Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants.

Authors:
Ali Amin Olama, PhD
Ali Amin Olama, PhD
University Of Cambridge
Dr.
Cambridge | United Kingdom
Tokhir Dadaev Edward J Saunders Paul J Newcombe Ezequiel Anokian Daniel A Leongamornlert Mark N Brook Clara Cieza-Borrella Martina Mijuskovic Sarah Wakerell Ali Amin Al Olama Fredrick R Schumacher Sonja I Berndt Sara Benlloch Mahbubl Ahmed Chee Goh Xin Sheng Zhuo Zhang Kenneth Muir Koveela Govindasami Artitaya Lophatananon Victoria L Stevens Susan M Gapstur Brian D Carter Catherine M Tangen Phyllis Goodman Ian M Thompson Jyotsna Batra Suzanne Chambers Leire Moya Judith Clements Lisa Horvath Wayne Tilley Gail Risbridger Henrik Gronberg Markus Aly Tobias Nordström Paul Pharoah Nora Pashayan Johanna Schleutker Teuvo L J Tammela Csilla Sipeky Anssi Auvinen Demetrius Albanes Stephanie Weinstein Alicja Wolk Niclas Hakansson Catharine West Alison M Dunning Neil Burnet Lorelei Mucci Edward Giovannucci Gerald Andriole Olivier Cussenot Géraldine Cancel-Tassin Stella Koutros Laura E Beane Freeman Karina Dalsgaard Sorensen Torben Falck Orntoft Michael Borre Lovise Maehle Eli Marie Grindedal David E Neal Jenny L Donovan Freddie C Hamdy Richard M Martin Ruth C Travis Tim J Key Robert J Hamilton Neil E Fleshner Antonio Finelli Sue Ann Ingles Mariana C Stern Barry Rosenstein Sarah Kerns Harry Ostrer Yong-Jie Lu Hong-Wei Zhang Ninghan Feng Xueying Mao Xin Guo Guomin Wang Zan Sun Graham G Giles Melissa C Southey Robert J MacInnis Liesel M FitzGerald Adam S Kibel Bettina F Drake Ana Vega Antonio Gómez-Caamaño Laura Fachal Robert Szulkin Martin Eklund Manolis Kogevinas Javier Llorca Gemma Castaño-Vinyals Kathryn L Penney Meir Stampfer Jong Y Park Thomas A Sellers Hui-Yi Lin Janet L Stanford Cezary Cybulski Dominika Wokolorczyk Jan Lubinski Elaine A Ostrander Milan S Geybels Børge G Nordestgaard Sune F Nielsen Maren Weisher Rasmus Bisbjerg Martin Andreas Røder Peter Iversen Hermann Brenner Katarina Cuk Bernd Holleczek Christiane Maier Manuel Luedeke Thomas Schnoeller Jeri Kim Christopher J Logothetis Esther M John Manuel R Teixeira Paula Paulo Marta Cardoso Susan L Neuhausen Linda Steele Yuan Chun Ding Kim De Ruyck Gert De Meerleer Piet Ost Azad Razack Jasmine Lim Soo-Hwang Teo Daniel W Lin Lisa F Newcomb Davor Lessel Marija Gamulin Tomislav Kulis Radka Kaneva Nawaid Usmani Chavdar Slavov Vanio Mitev Matthew Parliament Sandeep Singhal Frank Claessens Steven Joniau Thomas Van den Broeck Samantha Larkin Paul A Townsend Claire Aukim-Hastie Manuela Gago-Dominguez Jose Esteban Castelao Maria Elena Martinez Monique J Roobol Guido Jenster Ron H N van Schaik Florence Menegaux Thérèse Truong Yves Akoli Koudou Jianfeng Xu Kay-Tee Khaw Lisa Cannon-Albright Hardev Pandha Agnieszka Michael Andrzej Kierzek Stephen N Thibodeau Shannon K McDonnell Daniel J Schaid Sara Lindstrom Constance Turman Jing Ma David J Hunter Elio Riboli Afshan Siddiq Federico Canzian Laurence N Kolonel Loic Le Marchand Robert N Hoover Mitchell J Machiela Peter Kraft Matthew Freedman Fredrik Wiklund Stephen Chanock Brian E Henderson Douglas F Easton Christopher A Haiman Rosalind A Eeles David V Conti Zsofia Kote-Jarai

Nat Commun 2018 06 11;9(1):2256. Epub 2018 Jun 11.

The Institute of Cancer Research, London, SW7 3RP, UK.

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-04109-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995836PMC
June 2018
151 Reads
2 Citations
10.742 Impact Factor

Publication Analysis

Top Keywords

prostate cancer
20
susceptibility loci
8
cancer susceptibility
8
candidate variants
8
cancer
5
replaced candidates
4
candidates biological
4
remainder replaced
4
identified remainder
4
variants identified
4
biological annotation
4
set variants
4
enrichment promoter
4
promoter enhancer
4
indicates enrichment
4
variants indicates
4
credible set
4
catalogue candidate
4
annotation credible
4
tag snps
4

References

(Supplied by CrossRef)
Article in Br. J. Cancer
Z Kote-Jarai et al.
Br. J. Cancer 2011
Article in N. Engl. J. Med.
CC Pritchard et al.
N. Engl. J. Med. 2016
Article in Future Oncol.
C Mikropoulos et al.
Future Oncol. 2014
Article in Genet. Epidemiol.
DV Conti et al.
Genet. Epidemiol. 2004
Article in Genet. Epidemiol.
BL Fridley et al.
Genet. Epidemiol. 2009
Article in Stat. Med.
V Viallefont et al.
Stat. Med. 2001
Article in PLoS Genet.
C Wallace et al.
PLoS Genet. 2015
Article in N. Engl. J. Med.
CM Ewing et al.
N. Engl. J. Med. 2012
Article in PLoS Genet.
EJ Saunders et al.
PLoS Genet. 2014
Article in Nat. Genet.
S Akamatsu et al.
Nat. Genet. 2012

Similar Publications