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.
| Original language | English |
|---|---|
| Pages (from-to) | 92-94 |
| Number of pages | 3 |
| Journal | Nature |
| Volume | 551 |
| Issue number | 7678 |
| DOIs | |
| Publication status | Published - 2 Nov 2017 |
| Externally published | Yes |
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In: Nature, Vol. 551, No. 7678, 02.11.2017, p. 92-94.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
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 - Chen, Xiao Qing
AU - Fachal, Laura
AU - McCue, Karen
AU - Reed, Amy E.Mc Cart
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 - Bonanni, Bernardo
AU - Børresen-Dale, Anne Lise
AU - Brand, Judith S.
AU - Brauch, Hiltrud
AU - Brennan, Paul
AU - Brenner, Hermann
AU - Brinton, Louise
AU - Broberg, Per
AU - Brock, Ian W.
AU - Broeks, Annegien
AU - Brooks-Wilson, Angela
AU - Brucker, Sara Y.
AU - Brüning, Thomas
AU - Burwinkel, Barbara
AU - Butterbach, Katja
AU - Cai, Qiuyin
AU - Cai, Hui
AU - Caldés, Trinidad
AU - Canzian, Federico
AU - Carracedo, Angel
AU - Carter, Brian D.
AU - Castelao, Jose E.
AU - Chan, Tsun L.
AU - Cheng, Ting Yuan David
AU - Chia, Kee Seng
AU - Choi, Ji Yeob
AU - Christiansen, Hans
AU - Clarke, Christine L.
AU - NBCS Collaborators
AU - Collée, Margriet
AU - Conroy, Don M.
AU - Cordina-Duverger, Emilie
AU - Cornelissen, Sten
AU - Cox, David G.
AU - Cox, Angela
AU - Cross, Simon S.
AU - Cunningham, Julie M.
AU - Czene, Kamila
AU - Daly, Mary B.
AU - Devilee, Peter
AU - Doheny, Kimberly F.
AU - Dörk, Thilo
AU - Dos-Santos-Silva, Isabel
AU - Dumont, Martine
AU - Durcan, Lorraine
AU - Dwek, Miriam
AU - Eccles, Diana M.
AU - Ekici, Arif B.
AU - Eliassen, A. Heather
AU - Ellberg, Carolina
AU - Elvira, Mingajeva
AU - Engel, Christoph
AU - Eriksson, Mikael
AU - Fasching, Peter A.
AU - Figueroa, Jonine
AU - Flesch-Janys, Dieter
AU - Fletcher, Olivia
AU - Flyger, Henrik
AU - Fritschi, Lin
AU - Gaborieau, Valerie
AU - Gabrielson, Marike
AU - Gago-Dominguez, Manuela
AU - Gao, Yu Tang
AU - Gapstur, Susan M.
AU - García-Sáenz, José A.
AU - Gaudet, Mia M.
AU - Georgoulias, Vassilios
AU - Giles, Graham G.
AU - Glendon, Gord
AU - Goldberg, Mark S.
AU - Goldgar, David E.
AU - González-Neira, Anna
AU - Alnæs, Grethe I.Grenaker
AU - Grip, Mervi
AU - Gronwald, Jacek
AU - Grundy, Anne
AU - Guénel, Pascal
AU - Haeberle, Lothar
AU - Hahnen, Eric
AU - Haiman, Christopher A.
AU - Håkansson, Niclas
AU - Hamann, Ute
AU - Hamel, Nathalie
AU - Hankinson, Susan
AU - Harrington, Patricia
AU - Hart, Steven N.
AU - Hartikainen, Jaana M.
AU - Hartman, Mikael
AU - Hein, Alexander
AU - Heyworth, Jane
AU - Hicks, Belynda
AU - Hillemanns, Peter
AU - Ho, Dona N.
AU - Hollestelle, Antoinette
AU - Hooning, Maartje J.
AU - Hoover, Robert N.
AU - Hopper, John L.
AU - Hou, Ming Feng
AU - Hsiung, Chia Ni
AU - Huang, Guanmengqian
AU - Humphreys, Keith
AU - Ishiguro, Junko
AU - Ito, Hidemi
AU - Iwasaki, Motoki
AU - Iwata, Hiroji
AU - Jakubowska, Anna
AU - Janni, Wolfgang
AU - John, Esther M.
AU - Johnson, Nichola
AU - Jones, Kristine
AU - Jones, Michael
AU - Jukkola-Vuorinen, Arja
AU - Kaaks, Rudolf
AU - Kabisch, Maria
AU - Kaczmarek, Katarzyna
AU - Kang, Daehee
AU - Kasuga, Yoshio
AU - Kerin, Michael J.
AU - Khan, Sofia
AU - Khusnutdinova, Elza
AU - Kiiski, Johanna I.
AU - Kim, Sung Won
AU - Knight, Julia A.
AU - Kosma, Veli Matti
AU - Kristensen, Vessela N.
AU - Krüger, Ute
AU - Kwong, Ava
AU - Lambrechts, Diether
AU - Le Marchand, Loic
AU - Lee, Eunjung
AU - Lee, Min Hyuk
AU - Lee, Jong Won
AU - Lee, Chuen Neng
AU - Lejbkowicz, Flavio
AU - Li, Jingmei
AU - Lilyquist, Jenna
AU - Lindblom, Annika
AU - Lissowska, Jolanta
AU - Lo, Wing Yee
AU - Loibl, Sibylle
AU - Long, Jirong
AU - Lophatananon, Artitaya
AU - Lubinski, Jan
AU - Luccarini, Craig
AU - Lux, Michael P.
AU - Ma, Edmond S.K.
AU - MacInnis, Robert J.
AU - Maishman, Tom
AU - Makalic, Enes
AU - Malone, Kathleen E.
AU - Kostovska, Ivana Maleva
AU - Mannermaa, Arto
AU - Manoukian, Siranoush
AU - Manson, Jo Ann E.
AU - Margolin, Sara
AU - Mariapun, Shivaani
AU - Martinez, Maria Elena
AU - Matsuo, Keitaro
AU - Mavroudis, Dimitrios
AU - McKay, James
AU - McLean, Catriona
AU - Meijers-Heijboer, Hanne
AU - Meindl, Alfons
AU - Menéndez, Primitiva
AU - Menon, Usha
AU - Meyer, Jeffery
AU - Miao, Hui
AU - Miller, Nicola
AU - Taib, Nur Aishah Mohd
AU - Muir, Kenneth
AU - Mulligan, Anna Marie
AU - Mulot, Claire
AU - Neuhausen, Susan L.
AU - Nevanlinna, Heli
AU - Neven, Patrick
AU - Nielsen, Sune F.
AU - Noh, Dong Young
AU - Nordestgaard, Børge G.
AU - Norman, Aaron
AU - Olopade, Olufunmilayo I.
AU - Olson, Janet E.
AU - Olsson, Håkan
AU - Olswold, Curtis
AU - Orr, Nick
AU - Pankratz, V. Shane
AU - Park, Sue K.
AU - Park-Simon, Tjoung Won
AU - Lloyd, Rachel
AU - Perez, Jose I.A.
AU - Peterlongo, Paolo
AU - Peto, Julian
AU - Phillips, Kelly Anne
AU - Pinchev, Mila
AU - Plaseska-Karanfilska, Dijana
AU - Prentice, Ross
AU - Presneau, Nadege
AU - Prokofyeva, Darya
AU - Pugh, Elizabeth
AU - Pylkäs, Katri
AU - ABCTB Investigators
AU - kConFab/AOCS Investigators
AU - Schmidt, Daniel F.
AU - Southey, Melissa C.
AU - Milne, Roger L.
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.
UR - http://www.scopus.com/inward/record.url?scp=85033379332&partnerID=8YFLogxK
U2 - 10.1038/nature24284
DO - 10.1038/nature24284
M3 - Article
C2 - 29059683
AN - SCOPUS:85033379332
SN - 0028-0836
VL - 551
SP - 92
EP - 94
JO - Nature
JF - Nature
IS - 7678
ER -