Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium.

Roger L Milne; Barbara Burwinkel; Kyriaki Michailidou; Jose-Ignacio Arias-Perez; M Pilar Zamora; Primitiva Menéndez-Rodríguez; David Hardisson; Marta Mendiola; Anna González-Neira; Guillermo Pita; +171 more... M Rosario Alonso; Joe Dennis; Qin Wang; Manjeet K Bolla; Anthony Swerdlow; Alan Ashworth; Nick Orr; Minouk Schoemaker; Yon-Dschun Ko; Hiltrud Brauch; Ute Hamann; GENICA Network; Irene L Andrulis; Julia A Knight; Gord Glendon; Sandrine Tchatchou; kConFab Investigators; Australian Ovarian Cancer Study Group; Keitaro Matsuo; Hidemi Ito; Hiroji Iwata; Kazuo Tajima; Jingmei Li; Judith S Brand; Hermann Brenner; Aida Karina Dieffenbach; Volker Arndt; Christa Stegmaier; Diether Lambrechts; Gilian Peuteman; Marie-Rose Christiaens; Ann Smeets; Anna Jakubowska; Jan Lubinski; Katarzyna Jaworska-Bieniek; Katazyna Durda; Mikael Hartman; Miao Hui; Wei Yen Lim; Ching Wan Chan; Federick Marme; Rongxi Yang; Peter Bugert; Annika Lindblom; Sara Margolin; Montserrat García-Closas; Stephen J Chanock; Jolanta Lissowska; Jonine D Figueroa; Stig E Bojesen; Børge G Nordestgaard; Henrik Flyger; Maartje J Hooning; Mieke Kriege; Ans MW van den Ouweland; Linetta B Koppert; Olivia Fletcher; Nichola Johnson; Isabel dos-Santos-Silva

; Julian Peto

; Wei Zheng; Sandra Deming-Halverson; Martha J Shrubsole; Jirong Long; Jenny Chang-Claude; Anja Rudolph; Petra Seibold; Dieter Flesch-Janys; Robert Winqvist; Katri Pylkäs; Arja Jukkola-Vuorinen; Mervi Grip; Angela Cox; Simon S Cross; Malcolm WR Reed; Marjanka K Schmidt; Annegien Broeks; Sten Cornelissen; Linde Braaf; Daehee Kang; Ji-Yeob Choi; Sue K Park; Dong-Young Noh; Jacques Simard; Martine Dumont; Mark S Goldberg; France Labrèche; Peter A Fasching; Alexander Hein; Arif B Ekici; Matthias W Beckmann; Paolo Radice; Paolo Peterlongo; Jacopo Azzollini; Monica Barile; Elinor Sawyer; Ian Tomlinson; Michael Kerin; Nicola Miller; John L Hopper; Daniel F Schmidt; Enes Makalic; Melissa C Southey; Soo Hwang Teo; Cheng Har Yip; Kavitta Sivanandan; Wan-Ting Tay; Chen-Yang Shen; Chia-Ni Hsiung; Jyh-Cherng Yu; Ming-Feng Hou; Pascal Guénel; Therese Truong; Marie Sanchez; Claire Mulot; William Blot; Qiuyin Cai; Heli Nevanlinna; Taru A Muranen; Kristiina Aittomäki; Carl Blomqvist; Anna H Wu; Chiu-Chen Tseng; David Van Den Berg; Daniel O Stram; Natalia Bogdanova; Thilo Dörk; Kenneth Muir; Artitaya Lophatananon; Sarah Stewart-Brown; Pornthep Siriwanarangsan; Arto Mannermaa; Vesa Kataja; Veli-Matti Kosma; Jaana M Hartikainen; Xiao-Ou Shu; Wei Lu; Yu-Tang Gao; Ben Zhang; Fergus J Couch; Amanda E Toland; TNBCC; Drakoulis Yannoukakos; Suleeporn Sangrajrang; James McKay; Xianshu Wang; Janet E Olson; Celine Vachon; Kristen Purrington; Gianluca Severi; Laura Baglietto; Christopher A Haiman; Brian E Henderson; Fredrick Schumacher; Loic Le Marchand; Peter Devilee; Robert AEM Tollenaar; Caroline Seynaeve; Kamila Czene; Mikael Eriksson; Keith Humphreys; Hatef Darabi; Shahana Ahmed; Mitul Shah; Paul DP Pharoah; Per Hall; Graham G Giles; Javier Benítez; Alison M Dunning; Georgia Chenevix-Trench; Douglas F Easton; (2014) Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium. Human molecular genetics, 23 (22). pp. 6096-6111. ISSN 0964-6906 DOI: 10.1093/hmg/ddu311

Copy

Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.