Hereditary Breast and Ovarian Cancer (HEBON)

Department of Breast Surgery

249 Citations (Scopus)

Abstract

Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.

Original language	English
Journal	Nature Genetics
Volume	44
Issue number	3
Pages (from-to)	312-8
Number of pages	7
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.1049
Publication status	Published - 2012

Keywords

Breast Neoplasms
Chromosomes, Human, Pair 12
Chromosomes, Human, Pair 21
European Continental Ancestry Group
Female
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Logistic Models
Polymorphism, Single Nucleotide
Principal Component Analysis

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Ghoussaini, M., Fletcher, O., Michailidou, K., Turnbull, C., Schmidt, M. K., Dicks, E., Dennis, J., Wang, Q., Humphreys, M. K., Luccarini, C., Baynes, C., Conroy, D., Maranian, M., Ahmed, S., Driver, K., Johnson, N., Orr, N., dos Santos Silva, I., Waisfisz, Q., ... Netherlands Collaborative Group on Hereditary Breast and Ovarian Cancer (HEBON) (2012). Genome-wide association analysis identifies three new breast cancer susceptibility loci. Nature Genetics, 44(3), 312-8. https://doi.org/10.1038/ng.1049

Ghoussaini, M, Fletcher, O, Michailidou, K, Turnbull, C, Schmidt, MK, Dicks, E, Dennis, J, Wang, Q, Humphreys, MK, Luccarini, C, Baynes, C, Conroy, D, Maranian, M, Ahmed, S, Driver, K, Johnson, N, Orr, N, dos Santos Silva, I, Waisfisz, Q, Meijers-Heijboer, H, Uitterlinden, AG, Rivadeneira, F, Hall, P, Czene, K, Irwanto, A, Liu, J, Nevanlinna, H, Aittomäki, K, Blomqvist, C, Meindl, A, Schmutzler, RK, Müller-Myhsok, B, Lichtner, P, Chang-Claude, J, Hein, R, Nickels, S, Flesch-Janys, D, Tsimiklis, H, Makalic, E, Schmidt, D, Bui, M, Hopper, JL, Apicella, C, Park, DJ, Southey, M, Hunter, DJ, Bojesen, SE , Nordestgaard, BG , Nielsen, SF , Flyger, H & Netherlands Collaborative Group on Hereditary Breast and Ovarian Cancer (HEBON) 2012, 'Genome-wide association analysis identifies three new breast cancer susceptibility loci', Nature Genetics, vol. 44, no. 3, pp. 312-8. https://doi.org/10.1038/ng.1049

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title = "Genome-wide association analysis identifies three new breast cancer susceptibility loci",

abstract = "Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8\% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.",

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AU - Fletcher, Olivia

AU - Michailidou, Kyriaki

AU - Turnbull, Clare

AU - Schmidt, Marjanka K

AU - Dicks, Ed

AU - Dennis, Joe

AU - Wang, Qin

AU - Humphreys, Manjeet K

AU - Luccarini, Craig

AU - Baynes, Caroline

AU - Conroy, Don

AU - Maranian, Melanie

AU - Ahmed, Shahana

AU - Driver, Kristy

AU - Johnson, Nichola

AU - Orr, Nicholas

AU - dos Santos Silva, Isabel

AU - Waisfisz, Quinten

AU - Meijers-Heijboer, Hanne

AU - Uitterlinden, Andre G

AU - Rivadeneira, Fernando

AU - Hall, Per

AU - Czene, Kamila

AU - Irwanto, Astrid

AU - Liu, Jianjun

AU - Nevanlinna, Heli

AU - Aittomäki, Kristiina

AU - Blomqvist, Carl

AU - Meindl, Alfons

AU - Schmutzler, Rita K

AU - Müller-Myhsok, Bertram

AU - Lichtner, Peter

AU - Chang-Claude, Jenny

AU - Hein, Rebecca

AU - Nickels, Stefan

AU - Flesch-Janys, Dieter

AU - Tsimiklis, Helen

AU - Makalic, Enes

AU - Schmidt, Daniel

AU - Bui, Minh

AU - Hopper, John L

AU - Apicella, Carmel

AU - Park, Daniel J

AU - Southey, Melissa

AU - Hunter, David J

AU - Bojesen, Stig E

AU - Nordestgaard, Børge G

AU - Nielsen, Sune F

AU - Flyger, Henrik

AU - Netherlands Collaborative Group on Hereditary Breast and Ovarian Cancer (HEBON)

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AB - Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.

KW - Breast Neoplasms

KW - Chromosomes, Human, Pair 12

KW - Chromosomes, Human, Pair 21

KW - European Continental Ancestry Group

KW - Female

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Logistic Models

KW - Polymorphism, Single Nucleotide

KW - Principal Component Analysis

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DO - 10.1038/ng.1049

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VL - 44

SP - 312

EP - 318

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

Genome-wide association analysis identifies three new breast cancer susceptibility loci

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Keywords

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