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. 2018 Jul;50(7):968-978.
doi: 10.1038/s41588-018-0132-x. Epub 2018 Jun 18.

A Transcriptome-Wide Association Study of 229,000 Women Identifies New Candidate Susceptibility Genes for Breast Cancer

Lang Wu  1 Wei Shi  2 Jirong Long  1 Xingyi Guo  1 Kyriaki Michailidou  3   4 Jonathan Beesley  2 Manjeet K Bolla  3 Xiao-Ou Shu  1 Yingchang Lu  1 Qiuyin Cai  1 Fares Al-Ejeh  2 Esdy Rozali  2 Qin Wang  3 Joe Dennis  3 Bingshan Li  5 Chenjie Zeng  1 Helian Feng  6   7 Alexander Gusev  8   9   10 Richard T Barfield  6 Irene L Andrulis  11   12 Hoda Anton-Culver  13 Volker Arndt  14 Kristan J Aronson  15 Paul L Auer  16   17 Myrto Barrdahl  18 Caroline Baynes  19 Matthias W Beckmann  20 Javier Benitez  21   22 Marina Bermisheva  23   24 Carl Blomqvist  25   26 Natalia V Bogdanova  24   27   28 Stig E Bojesen  29   30   31 Hiltrud Brauch  32   33   34 Hermann Brenner  14   34   35 Louise Brinton  36 Per Broberg  37 Sara Y Brucker  38 Barbara Burwinkel  39   40 Trinidad Caldés  41 Federico Canzian  42 Brian D Carter  43 J Esteban Castelao  44 Jenny Chang-Claude  18   45 Xiaoqing Chen  2 Ting-Yuan David Cheng  46 Hans Christiansen  27 Christine L Clarke  47 NBCS CollaboratorsMargriet Collée  48 Sten Cornelissen  49 Fergus J Couch  50 David Cox  51   52 Angela Cox  53 Simon S Cross  54 Julie M Cunningham  50 Kamila Czene  55 Mary B Daly  56 Peter Devilee  57   58 Kimberly F Doheny  59 Thilo Dörk  24 Isabel Dos-Santos-Silva  60 Martine Dumont  61 Miriam Dwek  62 Diana M Eccles  63 Ursula Eilber  18 A Heather Eliassen  7   64 Christoph Engel  65 Mikael Eriksson  55 Laura Fachal  19 Peter A Fasching  20   66 Jonine Figueroa  36   67 Dieter Flesch-Janys  68   69 Olivia Fletcher  70 Henrik Flyger  71 Lin Fritschi  72 Marike Gabrielson  55 Manuela Gago-Dominguez  73   74 Susan M Gapstur  43 Montserrat García-Closas  36 Mia M Gaudet  43 Maya Ghoussaini  19 Graham G Giles  75   76 Mark S Goldberg  77   78 David E Goldgar  79 Anna González-Neira  21 Pascal Guénel  80 Eric Hahnen  81   82   83 Christopher A Haiman  84 Niclas Håkansson  85 Per Hall  55   86 Emily Hallberg  87 Ute Hamann  88 Patricia Harrington  19 Alexander Hein  20 Belynda Hicks  89 Peter Hillemanns  24 Antoinette Hollestelle  90 Robert N Hoover  36 John L Hopper  76 Guanmengqian Huang  88 Keith Humphreys  55 David J Hunter  7   91 Anna Jakubowska  92   93 Wolfgang Janni  94 Esther M John  95   96   97 Nichola Johnson  70 Kristine Jones  89 Michael E Jones  98 Audrey Jung  18 Rudolf Kaaks  18 Michael J Kerin  99 Elza Khusnutdinova  97   100 Veli-Matti Kosma  101   102   103 Vessela N Kristensen  104   105   106 Diether Lambrechts  107   108 Loic Le Marchand  109 Jingmei Li  110 Sara Lindström  111   112 Jolanta Lissowska  113 Wing-Yee Lo  32   33 Sibylle Loibl  114 Jan Lubinski  90 Craig Luccarini  19 Michael P Lux  20 Robert J MacInnis  75   76 Tom Maishman  115 Ivana Maleva Kostovska  24   116 Arto Mannermaa  101   102   103 JoAnn E Manson  7   117 Sara Margolin  118 Dimitrios Mavroudis  119 Hanne Meijers-Heijboer  120 Alfons Meindl  121 Usha Menon  122 Jeffery Meyer  50 Anna Marie Mulligan  123   124 Susan L Neuhausen  125 Heli Nevanlinna  126 Patrick Neven  127 Sune F Nielsen  29   30 Børge G Nordestgaard  29   30   31 Olufunmilayo I Olopade  128 Janet E Olson  87 Håkan Olsson  37 Paolo Peterlongo  129 Julian Peto  60 Dijana Plaseska-Karanfilska  116 Ross Prentice  16 Nadege Presneau  62 Katri Pylkäs  130   131 Brigitte Rack  94 Paolo Radice  132 Nazneen Rahman  133 Gad Rennert  134 Hedy S Rennert  134 Valerie Rhenius  19 Atocha Romero  41   135 Jane Romm  59 Anja Rudolph  18 Emmanouil Saloustros  136 Dale P Sandler  137 Elinor J Sawyer  138 Marjanka K Schmidt  49   139 Rita K Schmutzler  81   82   83 Andreas Schneeweiss  39   140 Rodney J Scott  141   142 Christopher G Scott  87 Sheila Seal  133 Mitul Shah  19 Martha J Shrubsole  1 Ann Smeets  127 Melissa C Southey  143 John J Spinelli  144   145 Jennifer Stone  146   147 Harald Surowy  39   40 Anthony J Swerdlow  98   148 Rulla M Tamimi  6   7   64 William Tapper  63 Jack A Taylor  137   149 Mary Beth Terry  150 Daniel C Tessier  151 Abigail Thomas  87 Kathrin Thöne  45 Rob A E M Tollenaar  152 Diana Torres  88   153 Thérèse Truong  80 Michael Untch  154 Celine Vachon  87 David Van Den Berg  84 Daniel Vincent  151 Quinten Waisfisz  131 Clarice R Weinberg  155 Camilla Wendt  118 Alice S Whittemore  96   97 Hans Wildiers  127 Walter C Willett  7   64   156 Robert Winqvist  130   131 Alicja Wolk  85 Lucy Xia  84 Xiaohong R Yang  36 Argyrios Ziogas  13 Elad Ziv  157 kConFab/AOCS InvestigatorsAlison M Dunning  19 Paul D P Pharoah  3   19 Jacques Simard  61 Roger L Milne  75   76 Stacey L Edwards  2 Peter Kraft  6   7 Douglas F Easton  3   19 Georgia Chenevix-Trench  158 Wei Zheng  159
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Free PMC article

A Transcriptome-Wide Association Study of 229,000 Women Identifies New Candidate Susceptibility Genes for Breast Cancer

Lang Wu et al. Nat Genet. .
Free PMC article

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.

Conflict of interest statement

Competing financial interests

The authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.. Manhattan plot of association results from the breast cancer transcriptome-wide association study.
Results are based on 122,977 cases and 105,974 controls. The red line represents P = 5.82 × 10−6. The blue line represents P = 1.00 × 10−3.
Figure 2.
Figure 2.. Heat maps of proliferation and colony formation efficiency in breast cells.
(a) Proliferation efficiency. (b) colony formation efficiency. Error bars, SD (N=2). P-values were determined by one-way ANOVA followed by Dunnett’s multiple comparisons test: *P-value < 0.05. NTC: non-target control.

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