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Nat Genet. 2020 Jan;52(1):56-73. doi: 10.1038/s41588-019-0537-1. Epub 2020 Jan 7.

Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

Fachal L, Aschard H, Beesley J, Barnes DR, Allen J, Kar S, Pooley KA, Dennis J, Michailidou K, Turman C, Soucy P, Lemaçon A, Lush M, Tyrer JP, Ghoussaini M, Moradi Marjaneh M, Jiang X, Agata S, Aittomäki K, Alonso MR, Andrulis IL, Anton-Culver H, Antonenkova NN, Arason A, Arndt V, Aronson KJ, Arun BK, Auber B, Auer PL, Azzollini J, Balmaña J, Barkardottir RB, Barrowdale D, Beeghly-Fadiel A, Benitez J, Bermisheva M, Białkowska K, Blanco AM, Blomqvist C, Blot W, Bogdanova NV, Bojesen SE, Bolla MK, Bonanni B, Borg A, Bosse K, Brauch H, Brenner H, Briceno I, Brock IW, Brooks-Wilson A, Brüning T, Burwinkel B, Buys SS, Cai Q, Caldés T, Caligo MA, Camp NJ, Campbell I, Canzian F, Carroll JS, Carter BD, Castelao JE, Chiquette J, Christiansen H, Chung WK, Claes KBM, Clarke CL; GEMO Study Collaborators; EMBRACE Collaborators, Collée JM, Cornelissen S, Couch FJ, Cox A, Cross SS, Cybulski C, Czene K, Daly MB, de la Hoya M, Devilee P, Diez O, Ding YC, Dite GS, Domchek SM, Dörk T, Dos-Santos-Silva I, Droit A, Dubois S, Dumont M, Duran M, Durcan L, Dwek M, Eccles DM, Engel C, Eriksson M, Evans DG, Fasching PA, Fletcher O, Floris G, Flyger H, Foretova L, Foulkes WD, Friedman E, Fritschi L, Frost D, Gabrielson M, Gago-Dominguez M, Gambino G, Ganz PA, Gapstur SM, Garber J, García-Sáenz JA, Gaudet MM, Georgoulias V, Giles GG, Glendon G, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Tibiletti MG, Greene MH, Grip M, Gronwald J, Grundy A, Guénel P, Hahnen E, Haiman CA, Håkansson N, Hall P, Hamann U, Harrington PA, Hartikainen JM, Hartman M, He W, Healey CS, Heemskerk-Gerritsen BAM, Heyworth J, Hillemanns P, Hogervorst FBL, Hollestelle A, Hooning MJ, Hopper JL, Howell A, Huang G, Hulick PJ, Imyanitov EN; KConFab Investigators; HEBON Investigators; ABCTB Investigators, Isaacs C, Iwasaki M, Jager A, Jakimovska M, Jakubowska A, James PA, Janavicius R, Jankowitz RC, John EM, Johnson N, Jones ME, Jukkola-Vuorinen A, Jung A, Kaaks R, Kang D, Kapoor PM, Karlan BY, Keeman R, Kerin MJ, Khusnutdinova E, Kiiski JI, Kirk J, Kitahara CM, Ko YD, Konstantopoulou I, Kosma VM, Koutros S, Kubelka-Sabit K, Kwong A, Kyriacou K, Laitman Y, Lambrechts D, Lee E, Leslie G, Lester J, Lesueur F, Lindblom A, Lo WY, Long J, Lophatananon A, Loud JT, Lubiński J, MacInnis RJ, Maishman T, Makalic E, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Martinez ME, Matsuo K, Maurer T, Mavroudis D, Mayes R, McGuffog L, McLean C, Mebirouk N, Meindl A, Miller A, Miller N, Montagna M, Moreno F, Muir K, Mulligan AM, Muñoz-Garzon VM, Muranen TA, Narod SA, Nassir R, Nathanson KL, Neuhausen SL, Nevanlinna H, Neven P, Nielsen FC, Nikitina-Zake L, Norman A, Offit K, Olah E, Olopade OI, Olsson H, Orr N, Osorio A, Pankratz VS, Papp J, Park SK, Park-Simon TW, Parsons MT, Paul J, Pedersen IS, Peissel B, Peshkin B, Peterlongo P, Peto J, Plaseska-Karanfilska D, Prajzendanc K, Prentice R, Presneau N, Prokofyeva D, Pujana MA, Pylkäs K, Radice P, Ramus SJ, Rantala J, Rau-Murthy R, Rennert G, Risch HA, Robson M, Romero A, Rossing M, Saloustros E, Sánchez-Herrero E, Sandler DP, Santamariña M, Saunders C, Sawyer EJ, Scheuner MT, Schmidt DF, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schöttker B, Schürmann P, Scott C, Scott RJ, Senter L, Seynaeve CM, Shah M, Sharma P, Shen CY, Shu XO, Singer CF, Slavin TP, Smichkoska S, Southey MC, Spinelli JJ, Spurdle AB, Stone J, Stoppa-Lyonnet D, Sutter C, Swerdlow AJ, Tamimi RM, Tan YY, Tapper WJ, Taylor JA, Teixeira MR, Tengström M, Teo SH, Terry MB, Teulé A, Thomassen M, Thull DL, Tischkowitz M, Toland AE, Tollenaar RAEM, Tomlinson I, Torres D, Torres-Mejía G, Troester MA, Truong T, Tung N, Tzardi M, Ulmer HU, Vachon CM, van Asperen CJ, van der Kolk LE, van Rensburg EJ, Vega A, Viel A, Vijai J, Vogel MJ, Wang Q, Wappenschmidt B, Weinberg CR, Weitzel JN, Wendt C, Wildiers H, Winqvist R, Wolk A, Wu AH, Yannoukakos D, Zhang Y, Zheng W, Hunter D, Pharoah PDP, Chang-Claude J, García-Closas M, Schmidt MK, Milne RL, Kristensen VN, French JD, Edwards SL, Antoniou AC, Chenevix-Trench G, Simard J, Easton DF, Kraft P, Dunning AM.

Collaborators (230)

Mari V, Berthet P, Castera L, Vaur D, Lallaoui H, Bignon YJ, Uhrhammer N, Bonadona V, Lasset C, Révillion F, Vennin P, Muller D, Gomes DM, Ingster O, Coupier I, Pujol P, Collonge-Rame MA, Mortemousque I, Bera O, Rose M, Baurand A, Bertolone G, Faivre L, Dreyfus H, Leroux D, Venat-Bouvet L, Bézieau S, Delnatte C, Chiesa J, Gilbert-Dussardier B, Gesta P, Prieur FP, Bronner M, Sokolowska J, Coulet F, Boutry-Kryza N, Calender A, Giraud S, Leone M, Fert-Ferrer S, Stoppa-Lyonnet D, Jiao Y, Lesueur FL, Mebirouk N, Barouk-Simonet E, Bubien V, Longy M, Sevenet N, Gladieff L, Toulas C, Reimineras A, Sobol H, Paillerets BB, Cabaret O, Caron O, Guillaud-Bataille M, Rouleau E, Belotti M, Buecher B, Caputo S, Colas C, Pauw A, Fourme E, Gauthier-Villars M, Golmard L, Moncoutier V, Saule C, Donaldson A, Murray A, Brady A, Brewer C, Pottinger C, Miller C, Gallagher D, Gregory H, Cook J, Eason J, Adlard J, Barwell J, Ong KR, Snape K, Walker L, Izatt L, Side L, Tischkowitz M, Rogers MT, Porteous ME, Ahmed M, Morrison PJ, Brennan P, Eeles R, Davidson R, Sexton A, Christian A, Trainer A, Spigelman A, Fellows A, Shelling A, Fazio A, Blackburn A, Crook A, Meiser B, Patterson B, Clarke C, Saunders C, Hunt C, Scott C, Amor D, Marsh D, Edkins E, Salisbury E, Haan E, Neidermayr E, Macrea F, Farshid G, Lindeman G, Trench G, Mann G, Giles G, Gill G, Thorne H, Campbell I, Hickie I, Winship I, Flanagan J, Kollias J, Visvader J, Stone J, Taylor J, Burke J, Saunus J, Forbes J, Hopper J, Beesley J, Kirk J, French J, Tucker K, Wu K, Phillips K, Lipton L, Andrews L, Lobb L, Walker L, Kentwell M, Spurdle M, Cummings M, Gleeson M, Harris M, Jenkins M, Young MA, Delatycki M, Wallis M, Burgess M, Price M, Brown M, Southey M, Bogwitz M, Field M, Friedlander M, Gattas M, Saleh M, Hayward N, Pachter N, Cohen P, Duijf P, James P, Simpson P, Fong P, Butow P, Williams R, Kefford R, Scott R, Milne R, Balleine R, Dawson SJ, Lok S, O'Connell S, Greening S, Nightingale S, Edwards S, Fox S, McLachlan SA, Lakhani S, Antill Y, Aalfs C, Meijers-Heijboer H, van Engelen K, Gille H, Boere I, Collée M, van Deurzen C, Hooning M, Obdeijn IM, van den Ouweland A, Seynaeve C, Siesling S, Verloop J, van Asperen C, Devilee P, van Cronenburg T, Blok R, de Boer M, Garcia EG, Adank M, Hogervorst F, Jenner D, van Leeuwen F, Rookus M, Russell N, Schmidt M, van den Belt-Dusebout S, Kets C, Mensenkamp A, de Bock T, van der Hout A, Mourits M, Oosterwijk J, Ausems M, Koudijs M, Clarke C, Marsh D, Scott R, Baxter R, Yip D, Carpenter J, Davis A, Pathmanathan N, Simpson P, Graham D, Sachchithananthan M.

Abstract

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

PMID:
31911677
PMCID:
PMC6974400
[Available on 2020-07-07]
DOI:
10.1038/s41588-019-0537-1

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