Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes - Institut Pasteur Access content directly
Journal Articles Nature Genetics Year : 2020

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

Laura Fachal (1) , Hugues Aschard (2, 3) , Jonathan Beesley (4) , Daniel Barnes (1) , Jamie Allen (1) , Siddhartha Kar , Karen Pooley , Joe Dennis (1) , Kyriaki Michailidou (5) , Constance Turman (3) , Penny Soucy , Audrey Lemaçon , Michael Lush , Jonathan Tyrer , Maya Ghoussaini , Mahdi Moradi Marjaneh , Xia Jiang , Simona Agata , Kristiina Aittomäki , M Rosario Alonso , Irene Andrulis , Hoda Anton-Culver , Natalia Antonenkova , Adalgeir Arason , Volker Arndt , Kristan Aronson , Banu Arun , Bernd Auber , Paul Auer , Jacopo Azzollini , Judith Balmaña , Rosa Barkardottir , Daniel Barrowdale , Alicia Beeghly-Fadiel , Javier Benitez , Marina Bermisheva , Katarzyna Białkowska , Amie Blanco , Carl Blomqvist , William Blot , Natalia Bogdanova , Stig Bojesen , Manjeet Bolla , Bernardo Bonanni , Ake Borg , Kristin Bosse , Hiltrud Brauch , Hermann Brenner , Ignacio Briceno , Ian Brock , Angela Brooks-Wilson , Thomas Brüning , Barbara Burwinkel , Saundra Buys , Qiuyin Cai , Trinidad Caldés , Maria Caligo , Nicola Camp , Ian Campbell , Federico Canzian , Jason Carroll , Brian Carter , Jose Castelao , Jocelyne Chiquette , Hans Christiansen , Wendy Chung , Kathleen Claes , Christine Clarke , J Margriet Collée , Sten Cornelissen , Fergus Couch , Angela Cox , Simon Cross , Cezary Cybulski , Kamila Czene , Mary Daly , Miguel de La Hoya , Peter Devilee , Orland Diez , Yuan Chun Ding , Gillian Dite , Susan Domchek , Thilo Dörk , Isabel Dos-Santos-Silva , Arnaud Droit , Stéphane Dubois , Martine Dumont , Mercedes Duran , Lorraine Durcan , Miriam Dwek , Diana Eccles , Christoph Engel , Mikael Eriksson , D Gareth Evans , Peter Fasching , Olivia Fletcher , Giuseppe Floris , Henrik Flyger , Lenka Foretova , William Foulkes , Eitan Friedman , Lin Fritschi , Debra Frost , Marike Gabrielson , Manuela Gago-Dominguez , Gaetana Gambino , Patricia Ganz , Susan Gapstur , Judy Garber , José García-Sáenz , Mia Gaudet , Vassilios Georgoulias , Graham Giles , Gord Glendon , Andrew Godwin , Mark Goldberg , David Goldgar , Anna González-Neira , Maria Grazia Tibiletti , Mark Greene , Mervi Grip , Jacek Gronwald , Anne Grundy , Pascal Guénel (6) , Eric Hahnen , Christopher Haiman , Niclas Håkansson , Per Hall , Ute Hamann , Patricia Harrington , Jaana Hartikainen , Mikael Hartman , Wei He , Catherine Healey , Bernadette Heemskerk-Gerritsen , Jane Heyworth , Peter Hillemanns , Frans Hogervorst , Antoinette Hollestelle , Maartje Hooning , John Hopper , Anthony Howell , Guanmengqian Huang , Peter Hulick , Evgeny Imyanitov , Claudine Isaacs , Motoki Iwasaki , Agnes Jager , Milena Jakimovska , Anna Jakubowska , Paul James , Ramunas Janavicius , Rachel Jankowitz , Esther John , Nichola Johnson , Michael Jones , Arja Jukkola-Vuorinen , Audrey Jung , Rudolf Kaaks , Daehee Kang , Pooja Middha Kapoor , Beth Karlan , Renske Keeman , Michael Kerin , Elza Khusnutdinova , Johanna Kiiski , Judy Kirk , Cari Kitahara , Yon-Dschun Ko , Irene Konstantopoulou , Veli-Matti Kosma , Stella Koutros , Katerina Kubelka-Sabit , Ava Kwong , Kyriacos Kyriacou , Yael Laitman , Diether Lambrechts , Eunjung Lee , Goska Leslie , Jenny Lester , Fabienne Lesueur (7, 8, 9) , Annika Lindblom , Wing-Yee Lo , Jirong Long , Artitaya Lophatananon , Jennifer Loud , Jan Lubiński , Robert Macinnis , Tom Maishman , Enes Makalic , Arto Mannermaa , Mehdi Manoochehri , Siranoush Manoukian , Sara Margolin , Maria Elena Martinez , Keitaro Matsuo , Tabea Maurer , Dimitrios Mavroudis , Rebecca Mayes , Lesley Mcguffog , Catriona Mclean , Noura Mebirouk (7, 8, 9, 10) , Alfons Meindl , Austin Miller , Nicola Miller , Marco Montagna , Fernando Moreno , Kenneth Muir , Anna Marie Mulligan , Victor Muñoz-Garzon , Taru Muranen , Steven Narod , Rami Nassir , Katherine Nathanson , Susan Neuhausen , Heli Nevanlinna , Patrick Neven , Finn Nielsen , Liene Nikitina-Zake , Aaron Norman , Kenneth Offit , Edith Olah , Olufunmilayo Olopade , Håkan Olsson , Nick Orr , Ana Osorio , V Shane Pankratz , Janos Papp , Sue Park , Tjoung-Won Park-Simon , Michael Parsons , James Paul , Inge Sokilde Pedersen , Bernard Peissel , Beth Peshkin , Paolo Peterlongo , Julian Peto , Dijana Plaseska-Karanfilska , Karolina Prajzendanc , Ross Prentice , Nadege Presneau , Darya Prokofyeva , Miquel Angel Pujana , Katri Pylkäs , Paolo Radice , Susan Ramus , Johanna Rantala , Rohini Rau-Murthy , Gad Rennert , Harvey Risch , Mark Robson , Atocha Romero , Maria Rossing , Emmanouil Saloustros , Estela Sánchez-Herrero , Dale Sandler , Marta Santamariña , Christobel Saunders , Elinor Sawyer , Maren Scheuner , Daniel Schmidt , Rita Schmutzler , Andreas Schneeweiss , Minouk Schoemaker , Ben Schöttker , Peter Schürmann , Christopher Scott , Rodney Scott , Leigha Senter , Caroline Seynaeve , Mitul Shah , Priyanka Sharma , Chen-Yang Shen , Xiao-Ou Shu , Christian Singer , Thomas Slavin , Snezhana Smichkoska , Melissa Southey , John Spinelli , Amanda Spurdle , Jennifer Stone , Dominique Stoppa-Lyonnet (10, 7, 11) , Christian Sutter , Anthony Swerdlow , Rulla Tamimi , Yen Yen Tan , William Tapper , Jack Taylor , Manuel Teixeira , Maria Tengström , Soo Hwang Teo , Mary Beth Terry , Alex Teulé , Mads Thomassen , Darcy Thull , Marc Tischkowitz , Amanda Toland , Rob Tollenaar , Ian Tomlinson , Diana Torres , Gabriela Torres-Mejía , Melissa Troester , Thérèse Truong (6) , Nadine Tung , Maria Tzardi , Hans-Ulrich Ulmer , Celine Vachon , Christi van Asperen , Lizet van Der Kolk , Elizabeth van Rensburg , Ana Vega , Alessandra Viel , Joseph Vijai , Maartje Vogel , Qin Wang , Barbara Wappenschmidt , Clarice Weinberg , Jeffrey Weitzel , Camilla Wendt , Hans Wildiers , Robert Winqvist , Alicja Wolk , Anna Wu , Drakoulis Yannoukakos , Yan Zhang , Wei Zheng , David Hunter , Paul Pharoah , Jenny Chang-Claude , Montserrat García-Closas , Marjanka Schmidt , Roger Milne , Vessela Kristensen , Juliet French , Stacey Edwards , Antonis Antoniou , Georgia Chenevix-Trench , Jacques Simard , Douglas Easton , Peter Kraft , Alison Dunning , M. Rosario Alonso , J. Margriet Collée , D. Gareth Evans , V. Shane Pankratz
Daniel Barnes
Siddhartha Kar
  • Function : Author
Karen Pooley
  • Function : Author
Joe Dennis
Penny Soucy
  • Function : Author
Audrey Lemaçon
  • Function : Author
Michael Lush
  • Function : Author
Jonathan Tyrer
Maya Ghoussaini
  • Function : Author
Mahdi Moradi Marjaneh
  • Function : Author
Xia Jiang
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Simona Agata
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Kristiina Aittomäki
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M Rosario Alonso
  • Function : Author
Irene Andrulis
Hoda Anton-Culver
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Natalia Antonenkova
  • Function : Author
Adalgeir Arason
  • Function : Author
Volker Arndt
Kristan Aronson
  • Function : Author
Banu Arun
  • Function : Author
Bernd Auber
  • Function : Author
Paul Auer
  • Function : Author
Jacopo Azzollini
Judith Balmaña
  • Function : Author
Rosa Barkardottir
  • Function : Author
Daniel Barrowdale
Alicia Beeghly-Fadiel
  • Function : Author
Javier Benitez
  • Function : Author
Marina Bermisheva
  • Function : Author
Katarzyna Białkowska
  • Function : Author
Amie Blanco
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Carl Blomqvist
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William Blot
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Natalia Bogdanova
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Stig Bojesen
Manjeet Bolla
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Bernardo Bonanni
Ake Borg
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Kristin Bosse
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Hiltrud Brauch
Hermann Brenner
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Ignacio Briceno
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Ian Brock
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Angela Brooks-Wilson
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Thomas Brüning
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Barbara Burwinkel
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Saundra Buys
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Qiuyin Cai
  • Function : Author
Trinidad Caldés
Maria Caligo
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Nicola Camp
  • Function : Author
Ian Campbell
  • Function : Author
Federico Canzian
Jason Carroll
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Brian Carter
  • Function : Author
Jose Castelao
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Jocelyne Chiquette
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Hans Christiansen
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Wendy Chung
Kathleen Claes
Christine Clarke
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J Margriet Collée
  • Function : Author
Sten Cornelissen
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Fergus Couch
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Angela Cox
  • Function : Author
Simon Cross
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Cezary Cybulski
  • Function : Author
Kamila Czene
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Mary Daly
  • Function : Author
Miguel de La Hoya
  • Function : Author
Peter Devilee
Orland Diez
  • Function : Author
Yuan Chun Ding
  • Function : Author
Gillian Dite
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Susan Domchek
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Thilo Dörk
Isabel Dos-Santos-Silva
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Arnaud Droit
Stéphane Dubois
  • Function : Author
Martine Dumont
  • Function : Author
Mercedes Duran
  • Function : Author
Lorraine Durcan
  • Function : Author
Miriam Dwek
Diana Eccles
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Christoph Engel
  • Function : Author
Mikael Eriksson
  • Function : Author
D Gareth Evans
  • Function : Author
Peter Fasching
  • Function : Author
Olivia Fletcher
  • Function : Author
Giuseppe Floris
  • Function : Author
Henrik Flyger
  • Function : Author
Lenka Foretova
  • Function : Author
William Foulkes
Eitan Friedman
  • Function : Author
Lin Fritschi
Debra Frost
  • Function : Author
Marike Gabrielson
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Manuela Gago-Dominguez
  • Function : Author
Gaetana Gambino
  • Function : Author
Patricia Ganz
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Susan Gapstur
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Judy Garber
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José García-Sáenz
Mia Gaudet
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Vassilios Georgoulias
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Graham Giles
Gord Glendon
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Andrew Godwin
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Mark Goldberg
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David Goldgar
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Anna González-Neira
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Maria Grazia Tibiletti
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Mark Greene
Mervi Grip
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Jacek Gronwald
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Anne Grundy
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Eric Hahnen
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Christopher Haiman
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Niclas Håkansson
Per Hall
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Ute Hamann
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Patricia Harrington
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Jaana Hartikainen
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Mikael Hartman
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Wei He
Catherine Healey
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Bernadette Heemskerk-Gerritsen
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Jane Heyworth
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Peter Hillemanns
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Frans Hogervorst
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Antoinette Hollestelle
Maartje Hooning
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John Hopper
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Anthony Howell
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Guanmengqian Huang
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Peter Hulick
Evgeny Imyanitov
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Claudine Isaacs
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Motoki Iwasaki
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Agnes Jager
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Milena Jakimovska
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Anna Jakubowska
Paul James
Ramunas Janavicius
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Rachel Jankowitz
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Esther John
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Nichola Johnson
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Michael Jones
Arja Jukkola-Vuorinen
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Audrey Jung
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Rudolf Kaaks
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Daehee Kang
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Pooja Middha Kapoor
Beth Karlan
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Renske Keeman
Michael Kerin
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Elza Khusnutdinova
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Johanna Kiiski
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Judy Kirk
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Cari Kitahara
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Yon-Dschun Ko
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Irene Konstantopoulou
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Veli-Matti Kosma
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Stella Koutros
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Katerina Kubelka-Sabit
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Ava Kwong
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Kyriacos Kyriacou
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Yael Laitman
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Diether Lambrechts
Eunjung Lee
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Goska Leslie
Jenny Lester
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Annika Lindblom
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Wing-Yee Lo
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Jirong Long
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Artitaya Lophatananon
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Jennifer Loud
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Jan Lubiński
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Robert Macinnis
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Tom Maishman
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Enes Makalic
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Arto Mannermaa
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Mehdi Manoochehri
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Siranoush Manoukian
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Sara Margolin
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Maria Elena Martinez
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Keitaro Matsuo
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Tabea Maurer
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Dimitrios Mavroudis
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Rebecca Mayes
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Lesley Mcguffog
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Catriona Mclean
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Alfons Meindl
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Austin Miller
Nicola Miller
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Marco Montagna
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Fernando Moreno
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Kenneth Muir
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Anna Marie Mulligan
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Victor Muñoz-Garzon
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Taru Muranen
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Steven Narod
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Rami Nassir
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Katherine Nathanson
Susan Neuhausen
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Heli Nevanlinna
Patrick Neven
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Finn Nielsen
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Liene Nikitina-Zake
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Aaron Norman
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Kenneth Offit
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Edith Olah
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Olufunmilayo Olopade
Håkan Olsson
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Nick Orr
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Ana Osorio
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V Shane Pankratz
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Janos Papp
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Sue Park
Tjoung-Won Park-Simon
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Michael Parsons
James Paul
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Inge Sokilde Pedersen
Bernard Peissel
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Beth Peshkin
Paolo Peterlongo
Julian Peto
Dijana Plaseska-Karanfilska
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Karolina Prajzendanc
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Ross Prentice
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Nadege Presneau
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Darya Prokofyeva
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Miquel Angel Pujana
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Katri Pylkäs
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Paolo Radice
Susan Ramus
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Johanna Rantala
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Rohini Rau-Murthy
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Gad Rennert
Harvey Risch
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Mark Robson
Atocha Romero
Maria Rossing
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Emmanouil Saloustros
Estela Sánchez-Herrero
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Dale Sandler
Marta Santamariña
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Christobel Saunders
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Elinor Sawyer
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Maren Scheuner
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Daniel Schmidt
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Rita Schmutzler
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Andreas Schneeweiss
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Minouk Schoemaker
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Ben Schöttker
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Peter Schürmann
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Christopher Scott
Rodney Scott
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Leigha Senter
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Caroline Seynaeve
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Mitul Shah
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Priyanka Sharma
Chen-Yang Shen
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Xiao-Ou Shu
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Christian Singer
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Thomas Slavin
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Snezhana Smichkoska
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Melissa Southey
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John Spinelli
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Amanda Spurdle
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Jennifer Stone
Christian Sutter
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Anthony Swerdlow
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Rulla Tamimi
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Yen Yen Tan
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William Tapper
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Jack Taylor
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Manuel Teixeira
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Maria Tengström
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Soo Hwang Teo
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Mary Beth Terry
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Alex Teulé
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Mads Thomassen
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Darcy Thull
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Marc Tischkowitz
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Amanda Toland
Rob Tollenaar
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Ian Tomlinson
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Diana Torres
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Gabriela Torres-Mejía
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Melissa Troester
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Nadine Tung
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Maria Tzardi
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Hans-Ulrich Ulmer
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Celine Vachon
Christi van Asperen
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Lizet van Der Kolk
  • Function : Author
Elizabeth van Rensburg
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Ana Vega
Alessandra Viel
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Joseph Vijai
Maartje Vogel
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Qin Wang
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Barbara Wappenschmidt
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Clarice Weinberg
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Jeffrey Weitzel
Camilla Wendt
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Hans Wildiers
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Robert Winqvist
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Alicja Wolk
Anna Wu
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Drakoulis Yannoukakos
Yan Zhang
Wei Zheng
David Hunter
Paul Pharoah
Jenny Chang-Claude
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Montserrat García-Closas
Marjanka Schmidt
Roger Milne
Vessela Kristensen
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Juliet French
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Stacey Edwards
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Antonis Antoniou
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Georgia Chenevix-Trench
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Jacques Simard
Douglas Easton
Peter Kraft
Alison Dunning
M. Rosario Alonso
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J. Margriet Collée
D. Gareth Evans
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V. Shane Pankratz
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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.
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Dates and versions

pasteur-03278553 , version 1 (26-01-2024)

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Laura Fachal, Hugues Aschard, Jonathan Beesley, Daniel Barnes, Jamie Allen, et al.. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes. Nature Genetics, 2020, 52 (1), pp.56-73. ⟨10.1038/s41588-019-0537-1⟩. ⟨pasteur-03278553⟩
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