Fine-mapping of 150 breast cancer risk regions identifies 178 high confidence target genes
Authors: Fachal Laura , Aschard Hugues , Beesley Jonathan , Barnes Daniel R. , Allen Jamie , Kar Siddhartha , Pooley Karen A. , Dennis Joe , Michailidou Kyriaki , Turman Constance , Soucy Penny , Lemaçon Audrey , Lush Michael , Tyrer Jonathan P. , Ghoussaini Maya , Marjaneh Mahdi Moradi , Jiang Xia , Agata Simona , Aittomäki Kristiina , Alonso M. Rosario , Andrulis Irene L. , Anton-Culver Hoda , Antonenkova Natalia N. , Arason Adalgeir , Arndt Volker , Aronson Kristan J. , Arun Banu K. , Auber Bernd , Auer Paul L. , Azzollini Jacopo , Balmaña Judith , Barkardottir Rosa B. , Barrowdale Daniel , Beeghly-Fadiel Alicia , Benitez Javier , Bermisheva Marina , Bialkowska Katarzyna , Blanco Amie M. , Blomqvist Carl , Blot William , Bogdanova Natalia V. , Bojesen Stig E. , Bolla Manjeet K. , Bonanni Bernardo , Borg Ake , Bosse Kristin , Brauch Hiltrud , Brenner Hermann , Briceno Ignacio , Brock Ian W. , Brooks-Wilson Angela , Brüning Thomas , Burwinkel Barbara , Buys Saundra S. , Cai Qiuyin , Caldés Trinidad , Caligo Maria A. , Camp Nicola J. , Campbell Ian , Canzian Federico , Carroll Jason S. , Carter Brian D. , Castelao Jose E. , Chiquette Jocelyne , Christiansen Hans , Chung Wendy K. , Claes Kathleen B.M. , Clarke Christine L. , Collaborators GEMO Study , Collaborators EMBRACE , Collée J. Margriet , Cornelissen Sten , Couch Fergus J. , Cox Angela , Cross Simon S. , Cybulski Cezary , Czene Kamila , Daly Mary B. , la Hoya Miguel de , Devilee Peter , Diez Orland , Ding Yuan Chun , Dite Gillian S. , Domchek Susan M. , Dörk Thilo , dos-Santos-Silva Isabel , Droit Arnaud , Dubois Stéphane , Dumont Martine , Duran Mercedes , Durcan Lorraine , Dwek Miriam , Eccles Diana M. , Engel Christoph , Eriksson Mikael , Evans D. Gareth , Fasching Peter A. , Fletcher Olivia , Floris Giuseppe , Flyger Henrik , Foretova Lenka , Foulkes William D. , Friedman Eitan , Fritschi Lin , Frost Debra , Gabrielson Marike , Gago-Dominguez Manuela , Gambino Gaetana , Ganz Patricia A. , Gapstur Susan M. , Garber Judy , García-Sáenz José A. , Gaudet Mia M. , Georgoulias Vassilios , Giles Graham G. , Glendon Gord , Godwin Andrew K. , Goldberg Mark S. , Goldgar David E. , González-Neira Anna , Greene Mark H. , Grip Mervi , Gronwald Jacek , Grundy Anne , Guénel Pascal , Hahnen Eric , Haiman Christopher A. , Håkansson Niclas , Hall Per , Hamann Ute , Harrington Patricia A. , Hartikainen Jaana M. , Hartman Mikael , He Wei , Healey Catherine S. , Heemskerk-Gerritsen Bernadette A.M. , Heyworth Jane , Hillemanns Peter , Hogervorst Frans B.L. , Hollestelle Antoinette , Hooning Maartje J. , Hopper John L. , Howell Anthony , Huang Guanmengqian , Hulick Peter J. , Imyanitov Evgeny N. ,   ABCTB Investigators,   KConFab Investigators,   HEBON Investigators, Isaacs Claudine , Iwasaki Motoki , Jager Agnes , Jakimovska Milena , Jakubowska Anna , James Paul , Janavicius Ramunas , Jankowitz Rachel C. , John Esther M. , Johnson Nichola , Jones Michael E. , Jukkola-Vuorinen Arja , Jung Audrey , Kaaks Rudolf , Kang Daehee , Karlan Beth Y. , Keeman Renske , Kerin Michael J. , Khusnutdinova Elza , Kiiski Johanna I. , Kirk Judy , Kitahara Cari M. , Ko Yon-Dschun , Konstantopoulou Irene , Kosma Veli-Matti , Koutros Stella , Kubelka-Sabit Katerina , Kwong Ava , Kyriacou Kyriacos , Laitman Yael , Lambrechts Diether , Lee Eunjung , Leslie Goska , Lester Jenny , Lesueur Fabienne , Lindblom Annika , Lo Wing-Yee , Long Jirong , Lophatananon Artitaya , Loud Jennifer T. , Lubinski Jan , MacInnis Robert J. , Maishman Tom , Makalic Enes , Mannermaa Arto , Manoochehri Mehdi , Manoukian Siranoush , Margolin Sara , Martinez Maria Elena , Matsuo Keitaro , Maurer Tabea , Mavroudis Dimitrios , Mayes Rebecca , McGuffog Lesley , McLean Catriona , Mebirouk Noura , Meindl Alfons , Middha Pooja , Miller Nicola , Miller Austin , Montagna Marco , Moreno Fernando , Mulligan Anna Marie , Muñoz-Garzon Victor M. , Muranen Taru A. , Narod Steven A. , Nassir Rami , Nathanson Katherine L. , Neuhausen Susan L. , Nevanlinna Heli , Neven Patrick , Nielsen Finn C. , Nikitina-Zake Liene , Norman Aaron , Offit Kenneth , Olah Edith , Olopade Olufunmilayo I. , Olsson Håkan , Orr Nick , Osorio Ana , Pankratz V. Shane , Papp Janos , Park Sue K. , Park-Simon Tjoung-Won , Parsons Michael T. , Paul James , Pedersen Inge Sokilde , Peissel Bernard , Peshkin Beth , Peterlongo Paolo , Peto Julian , Plaseska-Karanfilska Dijana , Prajzendanz Karolina , Prentice Ross , Presneau Nadege , Prokofyeva Darya , Pujana Miquel Angel , Pylkäs Katri , Radice Paolo , Ramus Susan J. , Rantala Johanna , Rau-Murthy Rohini , Rennert Gad , Risch Harvey A. , Robson Mark , Romero Atocha , Rossing Caroline Maria , Saloustros Emmanouil , Sánchez-Herrero Estela , Sandler Dale P. , Santamariña Marta , Saunders Christobel , Sawyer Elinor J. , Scheuner Maren T. , Schmidt Daniel F. , Schmutzler Rita K. , Schneeweiss Andreas , Schoemaker Minouk J. , Schöttker Ben , Schürmann Peter , Scott Christopher , Scott Rodney J. , Senter Leigha , Seynaeve Caroline MD , Shah Mitul , Sharma Priyanka , Shen Chen-Yang , Shu Xiao-Ou , Singer Christian F. , Slavin Thomas P. , Smichkoska Snezhana , Southey Melissa C. , Spinelli John J. , Spurdle Amanda B. , Stone Jennifer , Stoppa-Lyonnet Dominique , Sutter Christian , Swerdlow Anthony J. , Tamimi Rulla M. , Tan Yen Yen , Tapper William J. , Taylor Jack A. , Teixeira Manuel R. , Tengström Maria , Teo Soo H. , Terry Mary Beth , Teulé Alex , Thomassen Mads , Thull Darcy L. , Tibiletti Maria Grazia , Tischkowitz Marc , Toland Amanda E. , Tollenaar Rob A.E.M. , Tomlinson Ian , Torres Diana , Torres-Mejía Gabriela , Troester Melissa A. , Tung Nadine , Tzardi Maria , Ulmer Hans-Ulrich , Vachon Celine M. , van Asperen Christi J. , der Kolk Lizet E. van , van Rensburg Elizabeth J. , Vega Ana , Viel Alessandra , Vijai Joseph , Vogel Maatje J. , Wang Qin , Wappenschmidt Barbara , Weinberg Clarice R. , Weitzel Jeffrey N. , Wendt Camilla , Wildiers Hans , Winqvist Robert , Wolk Alicja , Wu Anna H. , Yannoukakos Drakoulis , Zhang Yan , Zheng Wei , Pharoah Paul D.P. , Chang-Claude Jenny , García-Closas Montserrat , Schmidt Marjanka K. , Milne Roger L. , Kristensen Vessela N. , French Juliet D. , Edwards Stacey L. , Antoniou Antonis C. , Chenevix-Trench Georgia , Simard Jacques , Easton Douglas F. , Kraft Peter , Dunning Alison M. 
Published: January 2019

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 within silicogenomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants (CCVs) 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 (HPPs) 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 potentially causal variants, using gene expression (eQTL), 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 178 highest confidence target genes.