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. 2019 Apr 15;10(1):1741.
doi: 10.1038/s41467-018-08053-5.

Genome-wide Association and Transcriptome Studies Identify Target Genes and Risk Loci for Breast Cancer

Manuel A Ferreira  1 Eric R Gamazon  2   3 Fares Al-Ejeh  4 Kristiina Aittomäki  5 Irene L Andrulis  6   7 Hoda Anton-Culver  8 Adalgeir Arason  9   10 Volker Arndt  11 Kristan J Aronson  12 Banu K Arun  13 Ella Asseryanis  14 Jacopo Azzollini  15 Judith Balmaña  16   17 Daniel R Barnes  18 Daniel Barrowdale  18 Matthias W Beckmann  19 Sabine Behrens  20 Javier Benitez  21   22 Marina Bermisheva  23 Katarzyna Białkowska  24 Carl Blomqvist  25   26 Natalia V Bogdanova  27   28   29 Stig E Bojesen  30   31   32 Manjeet K Bolla  18 Ake Borg  33 Hiltrud Brauch  34   35   36 Hermann Brenner  11   36   37 Annegien Broeks  38 Barbara Burwinkel  39   40 Trinidad Caldés  41 Maria A Caligo  42 Daniele Campa  20   43 Ian Campbell  44   45 Federico Canzian  46 Jonathan Carter  47 Brian D Carter  48 Jose E Castelao  49 Jenny Chang-Claude  20   50 Stephen J Chanock  51 Hans Christiansen  27 Wendy K Chung  52 Kathleen B M Claes  53 Christine L Clarke  54 EMBRACE CollaboratorsGC-HBOC Study CollaboratorsGEMO Study CollaboratorsFergus J Couch  55 Angela Cox  56 Simon S Cross  57 Kamila Czene  58 Mary B Daly  59 Miguel de la Hoya  41 Joe Dennis  18 Peter Devilee  60   61 Orland Diez  16   62 Thilo Dörk  28 Alison M Dunning  63 Miriam Dwek  64 Diana M Eccles  65 Bent Ejlertsen  66 Carolina Ellberg  67 Christoph Engel  68 Mikael Eriksson  58 Peter A Fasching  19   69 Olivia Fletcher  70 Henrik Flyger  71 Eitan Friedman  72   73 Debra Frost  18 Marike Gabrielson  58 Manuela Gago-Dominguez  74   75 Patricia A Ganz  76 Susan M Gapstur  48 Judy Garber  77 Montserrat García-Closas  51   78 José A García-Sáenz  79 Mia M Gaudet  48 Graham G Giles  80   81   82 Gord Glendon  6 Andrew K Godwin  83 Mark S Goldberg  84   85 David E Goldgar  86 Anna González-Neira  22 Mark H Greene  87 Jacek Gronwald  24 Pascal Guénel  88 Christopher A Haiman  89 Per Hall  58   90 Ute Hamann  91 Wei He  58 Jane Heyworth  92 Frans B L Hogervorst  93 Antoinette Hollestelle  94 Robert N Hoover  51 John L Hopper  81 Peter J Hulick  95   96 Keith Humphreys  58 Evgeny N Imyanitov  97 ABCTB InvestigatorsHEBON InvestigatorsBCFR InvestigatorsClaudine Isaacs  98 Milena Jakimovska  99 Anna Jakubowska  24   100 Paul A James  45   101 Ramunas Janavicius  102 Rachel C Jankowitz  103 Esther M John  104 Nichola Johnson  70 Vijai Joseph  105 Beth Y Karlan  106 Elza Khusnutdinova  23   107 Johanna I Kiiski  108 Yon-Dschun Ko  109 Michael E Jones  110 Irene Konstantopoulou  111 Vessela N Kristensen  112   113 Yael Laitman  72 Diether Lambrechts  114   115 Conxi Lazaro  116 Goska Leslie  18 Jenny Lester  106 Fabienne Lesueur  117   118   119 Sara Lindström  120   121 Jirong Long  122 Jennifer T Loud  87 Jan Lubiński  24 Enes Makalic  81 Arto Mannermaa  123   124   125 Mehdi Manoochehri  91 Sara Margolin  90   126 Tabea Maurer  50 Dimitrios Mavroudis  127 Lesley McGuffog  18 Alfons Meindl  128 Usha Menon  129 Kyriaki Michailidou  18   130 Austin Miller  131 Marco Montagna  132 Fernando Moreno  79 Lidia Moserle  132 Anna Marie Mulligan  133   134 Katherine L Nathanson  135 Susan L Neuhausen  136 Heli Nevanlinna  108 Ines Nevelsteen  137 Finn C Nielsen  138 Liene Nikitina-Zake  139 Robert L Nussbaum  140 Kenneth Offit  105   141 Edith Olah  142 Olufunmilayo I Olopade  143 Håkan Olsson  67 Ana Osorio  21   22 Janos Papp  142 Tjoung-Won Park-Simon  28 Michael T Parsons  4 Inge Sokilde Pedersen  144   145   146 Ana Peixoto  147 Paolo Peterlongo  148 Paul D P Pharoah  18   63 Dijana Plaseska-Karanfilska  99 Bruce Poppe  53 Nadege Presneau  64 Paolo Radice  149 Johanna Rantala  150 Gad Rennert  151 Harvey A Risch  152 Emmanouil Saloustros  153 Kristin Sanden  154 Elinor J Sawyer  155 Marjanka K Schmidt  38   156 Rita K Schmutzler  157   158 Priyanka Sharma  159 Xiao-Ou Shu  122 Jacques Simard  160 Christian F Singer  14 Penny Soucy  160 Melissa C Southey  161   162 John J Spinelli  163   164 Amanda B Spurdle  4 Jennifer Stone  81   165 Anthony J Swerdlow  110   166 William J Tapper  65 Jack A Taylor  167   168 Manuel R Teixeira  147   169 Mary Beth Terry  170 Alex Teulé  171 Mads Thomassen  172 Kathrin Thöne  50 Darcy L Thull  173 Marc Tischkowitz  174   175 Amanda E Toland  176 Diana Torres  91   177 Thérèse Truong  88 Nadine Tung  178 Celine M Vachon  179 Christi J van Asperen  180 Ans M W van den Ouweland  181 Elizabeth J van Rensburg  182 Ana Vega  183 Alessandra Viel  184 Qin Wang  18 Barbara Wappenschmidt  157   158 Jeffrey N Weitzel  185 Camilla Wendt  126 Robert Winqvist  186   187 Xiaohong R Yang  51 Drakoulis Yannoukakos  111 Argyrios Ziogas  8 Peter Kraft  188   189 Antonis C Antoniou  18 Wei Zheng  122 Douglas F Easton  18   63 Roger L Milne  80   81   161 Jonathan Beesley  4 Georgia Chenevix-Trench  4
Collaborators, Affiliations
Free PMC article

Genome-wide Association and Transcriptome Studies Identify Target Genes and Risk Loci for Breast Cancer

Manuel A Ferreira et al. Nat Commun. .
Free PMC article

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.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Examples of previously unreported target gene predictions at known breast cancer risk loci. Variants are represented by points colored according to the LD with the sentinel risk variant (red: ≥0.8, orange: 0.6–0.8, green: 0.4–0.6, light blue: 0.2–0.4, and dark blue: <0.2). Sentinel risk variants (triangles) were identified based on joint association analysis. Figure shows on the y-axis the evidence for breast cancer association (−log10 of the P-value in the original published GWAS results, obtained in that study using an inverse-variance meta-analysis), and on the x-axis chromosomal position. Gene structures from GENCODE v19 gene annotations are shown and the predicted target genes shown in red. a The sentinel risk variant at this locus (rs875311) was in LD with sentinel eQTL for CFL1 (in whole blood) and for EFEMP2 (in CD8+ T cells only). b The sentinel risk variant (rs11049425, target gene: CCDC91) represents a secondary association signal in this region. c The sentinel risk variant at this locus (rs8105994) is in LD with sentinel eQTL for two previously unreported target gene predictions (AC010335.1 and LRRC25) and four previously predicted targets (CTD-3137H5.1ELLPGPEP1 and SSBP4; (Supplementary Data 5). Regional association plots for the remaining target gene predictions for overall breast cancer (Supplementary Data 3) are provided in Supplementary Figure 1
Fig. 2
Fig. 2
Manhattan plots summarizing association results for overall breast cancer. a Association results (−log10 of the P-value obtained using an inverse-variance meta- analysis) from the single-variant GWAS originally reported by Michailidou et al.. b Single-variant GWAS adjusted for 212 sentinel risk variants and LD-score intercept; P-values were obtained with the GCTA-COJO joint analysis. c Gene-based analysis of adjusted GWAS results; P-values were obtained with the EUGENE gene-based test of association
Fig. 3
Fig. 3
Examples of significant gene-based associations at loci not previously reported in breast cancer GWAS. Variants are represented by points colored according to the LD with the sentinel risk variant (red: ≥0.8, orange: 0.6–0.8, green: 0.4–0.6, light blue: 0.2–0.4, and dark blue: <0.2). Sentinel eQTL included in the EUGENE analysis (triangles) were identified from published eQTL studies of five different tissue types. Figure shows on the y-axis the evidence for breast cancer association (−log10 of the P-value in the published GWAS after adjusting for the association with the sentinel risk variants using the COJO-COND test, and the LD-score intercept), and on the x-axis chromosomal position. The sentinel eQTL most associated with breast cancer risk is depicted by a black triangle; other sentinel eQTL included in the gene-based test are depicted by red triangles. Gene structures from GENCODE v19 gene annotations are shown and the predicted target genes shown in red. ac show examples of three previously unreported loci which respectively implicate PPP2R1B, IMP3 and GSTM2 as candidate breast cancer susceptibility genes. Regional association plots for the remaining eight gene- based associations are provided in Supplementary Figure 2
Fig. 4
Fig. 4
Examples of previously unreported target gene predictions at known ER- negative breast cancer risk loci. Variants are represented by points colored according to the LD with the sentinel risk variant (red: ≥0.8, orange: 0.6–0.8, green: 0.4–0.6, light blue: 0.2–0.4, and dark blue: <0.2). Sentinel risk variants (triangles) were identified based on joint association analysis. Figure shows on the y-axis the evidence for ER-negative breast cancer association (−log10 of the P-value in the original published GWAS results, obtained in that study using an inverse-variance meta-analysis), and on the x-axis chromosomal position. Gene structures from GENCODE v19 gene annotations are shown and the predicted target genes shown in red. The sentinel risk variants are in LD with sentinel eQTL for MDM4 and PIK3C2B (a), ZNF703 (b), and ATM (c; Supplementary Data 17). Regional association plots for the remaining 14 previously unreported target gene predictions are provided in Supplementary Figure 3

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