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

Ferreira, Manuel A.; Gamazon, Eric R.; Al-Ejeh, Fares; Aittomäki, Kristiina; Andrulis, Irene L.; Anton-Culver, Hoda; Arason, Adalgeir; Arndt, Volker; Aronson, Kristan J.; Arun, Banu K.; Asseryanis, Ella; Azzollini, Jacopo; Balmaña, Judith; Barnes, Daniel R.; Barrowdale, Daniel; Beckmann, Matthias W.; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Bialkowska, Katarzyna; Forbes, John; John, EM; Johnson, N; Joseph, V; Karlan, BY; Khusnutdinova, E; Kiiski, J; Ko, Y-D; Jones, ME; Konstantopoulou, I; Kristensen, VN; Laitman, Y; Lambrechts, D; Lazaro, C; Leslie, G; Lester, J; Lesueur, F; Lindstrom, S; Long, J; Loud, JT; Lubinski, J; Makalic, E; Mannermaa, A; Manoochehri, M; Margolin, S; Maurer, T; Mavroudis, D; McGuffog, L; Meindl, A; Menon, U; Michailidou, K; Miller, A; Montagna, M; Moreno, F; Moserle, L; Mulligan, AM; Nathanson, KL; Neuhausen, SL; Nevanlinna, H; Nevelsteen, I; Nielsen, FC; Nikitina-Zake, L; Nussbaum, RL; Offit, K; Olah, E; Olopade, O; Olsson, H; Osorio, A; Papp, J; Park-Simon, T-W; Parsons, MT; Pedersen, IS; Peixoto, A; Peterlongo, P; Pharoah, PDP; Plaseska-Karanfilska, D; Poppe, B; Presneau, N; Radice, P; Rantala, J; Rennert, G; Risch, HA; Saloustros, E; Sanden, K; Sawyer, EJ; Schmidt, MK; Schmutzler, RK; Sharma, P; Shu, X-O; Simard, J; Singer, CF; Soucy, P; Southey, MC; Spinelli, JJ; Spurdle, AB; Stone, J; Swerdlow, AJ; Tapper, WJ; Taylor, JA; Teixeira, MR; Terry, MB; Teule, A; Thomassen, M; Thoene, K; Thull, DL; Tischkowitz, M; Toland, AE; Torres, D; Truong, T; Tung, N; Vachon, CM; van Asperen, CJ; van den Ouweland, AMW; van Rensburg, EJ; Vega, A; Viel, A; Wang, Q; Wappenschmidt, B; Weitzel, JN; Wendt, C; Winqvist, R; Blomqvist, Carl; Yang, XR; Yannoukakos, D; Ziogas, A; Kraft, P; Antoniou, AC; Zheng, W; Easton, DF; Milne, RL; Beesley, J; Chenevix-Trench, G; Bogdanova, N; Arnold, N; Auber, B; Bogdanova-Markov, N; Borde, J; Caliebe, A; Ditsch, N; Dworniczak, B; Engert, S; Faust, U; Gehrig, A; Bojesen, SE; Hahnen, E; Hauke, J; Hentschel, J; Herold, N; Honisch, E; Just, W; Kast, K; Larsen, M; Lemke, J; Huu, PN; Bolla, MK; Niederacher, D; Ott, C-E; Platzer, K; Pohl-Rescigno, E; Ramser, J; Rhiem, K; Steinemann, D; Sutter, C; Varon-Mateeva, R; Wang-Gohrke, S; Borg, A; Weber, BHF; Prieur, F; Pujol, P; Sagne, C; Sevenet, N; Sobol, H; Sokolowska, J; Stoppa-Lyonnet, D; Venat-Bouvet, L; Adlard, J; Brauch, H; Ahmed, M; Barwell, J; Brady, A; Brewer, C; Cook, J; Davidson, R; Donaldson, A; Eason, J; Eeles, R; Evans, DG; Brenner, H; Gregory, H; Hanson, H; Henderson, A; Hodgson, S; Izatt, L; Kennedy, MJ; Lalloo, F; Miller, C; Morrison, PJ; Ong, K-R; Broeks, A; Perkins, J; Porteous, ME; Rogers, MT; Side, LE; Snape, K; Walker, L; Harrington, PA; Heemskerk-Gerritsen, BAM; Rookus, MA; Seynaeve, CM; Burwinkel, B; van der Baan, FH; van der Hout, AH; van der Kolk, LE; van der Luijt, RB; van Deurzen, CHM; van Doorn, HC; van Engelen, K; van Hest, L; van Os, TAM; Verhoef, S; Caldes, T; Vogel, MJ; Wijnen, JT; Miron, A; Kapuscinski, M; Bane, A; Ross, E; Buys, SS; Conner, TA; Balleine, R; Baxter, R; Caligo, MA; Braye, S; Carpenter, J; Dahlstrom, J; Lee, SC; Marsh, D; Morey, A; Pathmanathan, N; Simpson, P; Spigelman, A; Campa, D; Wilcken, N; Yip, D; Campbell, I; Canzian, F; Carter, J; Carter, BD; Castelao, JE; Chang-Claude, J; Chanock, SJ; Christiansen, H; Chung, WK; Claes, KBM; Clarke, CL; Couch, FJ; Cox, A; Cross, SS; Czene, K; Daly, MB; de la Hoya, M; Dennis, J; Devilee, P; Diez, O; Doerk, T; Dunning, AM; Dwek, M; Eccles, DM; Ejlertsen, B; Ellberg, C; Engel, C; Eriksson, M; Fasching, PA; Fletcher, O; Flyger, H; Friedman, E; Frost, D; Gabrielson, M; Gago-Dominguez, M; Ganz, PA; Gapstur, SM; Garber, J; Garcia-Closas, M; Garcia-Saenz, JA; Gaudet, MM; Giles, GG; Glendon, G; Godwin, AK; Goldberg, MS; Goldgar, DE; Gonzalez-Neira, A; Greene, MH; Gronwald, J; Guenel, P; Haiman, CA; Hall, P; Hamann, U; He, W; Heyworth, J; Hogervorst, FBL; Hollestelle, A; Hoover, RN; Hopper, JL; Hulick, PJ; Humphreys, K; Imyanitov, EN; Isaacs, C; Jakimovska, M; Jakubowska, A; James, PA; Janavicius, R; Jankowitz, RC

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

journal contribution

posted on 2025-05-09, 18:48 authored by Manuel A. Ferreira, Eric R. Gamazon, Fares Al-Ejeh, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Adalgeir Arason, Volker Arndt, Kristan J. Aronson, Banu K. Arun, Ella Asseryanis, Jacopo Azzollini, Judith Balmaña, Daniel R. Barnes, Daniel Barrowdale, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Katarzyna Bialkowska, John ForbesJohn Forbes, EM John, N Johnson, V Joseph, BY Karlan, E Khusnutdinova, J Kiiski, Y-D Ko, ME Jones, I Konstantopoulou, VN Kristensen, Y Laitman, D Lambrechts, C Lazaro, G Leslie, J Lester, F Lesueur, S Lindstrom, J Long, JT Loud, J Lubinski, E Makalic, A Mannermaa, M Manoochehri, S Margolin, T Maurer, D Mavroudis, L McGuffog, A Meindl, U Menon, K Michailidou, A Miller, M Montagna, F Moreno, L Moserle, AM Mulligan, KL Nathanson, SL Neuhausen, H Nevanlinna, I Nevelsteen, FC Nielsen, L Nikitina-Zake, RL Nussbaum, K Offit, E Olah, O Olopade, H Olsson, A Osorio, J Papp, T-W Park-Simon, MT Parsons, IS Pedersen, A Peixoto, P Peterlongo, PDP Pharoah, D Plaseska-Karanfilska, B Poppe, N Presneau, P Radice, J Rantala, G Rennert, HA Risch, E Saloustros, K Sanden, EJ Sawyer, MK Schmidt, RK Schmutzler, P Sharma, X-O Shu, J Simard, CF Singer, P Soucy, MC Southey, JJ Spinelli, AB Spurdle, J Stone, AJ Swerdlow, WJ Tapper, JA Taylor, MR Teixeira, MB Terry, A Teule, M Thomassen, K Thoene, DL Thull, M Tischkowitz, AE Toland, D Torres, T Truong, N Tung, CM Vachon, CJ van Asperen, AMW van den Ouweland, EJ van Rensburg, A Vega, A Viel, Q Wang, B Wappenschmidt, JN Weitzel, C Wendt, R Winqvist, Carl Blomqvist, XR Yang, D Yannoukakos, A Ziogas, P Kraft, AC Antoniou, W Zheng, DF Easton, RL Milne, J Beesley, G Chenevix-Trench, N Bogdanova, N Arnold, B Auber, N Bogdanova-Markov, J Borde, A Caliebe, N Ditsch, B Dworniczak, S Engert, U Faust, A Gehrig, SE Bojesen, E Hahnen, J Hauke, J Hentschel, N Herold, E Honisch, W Just, K Kast, M Larsen, J Lemke, PN Huu, MK Bolla, D Niederacher, C-E Ott, K Platzer, E Pohl-Rescigno, J Ramser, K Rhiem, D Steinemann, C Sutter, R Varon-Mateeva, S Wang-Gohrke, A Borg, BHF Weber, F Prieur, P Pujol, C Sagne, N Sevenet, H Sobol, J Sokolowska, D Stoppa-Lyonnet, L Venat-Bouvet, J Adlard, H Brauch, M Ahmed, J Barwell, A Brady, C Brewer, J Cook, R Davidson, A Donaldson, J Eason, R Eeles, DG Evans, H Brenner, H Gregory, H Hanson, A Henderson, S Hodgson, L Izatt, MJ Kennedy, F Lalloo, C Miller, PJ Morrison, K-R Ong, A Broeks, J Perkins, ME Porteous, MT Rogers, LE Side, K Snape, L Walker, PA Harrington, BAM Heemskerk-Gerritsen, MA Rookus, CM Seynaeve, B Burwinkel, FH van der Baan, AH van der Hout, LE van der Kolk, RB van der Luijt, CHM van Deurzen, HC van Doorn, K van Engelen, L van Hest, TAM van Os, S Verhoef, T Caldes, MJ Vogel, JT Wijnen, A Miron, M Kapuscinski, A Bane, E Ross, SS Buys, TA Conner, R Balleine, R Baxter, MA Caligo, S Braye, J Carpenter, J Dahlstrom, SC Lee, D Marsh, A Morey, N Pathmanathan, P Simpson, A Spigelman, D Campa, N Wilcken, D Yip, I Campbell, F Canzian, J Carter, BD Carter, JE Castelao, J Chang-Claude, SJ Chanock, H Christiansen, WK Chung, KBM Claes, CL Clarke, FJ Couch, A Cox, SS Cross, K Czene, MB Daly, M de la Hoya, J Dennis, P Devilee, O Diez, T Doerk, AM Dunning, M Dwek, DM Eccles, B Ejlertsen, C Ellberg, C Engel, M Eriksson, PA Fasching, O Fletcher, H Flyger, E Friedman, D Frost, M Gabrielson, M Gago-Dominguez, PA Ganz, SM Gapstur, J Garber, M Garcia-Closas, JA Garcia-Saenz, MM Gaudet, GG Giles, G Glendon, AK Godwin, MS Goldberg, DE Goldgar, A Gonzalez-Neira, MH Greene, J Gronwald, P Guenel, CA Haiman, P Hall, U Hamann, W He, J Heyworth, FBL Hogervorst, A Hollestelle, RN Hoover, JL Hopper, PJ Hulick, K Humphreys, EN Imyanitov, C Isaacs, M Jakimovska, A Jakubowska, PA James, R Janavicius, RC Jankowitz

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.

History

Journal title

Nature Communications

Volume

10

Article number

1741

Publisher

Nature Publishing Group

Place published

London

Language

en, English

College/Research Centre

Faculty of Health and Medicine

School

School of Medicine and Public Health

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