Association analysis identifies 65 new breast cancer risk loci

Kyriaki Michailidou; Sara Lindström; Joe Dennis; Jonathan Beesley; Shirley Hui; Siddhartha Kar; Audrey Lemaçon; Penny Soucy; Dylan Glubb; Asha Rostamianfar; Manjeet K Bolla; Qin Wang; Jonathan Tyrer; Ed Dicks; Andrew Lee; Zhaoming Wang; Jamie Allen; Renske Keeman; Ursula Eilber; Juliet D French; Xiao Qing Chen; Laura Fachal; Karen McCue; Amy E McCart Reed; Maya Ghoussaini; Jason S Carroll; Xia Jiang; Hilary Finucane; Marcia Adams; Muriel A Adank; Habibul Ahsan; Kristiina Aittomäki; Hoda Anton-Culver; Natalia N Antonenkova; Volker Arndt; Kristan J Aronson; Banu Arun; Paul L Auer; François Bacot; Myrto Barrdahl; Caroline Baynes; Matthias W Beckmann; Sabine Behrens; Javier Benitez; Marina Bermisheva; Leslie Bernstein; Carl Blomqvist; Natalia V Bogdanova; Stig E Bojesen; NBCS Collaborators; Børge G Nordestgaard; Jacques Simard; Peter Kraft; Douglas F. Easton

doi:10.1038/nature24284

Association analysis identifies 65 new breast cancer risk loci

Kyriaki Michailidou, Sara Lindström, Joe Dennis, Jonathan Beesley, Shirley Hui, Siddhartha Kar, Audrey Lemaçon, Penny Soucy, Dylan Glubb, Asha Rostamianfar, Manjeet K Bolla, Qin Wang, Jonathan Tyrer, Ed Dicks, Andrew Lee, Zhaoming Wang, Jamie Allen, Renske Keeman, Ursula Eilber, Juliet D FrenchXiao Qing Chen, Laura Fachal, Karen McCue, Amy E McCart Reed, Maya Ghoussaini, Jason S Carroll, Xia Jiang, Hilary Finucane, Marcia Adams, Muriel A Adank, Habibul Ahsan, Kristiina Aittomäki, Hoda Anton-Culver, Natalia N Antonenkova, Volker Arndt, Kristan J Aronson, Banu Arun, Paul L Auer, François Bacot, Myrto Barrdahl, Caroline Baynes, Matthias W Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Leslie Bernstein, Carl Blomqvist, Natalia V Bogdanova, Stig E Bojesen, NBCS Collaborators, Børge G Nordestgaard, Jacques Simard, Peter Kraft, Douglas F. Easton

Institut for Klinisk Medicin

423 Citationer (Scopus)

Abstract

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10^-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

Originalsprog	Engelsk
Tidsskrift	Nature
Vol/bind	551
Udgave nummer	7678
Sider (fra-til)	92-94
Antal sider	3
ISSN	0028-0836
DOI	https://doi.org/10.1038/nature24284
Status	Udgivet - 2 nov. 2017

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Michailidou, K., Lindström, S., Dennis, J., Beesley, J., Hui, S., Kar, S., Lemaçon, A., Soucy, P., Glubb, D., Rostamianfar, A., Bolla, M. K., Wang, Q., Tyrer, J., Dicks, E., Lee, A., Wang, Z., Allen, J., Keeman, R., Eilber, U., ... Easton, D. F. (2017). Association analysis identifies 65 new breast cancer risk loci. Nature, 551(7678), 92-94. https://doi.org/10.1038/nature24284

Michailidou, K, Lindström, S, Dennis, J, Beesley, J, Hui, S, Kar, S, Lemaçon, A, Soucy, P, Glubb, D, Rostamianfar, A, Bolla, MK, Wang, Q, Tyrer, J, Dicks, E, Lee, A, Wang, Z, Allen, J, Keeman, R, Eilber, U, French, JD, Qing Chen, X, Fachal, L, McCue, K, McCart Reed, AE, Ghoussaini, M, Carroll, JS, Jiang, X, Finucane, H, Adams, M, Adank, MA, Ahsan, H, Aittomäki, K, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Arun, B, Auer, PL, Bacot, F, Barrdahl, M, Baynes, C, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Bogdanova, NV, Bojesen, SE, NBCS Collaborators, Nordestgaard, BG, Simard, J, Kraft, P & Easton, DF 2017, 'Association analysis identifies 65 new breast cancer risk loci', Nature, bind 551, nr. 7678, s. 92-94. https://doi.org/10.1038/nature24284

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title = "Association analysis identifies 65 new breast cancer risk loci",

abstract = "Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.",

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author = "Kyriaki Michailidou and Sara Lindstr{\"o}m and Joe Dennis and Jonathan Beesley and Shirley Hui and Siddhartha Kar and Audrey Lema{\c c}on and Penny Soucy and Dylan Glubb and Asha Rostamianfar and Bolla, {Manjeet K} and Qin Wang and Jonathan Tyrer and Ed Dicks and Andrew Lee and Zhaoming Wang and Jamie Allen and Renske Keeman and Ursula Eilber and French, {Juliet D} and {Qing Chen}, Xiao and Laura Fachal and Karen McCue and {McCart Reed}, {Amy E} and Maya Ghoussaini and Carroll, {Jason S} and Xia Jiang and Hilary Finucane and Marcia Adams and Adank, {Muriel A} and Habibul Ahsan and Kristiina Aittom{\"a}ki and Hoda Anton-Culver and Antonenkova, {Natalia N} and Volker Arndt and Aronson, {Kristan J} and Banu Arun and Auer, {Paul L} and Fran{\c c}ois Bacot and Myrto Barrdahl and Caroline Baynes and Beckmann, {Matthias W} and Sabine Behrens and Javier Benitez and Marina Bermisheva and Leslie Bernstein and Carl Blomqvist and Bogdanova, {Natalia V} and Bojesen, {Stig E} and {NBCS Collaborators} and Nordestgaard, {B{\o}rge G} and Jacques Simard and Peter Kraft and Easton, {Douglas F.}",

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T1 - Association analysis identifies 65 new breast cancer risk loci

AU - Michailidou, Kyriaki

AU - Lindström, Sara

AU - Dennis, Joe

AU - Beesley, Jonathan

AU - Hui, Shirley

AU - Kar, Siddhartha

AU - Lemaçon, Audrey

AU - Soucy, Penny

AU - Glubb, Dylan

AU - Rostamianfar, Asha

AU - Bolla, Manjeet K

AU - Wang, Qin

AU - Tyrer, Jonathan

AU - Dicks, Ed

AU - Lee, Andrew

AU - Wang, Zhaoming

AU - Allen, Jamie

AU - Keeman, Renske

AU - Eilber, Ursula

AU - French, Juliet D

AU - Qing Chen, Xiao

AU - Fachal, Laura

AU - McCue, Karen

AU - McCart Reed, Amy E

AU - Ghoussaini, Maya

AU - Carroll, Jason S

AU - Jiang, Xia

AU - Finucane, Hilary

AU - Adams, Marcia

AU - Adank, Muriel A

AU - Ahsan, Habibul

AU - Aittomäki, Kristiina

AU - Anton-Culver, Hoda

AU - Antonenkova, Natalia N

AU - Arndt, Volker

AU - Aronson, Kristan J

AU - Arun, Banu

AU - Auer, Paul L

AU - Bacot, François

AU - Barrdahl, Myrto

AU - Baynes, Caroline

AU - Beckmann, Matthias W

AU - Behrens, Sabine

AU - Benitez, Javier

AU - Bermisheva, Marina

AU - Bernstein, Leslie

AU - Blomqvist, Carl

AU - Bogdanova, Natalia V

AU - Bojesen, Stig E

AU - NBCS Collaborators

AU - Nordestgaard, Børge G

AU - Simard, Jacques

AU - Kraft, Peter

AU - Easton, Douglas F.

PY - 2017/11/2

Y1 - 2017/11/2

N2 - Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

AB - Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

KW - Journal Article

U2 - 10.1038/nature24284

DO - 10.1038/nature24284

M3 - Letter

C2 - 29059683

SN - 0028-0836

VL - 551

SP - 92

EP - 94

JO - Nature

JF - Nature

IS - 7678

ER -

Association analysis identifies 65 new breast cancer risk loci

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