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

Laura Fachal , Hugues Aschard (1) , Jonathan Beesley (2) , Daniel Barnes (3) , Jamie Allen (4) , Siddhartha Kar , Karen Pooley , Joe Dennis (3) , Kyriaki Michailidou (5) , Constance Turman (6) , 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 (7) , 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 , 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 , 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 , 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 (7) , 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

1 Département de Biologie Computationnelle - Department of Computational Biology
2 QIMR Berghofer Medical Research Institute
3 CAM - University of Cambridge [UK]
4 NSCAD
5 UCY - University of Cyprus [Nicosia]
6 Harvard T.H. Chan School of Public Health
7 CESP - Centre de recherche en épidémiologie et santé des populations

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.

Domains: Life Sciences [q-bio]; Genetics; Human genetics; Life Sciences [q-bio]; Santé publique et épidémiologie; Statistics [stat]; Methodology [stat.ME]; Statistics [stat]; Applications [stat.AP]; Computer Science [cs]; Bioinformatics [q-bio.QM]

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⟩