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

TY - JOUR

T1 - Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium

AU - Milne, Roger L

AU - Burwinkel, Barbara

AU - Michailidou, Kyriaki

AU - Arias-Perez, Jose-Ignacio

AU - Zamora, M Pilar

AU - Menéndez-Rodríguez, Primitiva

AU - Hardisson, David

AU - Mendiola, Marta

AU - González-Neira, Anna

AU - Pita, Guillermo

AU - Alonso, M Rosario

AU - Dennis, Joe

AU - Wang, Qin

AU - Bolla, Manjeet K

AU - Swerdlow, Anthony

AU - Ashworth, Alan

AU - Orr, Nick

AU - Schoemaker, Minouk

AU - Ko, Yon-Dschun

AU - Brauch, Hiltrud

AU - Hamann, Ute

AU - Andrulis, Irene L

AU - Knight, Julia A

AU - Glendon, Gord

AU - Tchatchou, Sandrine

AU - Matsuo, Keitaro

AU - Ito, Hidemi

AU - Iwata, Hiroji

AU - Tajima, Kazuo

AU - Li, Jingmei

AU - Brand, Judith S

AU - Brenner, Hermann

AU - Dieffenbach, Aida Karina

AU - Arndt, Volker

AU - Stegmaier, Christa

AU - Lambrechts, Diether

AU - Peuteman, Gilian

AU - Christiaens, Marie-Rose

AU - Smeets, Ann

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Jaworska-Bieniek, Katarzyna

AU - Durda, Katazyna

AU - Hartman, Mikael

AU - Hui, Miao

AU - Yen Lim, Wei

AU - Wan Chan, Ching

AU - Marme, Federick

AU - Yang, Rongxi

AU - Bugert, Peter

AU - Lindblom, Annika

AU - Margolin, Sara

AU - García-Closas, Montserrat

AU - Chanock, Stephen J

AU - Lissowska, Jolanta

AU - Figueroa, Jonine D

AU - Bojesen, Stig E

AU - Nordestgaard, Børge G

AU - Flyger, Henrik

AU - Hooning, Maartje J

AU - Kriege, Mieke

AU - van den Ouweland, Ans M W

AU - Koppert, Linetta B

AU - Fletcher, Olivia

AU - Johnson, Nichola

AU - dos-Santos-Silva, Isabel

AU - Peto, Julian

AU - Zheng, Wei

AU - Deming-Halverson, Sandra

AU - Shrubsole, Martha J

AU - Long, Jirong

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Seibold, Petra

AU - Flesch-Janys, Dieter

AU - Winqvist, Robert

AU - Pylkäs, Katri

AU - Jukkola-Vuorinen, Arja

AU - Grip, Mervi

AU - Cox, Angela

AU - Cross, Simon S

AU - Reed, Malcolm W R

AU - Schmidt, Marjanka K

AU - Broeks, Annegien

AU - Cornelissen, Sten

AU - Braaf, Linde

AU - Kang, Daehee

AU - Choi, Ji-Yeob

AU - Park, Sue K

AU - Noh, Dong-Young

AU - Simard, Jacques

AU - Dumont, Martine

AU - Goldberg, Mark S

AU - Labrèche, France

AU - Fasching, Peter A

AU - Hein, Alexander

AU - Ekici, Arif B

AU - Beckmann, Matthias W

AU - Radice, Paolo

AU - Peterlongo, Paolo

AU - Azzollini, Jacopo

AU - Barile, Monica

AU - Sawyer, Elinor

AU - Tomlinson, Ian

AU - Kerin, Michael

AU - Miller, Nicola

AU - Hopper, John L

AU - Schmidt, Daniel F

AU - Makalic, Enes

AU - Southey, Melissa C

AU - Hwang Teo, Soo

AU - Har Yip, Cheng

AU - Sivanandan, Kavitta

AU - Tay, Wan-Ting

AU - Shen, Chen-Yang

AU - Hsiung, Chia-Ni

AU - Yu, Jyh-Cherng

AU - Hou, Ming-Feng

AU - Guénel, Pascal

AU - Truong, Therese

AU - Sanchez, Marie

AU - Mulot, Claire

AU - Blot, William

AU - Cai, Qiuyin

AU - Nevanlinna, Heli

AU - Muranen, Taru A

AU - Aittomäki, Kristiina

AU - Blomqvist, Carl

AU - Wu, Anna H

AU - Tseng, Chiu-Chen

AU - Van Den Berg, David

AU - Stram, Daniel O

AU - Bogdanova, Natalia

AU - Dörk, Thilo

AU - Muir, Kenneth

AU - Lophatananon, Artitaya

AU - Stewart-Brown, Sarah

AU - Siriwanarangsan, Pornthep

AU - Mannermaa, Arto

AU - Kataja, Vesa

AU - Kosma, Veli-Matti

AU - Hartikainen, Jaana M

AU - Shu, Xiao-Ou

AU - Lu, Wei

AU - Gao, Yu-Tang

AU - Zhang, Ben

AU - Couch, Fergus J

AU - Toland, Amanda E

AU - Yannoukakos, Drakoulis

AU - Sangrajrang, Suleeporn

AU - McKay, James

AU - Wang, Xianshu

AU - Olson, Janet E

AU - Vachon, Celine

AU - Purrington, Kristen

AU - Severi, Gianluca

AU - Baglietto, Laura

AU - Haiman, Christopher A

AU - Henderson, Brian E

AU - Schumacher, Fredrick

AU - Le Marchand, Loic

AU - Devilee, Peter

AU - Tollenaar, Robert A E M

AU - Seynaeve, Caroline

AU - Czene, Kamila

AU - Eriksson, Mikael

AU - Humphreys, Keith

AU - Darabi, Hatef

AU - Ahmed, Shahana

AU - Shah, Mitul

AU - Pharoah, Paul D P

AU - Hall, Per

AU - Giles, Graham G

AU - Benítez, Javier

AU - Dunning, Alison M

AU - Chenevix-Trench, Georgia

AU - Easton, Douglas F

AU - GENICA Network

AU - Harth, Volker

N1 - © The Author 2014. Published by Oxford University Press.

PY - 2014/11/15

Y1 - 2014/11/15

N2 - 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.

AB - 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.

U2 - 10.1093/hmg/ddu311

DO - 10.1093/hmg/ddu311

M3 - SCORING: Journal article

C2 - 24943594

VL - 23

SP - 6096

EP - 6111

JO - HUM MOL GENET

JF - HUM MOL GENET

SN - 0964-6906

IS - 22

ER -