TY - JOUR

T1 - Common non-synonymous SNPs associated with breast cancer susceptibility

T2 - 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 - Bojesen, Stig E

AU - Nordestgaard, Børge G

AU - GENICA Network

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

PY - 2014

Y1 - 2014

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 - Journal article

C2 - 24943594

VL - 23

SP - 6096

EP - 6111

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 22

ER -