Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

EMBRACE Collaborators; GC-HBOC Study Collaborators; GEMO Study Collaborators; ABCTB Investigators; HEBON Investigators; BCFR Investigators; Jennifer Stone

doi:10.1038/s41467-018-08053-5

Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, ABCTB Investigators, HEBON Investigators, BCFR Investigators, Jennifer Stone

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Abstract

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

Original language	English
Article number	1741
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-08053-5
Publication status	Published - 1 Dec 2019

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10.1038/s41467-018-08053-5Licence: CC BY

Cite this

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title = "Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer",

abstract = "Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.",

author = "{EMBRACE Collaborators} and {GC-HBOC Study Collaborators} and {GEMO Study Collaborators} and {ABCTB Investigators} and {HEBON Investigators} and {BCFR Investigators} and Ferreira, {Manuel A.} and Gamazon, {Eric R.} and Fares Al-Ejeh and Kristiina Aittom{\"a}ki and Andrulis, {Irene L.} and Hoda Anton-Culver and Adalgeir Arason and Volker Arndt and Aronson, {Kristan J.} and Arun, {Banu K.} and Ella Asseryanis and Jacopo Azzollini and Judith Balma{\~n}a and Barnes, {Daniel R.} and Daniel Barrowdale and Beckmann, {Matthias W.} and Sabine Behrens and Javier Benitez and Marina Bermisheva and Katarzyna Bia{\l}kowska and Carl Blomqvist and Bogdanova, {Natalia V.} and Bojesen, {Stig E.} and Bolla, {Manjeet K.} and Ake Borg and Hiltrud Brauch and Hermann Brenner and Annegien Broeks and Barbara Burwinkel and Trinidad Cald{\'e}s and Caligo, {Maria A.} and Daniele Campa and Ian Campbell and Federico Canzian and Jonathan Carter and Carter, {Brian D.} and Castelao, {Jose E.} and Jenny Chang-Claude and Chanock, {Stephen J.} and Hans Christiansen and Chung, {Wendy K.} and Claes, {Kathleen B.M.} and Clarke, {Christine L.} and Julian Adlard and Munaza Ahmed and Julian Barwell and Angela Brady and Carole Brewer and Jackie Cook and Rosemarie Davidson and Alan Donaldson and Jacqueline Eason and Ros Eeles and Evans, {D. Gareth} and Helen Gregory and Helen Hanson and Alex Henderson and Shirley Hodgson and Louise Izatt and Kennedy, {M. 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year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-018-08053-5",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group - Macmillan Publishers",

number = "1",

}

TY - JOUR

T1 - Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

AU - EMBRACE Collaborators

AU - GC-HBOC Study Collaborators

AU - GEMO Study Collaborators

AU - ABCTB Investigators

AU - HEBON Investigators

AU - BCFR Investigators

AU - Ferreira, Manuel A.

AU - Gamazon, Eric R.

AU - Al-Ejeh, Fares

AU - Aittomäki, Kristiina

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Arason, Adalgeir

AU - Arndt, Volker

AU - Aronson, Kristan J.

AU - Arun, Banu K.

AU - Asseryanis, Ella

AU - Azzollini, Jacopo

AU - Balmaña, Judith

AU - Barnes, Daniel R.

AU - Barrowdale, Daniel

AU - Beckmann, Matthias W.

AU - Behrens, Sabine

AU - Benitez, Javier

AU - Bermisheva, Marina

AU - Białkowska, Katarzyna

AU - Blomqvist, Carl

AU - Bogdanova, Natalia V.

AU - Bojesen, Stig E.

AU - Bolla, Manjeet K.

AU - Borg, Ake

AU - Brauch, Hiltrud

AU - Brenner, Hermann

AU - Broeks, Annegien

AU - Burwinkel, Barbara

AU - Caldés, Trinidad

AU - Caligo, Maria A.

AU - Campa, Daniele

AU - Campbell, Ian

AU - Canzian, Federico

AU - Carter, Jonathan

AU - Carter, Brian D.

AU - Castelao, Jose E.

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J.

AU - Christiansen, Hans

AU - Chung, Wendy K.

AU - Claes, Kathleen B.M.

AU - Clarke, Christine L.

AU - Adlard, Julian

AU - Ahmed, Munaza

AU - Barwell, Julian

AU - Brady, Angela

AU - Brewer, Carole

AU - Cook, Jackie

AU - Davidson, Rosemarie

AU - Donaldson, Alan

AU - Eason, Jacqueline

AU - Eeles, Ros

AU - Evans, D. Gareth

AU - Gregory, Helen

AU - Hanson, Helen

AU - Henderson, Alex

AU - Hodgson, Shirley

AU - Izatt, Louise

AU - Kennedy, M. John

AU - Lalloo, Fiona

AU - Miller, Clare

AU - Morrison, Patrick J.

AU - Ong, Kai ren

AU - Perkins, Jo

AU - Porteous, Mary E.

AU - Rogers, Mark T.

AU - Side, Lucy E.

AU - Snape, Katie

AU - Walker, Lisa

AU - Harrington, Patricia A.

AU - Arnold, Norbert

AU - Auber, Bernd

AU - Bogdanova-Markov, Nadja

AU - Borde, Julika

AU - Caliebe, Almuth

AU - Ditsch, Nina

AU - Dworniczak, Bernd

AU - Engert, Stefanie

AU - Faust, Ulrike

AU - Gehrig, Andrea

AU - Hahnen, Eric

AU - Hauke, Jan

AU - Hentschel, Julia

AU - Herold, Natalie

AU - Honisch, Ellen

AU - Just, Walter

AU - Kast, Karin

AU - Larsen, Mirjam

AU - Lemke, Johannes

AU - Nguyen, Huu Phuc

AU - Niederacher, Dieter

AU - Ott, Claus Eric

AU - Platzer, Konrad

AU - Pohl-Rescigno, Esther

AU - Ramser, Juliane

AU - Rhiem, Kerstin

AU - Steinemann, Doris

AU - Sutter, Christian

AU - Varon-Mateeva, Raymonda

AU - Wang-Gohrke, Shan

AU - Weber, Bernhard H.F.

AU - Prieur, Fabienne

AU - Pujol, Pascal

AU - Sagne, Charlotte

AU - Sevenet, Nicolas

AU - Sobol, Hagay

AU - Sokolowska, Johanna

AU - Stoppa-Lyonnet, Dominique

AU - Venat-Bouvet, Laurence

AU - Couch, Fergus J.

AU - Cox, Angela

AU - Cross, Simon S.

AU - Czene, Kamila

AU - Daly, Mary B.

AU - de la Hoya, Miguel

AU - Dennis, Joe

AU - Devilee, Peter

AU - Diez, Orland

AU - Dörk, Thilo

AU - Dunning, Alison M.

AU - Dwek, Miriam

AU - Eccles, Diana M.

AU - Ejlertsen, Bent

AU - Ellberg, Carolina

AU - Engel, Christoph

AU - Eriksson, Mikael

AU - Fasching, Peter A.

AU - Fletcher, Olivia

AU - Flyger, Henrik

AU - Friedman, Eitan

AU - Frost, Debra

AU - Gabrielson, Marike

AU - Gago-Dominguez, Manuela

AU - Ganz, Patricia A.

AU - Gapstur, Susan M.

AU - Garber, Judy

AU - García-Closas, Montserrat

AU - García-Sáenz, José A.

AU - Gaudet, Mia M.

AU - Giles, Graham G.

AU - Glendon, Gord

AU - Godwin, Andrew K.

AU - Goldberg, Mark S.

AU - Goldgar, David E.

AU - González-Neira, Anna

AU - Greene, Mark H.

AU - Gronwald, Jacek

AU - Guénel, Pascal

AU - Haiman, Christopher A.

AU - Hall, Per

AU - Hamann, Ute

AU - He, Wei

AU - Heyworth, Jane

AU - Hogervorst, Frans B.L.

AU - Hollestelle, Antoinette

AU - Hoover, Robert N.

AU - Hopper, John L.

AU - Hulick, Peter J.

AU - Humphreys, Keith

AU - Imyanitov, Evgeny N.

AU - Balleine, Rosemary

AU - Baxter, Robert

AU - Braye, Stephen

AU - Carpenter, Jane

AU - Dahlstrom, Jane

AU - Forbes, John

AU - Lee, Soon C.

AU - Marsh, Deborah

AU - Morey, Adrienne

AU - Pathmanathan, Nirmala

AU - Simpson, Peter

AU - Spigelman, Allan

AU - Wilcken, Nicholas

AU - Yip, Desmond

AU - Heemskerk-Gerritsen, Bernadette A.M.

AU - Rookus, Matti A.

AU - Seynaeve, Caroline M.

AU - van der Baan, Frederieke H.

AU - van der Hout, Annemieke H.

AU - van der Kolk, Lizet E.

AU - van der Luijt, Rob B.

AU - van Deurzen, Carolien H.M.

AU - van Doorn, Helena C.

AU - van Engelen, Klaartje

AU - van Hest, Liselotte

AU - van Os, Theo A.M.

AU - Verhoef, Senno

AU - Vogel, Maartje J.

AU - Wijnen, Juul T.

AU - Miron, Alexander

AU - Kapuscinski, Miroslav

AU - Bane, Anita

AU - Ross, Eric

AU - Buys, Saundra S.

AU - Conner, Thomas A.

AU - Isaacs, Claudine

AU - Jakimovska, Milena

AU - Jakubowska, Anna

AU - James, Paul A.

AU - Janavicius, Ramunas

AU - Jankowitz, Rachel C.

AU - John, Esther M.

AU - Johnson, Nichola

AU - Joseph, Vijai

AU - Karlan, Beth Y.

AU - Khusnutdinova, Elza

AU - Kiiski, Johanna I.

AU - Ko, Yon Dschun

AU - Jones, Michael E.

AU - Konstantopoulou, Irene

AU - Kristensen, Vessela N.

AU - Laitman, Yael

AU - Lambrechts, Diether

AU - Lazaro, Conxi

AU - Leslie, Goska

AU - Lester, Jenny

AU - Lesueur, Fabienne

AU - Lindström, Sara

AU - Long, Jirong

AU - Loud, Jennifer T.

AU - Lubiński, Jan

AU - Makalic, Enes

AU - Mannermaa, Arto

AU - Manoochehri, Mehdi

AU - Margolin, Sara

AU - Maurer, Tabea

AU - Mavroudis, Dimitrios

AU - McGuffog, Lesley

AU - Meindl, Alfons

AU - Menon, Usha

AU - Michailidou, Kyriaki

AU - Miller, Austin

AU - Montagna, Marco

AU - Moreno, Fernando

AU - Moserle, Lidia

AU - Mulligan, Anna Marie

AU - Nathanson, Katherine L.

AU - Neuhausen, Susan L.

AU - Nevanlinna, Heli

AU - Nevelsteen, Ines

AU - Nielsen, Finn C.

AU - Nikitina-Zake, Liene

AU - Nussbaum, Robert L.

AU - Offit, Kenneth

AU - Olah, Edith

AU - Olopade, Olufunmilayo I.

AU - Olsson, Håkan

AU - Osorio, Ana

AU - Papp, Janos

AU - Stone, Jennifer

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

AB - Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

UR - http://www.scopus.com/inward/record.url?scp=85064432929&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-08053-5

DO - 10.1038/s41467-018-08053-5

M3 - Article

C2 - 30988301

AN - SCOPUS:85064432929

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1741

ER -

Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

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