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


ABSTRACT: 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.

SUBMITTER: Milne RL 

PROVIDER: S-EPMC4204770 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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

Milne Roger L RL   Burwinkel Barbara B   Michailidou Kyriaki K   Arias-Perez Jose-Ignacio JI   Zamora M Pilar MP   Menéndez-Rodríguez Primitiva P   Hardisson David D   Mendiola Marta M   González-Neira Anna A   Pita Guillermo G   Alonso M Rosario MR   Dennis Joe J   Wang Qin Q   Bolla Manjeet K MK   Swerdlow Anthony A   Ashworth Alan A   Orr Nick N   Schoemaker Minouk M   Ko Yon-Dschun YD   Brauch Hiltrud H   Hamann Ute U   Andrulis Irene L IL   Knight Julia A JA   Glendon Gord G   Tchatchou Sandrine S   Matsuo Keitaro K   Ito Hidemi H   Iwata Hiroji H   Tajima Kazuo K   Li Jingmei J   Brand Judith S JS   Brenner Hermann H   Dieffenbach Aida Karina AK   Arndt Volker V   Stegmaier Christa C   Lambrechts Diether D   Peuteman Gilian G   Christiaens Marie-Rose MR   Smeets Ann A   Jakubowska Anna A   Lubinski Jan J   Jaworska-Bieniek Katarzyna K   Durda Katazyna K   Hartman Mikael M   Hui Miao M   Yen Lim Wei W   Wan Chan Ching C   Marme Federick F   Yang Rongxi R   Bugert Peter P   Lindblom Annika A   Margolin Sara S   García-Closas Montserrat M   Chanock Stephen J SJ   Lissowska Jolanta J   Figueroa Jonine D JD   Bojesen Stig E SE   Nordestgaard Børge G BG   Flyger Henrik H   Hooning Maartje J MJ   Kriege Mieke M   van den Ouweland Ans M W AM   Koppert Linetta B LB   Fletcher Olivia O   Johnson Nichola N   dos-Santos-Silva Isabel I   Peto Julian J   Zheng Wei W   Deming-Halverson Sandra S   Shrubsole Martha J MJ   Long Jirong J   Chang-Claude Jenny J   Rudolph Anja A   Seibold Petra P   Flesch-Janys Dieter D   Winqvist Robert R   Pylkäs Katri K   Jukkola-Vuorinen Arja A   Grip Mervi M   Cox Angela A   Cross Simon S SS   Reed Malcolm W R MW   Schmidt Marjanka K MK   Broeks Annegien A   Cornelissen Sten S   Braaf Linde L   Kang Daehee D   Choi Ji-Yeob JY   Park Sue K SK   Noh Dong-Young DY   Simard Jacques J   Dumont Martine M   Goldberg Mark S MS   Labrèche France F   Fasching Peter A PA   Hein Alexander A   Ekici Arif B AB   Beckmann Matthias W MW   Radice Paolo P   Peterlongo Paolo P   Azzollini Jacopo J   Barile Monica M   Sawyer Elinor E   Tomlinson Ian I   Kerin Michael M   Miller Nicola N   Hopper John L JL   Schmidt Daniel F DF   Makalic Enes E   Southey Melissa C MC   Hwang Teo Soo S   Har Yip Cheng C   Sivanandan Kavitta K   Tay Wan-Ting WT   Shen Chen-Yang CY   Hsiung Chia-Ni CN   Yu Jyh-Cherng JC   Hou Ming-Feng MF   Guénel Pascal P   Truong Therese T   Sanchez Marie M   Mulot Claire C   Blot William W   Cai Qiuyin Q   Nevanlinna Heli H   Muranen Taru A TA   Aittomäki Kristiina K   Blomqvist Carl C   Wu Anna H AH   Tseng Chiu-Chen CC   Van Den Berg David D   Stram Daniel O DO   Bogdanova Natalia N   Dörk Thilo T   Muir Kenneth K   Lophatananon Artitaya A   Stewart-Brown Sarah S   Siriwanarangsan Pornthep P   Mannermaa Arto A   Kataja Vesa V   Kosma Veli-Matti VM   Hartikainen Jaana M JM   Shu Xiao-Ou XO   Lu Wei W   Gao Yu-Tang YT   Zhang Ben B   Couch Fergus J FJ   Toland Amanda E AE   Yannoukakos Drakoulis D   Sangrajrang Suleeporn S   McKay James J   Wang Xianshu X   Olson Janet E JE   Vachon Celine C   Purrington Kristen K   Severi Gianluca G   Baglietto Laura L   Haiman Christopher A CA   Henderson Brian E BE   Schumacher Fredrick F   Le Marchand Loic L   Devilee Peter P   Tollenaar Robert A E M RA   Seynaeve Caroline C   Czene Kamila K   Eriksson Mikael M   Humphreys Keith K   Darabi Hatef H   Ahmed Shahana S   Shah Mitul M   Pharoah Paul D P PD   Hall Per P   Giles Graham G GG   Benítez Javier J   Dunning Alison M AM   Chenevix-Trench Georgia G   Easton Douglas F DF  

Human molecular genetics 20140618 22


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  ...[more]

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