A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

Lang Wu; Wei Shi; Jirong Long; Xingyi Guo; Kyriaki Michailidou; Jonathan Beesley; Manjeet K Bolla; Xiao-Ou Shu; Yingchang Lu; Qiuyin Cai; Fares Al-Ejeh; Esdy Rozali; Qin Wang; Joe Dennis; Bingshan Li; Chenjie Zeng; Helian Feng; Alexander Gusev; Richard T Barfield; Irene L Andrulis; Hoda Anton-Culver; Volker Arndt; Kristan J Aronson; Paul L Auer; Myrto Barrdahl; Caroline Baynes; Matthias W Beckmann; Javier Benitez; Marina Bermisheva; Carl Blomqvist; Natalia V Bogdanova; Stig E Bojesen; Hiltrud Brauch; Hermann Brenner; Louise Brinton; Per Broberg; Sara Y Brucker; Barbara Burwinkel; Trinidad Caldés; Federico Canzian; Brian D Carter; J Esteban Castelao; Jenny Chang-Claude; Xiaoqing Chen; Ting-Yuan David Cheng; Hans Christiansen; Christine L Clarke; Henrik Flyger; Sune F Nielsen; Børge G Nordestgaard; NBCS Collaborators

doi:10.1038/s41588-018-0132-x

A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

Lang Wu, Wei Shi, Jirong Long, Xingyi Guo, Kyriaki Michailidou, Jonathan Beesley, Manjeet K Bolla, Xiao-Ou Shu, Yingchang Lu, Qiuyin Cai, Fares Al-Ejeh, Esdy Rozali, Qin Wang, Joe Dennis, Bingshan Li, Chenjie Zeng, Helian Feng, Alexander Gusev, Richard T Barfield, Irene L AndrulisHoda Anton-Culver, Volker Arndt, Kristan J Aronson, Paul L Auer, Myrto Barrdahl, Caroline Baynes, Matthias W Beckmann, Javier Benitez, Marina Bermisheva, Carl Blomqvist, Natalia V Bogdanova, Stig E Bojesen, Hiltrud Brauch, Hermann Brenner, Louise Brinton, Per Broberg, Sara Y Brucker, Barbara Burwinkel, Trinidad Caldés, Federico Canzian, Brian D Carter, J Esteban Castelao, Jenny Chang-Claude, Xiaoqing Chen, Ting-Yuan David Cheng, Hans Christiansen, Christine L Clarke, Henrik Flyger, Sune F Nielsen, Børge G Nordestgaard, NBCS Collaborators

Institut for Klinisk Medicin

59 Citationer (Scopus)

Abstract

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10 ^-6 , including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	50
Udgave nummer	7
Sider (fra-til)	968-978
Antal sider	11
ISSN	1061-4036
DOI	https://doi.org/10.1038/s41588-018-0132-x
Status	Udgivet - 1 jul. 2018

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314198/Licens: Andet

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Wu, L., Shi, W., Long, J., Guo, X., Michailidou, K., Beesley, J., Bolla, M. K., Shu, X.-O., Lu, Y., Cai, Q., Al-Ejeh, F., Rozali, E., Wang, Q., Dennis, J., Li, B., Zeng, C., Feng, H., Gusev, A., Barfield, R. T., ... NBCS Collaborators (2018). A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer. Nature Genetics, 50(7), 968-978. https://doi.org/10.1038/s41588-018-0132-x

Wu, L, Shi, W, Long, J, Guo, X, Michailidou, K, Beesley, J, Bolla, MK, Shu, X-O, Lu, Y, Cai, Q, Al-Ejeh, F, Rozali, E, Wang, Q, Dennis, J, Li, B, Zeng, C, Feng, H, Gusev, A, Barfield, RT, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Barrdahl, M, Baynes, C, Beckmann, MW, Benitez, J, Bermisheva, M, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Brauch, H, Brenner, H, Brinton, L, Broberg, P, Brucker, SY, Burwinkel, B, Caldés, T, Canzian, F, Carter, BD, Castelao, JE, Chang-Claude, J, Chen, X, Cheng, T-YD, Christiansen, H, Clarke, CL, Flyger, H, Nielsen, SF, Nordestgaard, BG & NBCS Collaborators 2018, 'A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer', Nature Genetics, bind 50, nr. 7, s. 968-978. https://doi.org/10.1038/s41588-018-0132-x

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title = "A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer",

abstract = " The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10 -6 , including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology. ",

author = "Lang Wu and Wei Shi and Jirong Long and Xingyi Guo and Kyriaki Michailidou and Jonathan Beesley and Bolla, {Manjeet K} and Xiao-Ou Shu and Yingchang Lu and Qiuyin Cai and Fares Al-Ejeh and Esdy Rozali and Qin Wang and Joe Dennis and Bingshan Li and Chenjie Zeng and Helian Feng and Alexander Gusev and Barfield, {Richard T} and Andrulis, {Irene L} and Hoda Anton-Culver and Volker Arndt and Aronson, {Kristan J} and Auer, {Paul L} and Myrto Barrdahl and Caroline Baynes and Beckmann, {Matthias W} and Javier Benitez and Marina Bermisheva and Carl Blomqvist and Bogdanova, {Natalia V} and Bojesen, {Stig E} and Hiltrud Brauch and Hermann Brenner and Louise Brinton and Per Broberg and Brucker, {Sara Y} and Barbara Burwinkel and Trinidad Cald{\'e}s and Federico Canzian and Carter, {Brian D} and Castelao, {J Esteban} and Jenny Chang-Claude and Xiaoqing Chen and Cheng, {Ting-Yuan David} and Hans Christiansen and Clarke, {Christine L} and Henrik Flyger and Nielsen, {Sune F} and Nordestgaard, {B{\o}rge G} and {NBCS Collaborators}",

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T1 - A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

AU - Wu, Lang

AU - Shi, Wei

AU - Long, Jirong

AU - Guo, Xingyi

AU - Michailidou, Kyriaki

AU - Beesley, Jonathan

AU - Bolla, Manjeet K

AU - Shu, Xiao-Ou

AU - Lu, Yingchang

AU - Cai, Qiuyin

AU - Al-Ejeh, Fares

AU - Rozali, Esdy

AU - Wang, Qin

AU - Dennis, Joe

AU - Li, Bingshan

AU - Zeng, Chenjie

AU - Feng, Helian

AU - Gusev, Alexander

AU - Barfield, Richard T

AU - Andrulis, Irene L

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Aronson, Kristan J

AU - Auer, Paul L

AU - Barrdahl, Myrto

AU - Baynes, Caroline

AU - Beckmann, Matthias W

AU - Benitez, Javier

AU - Bermisheva, Marina

AU - Blomqvist, Carl

AU - Bogdanova, Natalia V

AU - Bojesen, Stig E

AU - Brauch, Hiltrud

AU - Brenner, Hermann

AU - Brinton, Louise

AU - Broberg, Per

AU - Brucker, Sara Y

AU - Burwinkel, Barbara

AU - Caldés, Trinidad

AU - Canzian, Federico

AU - Carter, Brian D

AU - Castelao, J Esteban

AU - Chang-Claude, Jenny

AU - Chen, Xiaoqing

AU - Cheng, Ting-Yuan David

AU - Christiansen, Hans

AU - Clarke, Christine L

AU - Flyger, Henrik

AU - Nielsen, Sune F

AU - Nordestgaard, Børge G

AU - NBCS Collaborators

PY - 2018/7/1

Y1 - 2018/7/1

N2 - The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10 -6 , including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

AB - The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10 -6 , including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

U2 - 10.1038/s41588-018-0132-x

DO - 10.1038/s41588-018-0132-x

M3 - Journal article

C2 - 29915430

SN - 1061-4036

VL - 50

SP - 968

EP - 978

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

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