Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer.
Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer.
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DOI：
10.1038/ng.3242
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发表时间：
2015-04
期刊：
影响因子：
30.8
通讯作者：
Easton DF
中科院分区：
文献类型：
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作者：
Michailidou K;Beesley J;Lindstrom S;Canisius S;Dennis J;Lush MJ;Maranian MJ;Bolla MK;Wang Q;Shah M;Perkins BJ;Czene K;Eriksson M;Darabi H;Brand JS;Bojesen SE;Nordestgaard BG;Flyger H;Nielsen SF;Rahman N;Turnbull C;BOCS;Fletcher O;Peto J;Gibson L;dos-Santos-Silva I;Chang-Claude J;Flesch-Janys D;Rudolph A;Eilber U;Behrens S;Nevanlinna H;Muranen TA;Aittomäki K;Blomqvist C;Khan S;Aaltonen K;Ahsan H;Kibriya MG;Whittemore AS;John EM;Malone KE;Gammon MD;Santella RM;Ursin G;Makalic E;Schmidt DF;Casey G;Hunter DJ;Gapstur SM;Gaudet MM;Diver WR;Haiman CA;Schumacher F;Henderson BE;Le Marchand L;Berg CD;Chanock SJ;Figueroa J;Hoover RN;Lambrechts D;Neven P;Wildiers H;van Limbergen E;Schmidt MK;Broeks A;Verhoef S;Cornelissen S;Couch FJ;Olson JE;Hallberg E;Vachon C;Waisfisz Q;Meijers-Heijboer H;Adank MA;van der Luijt RB;Li J;Liu J;Humphreys K;Kang D;Choi JY;Park SK;Yoo KY;Matsuo K;Ito H;Iwata H;Tajima K;Guénel P;Truong T;Mulot C;Sanchez M;Burwinkel B;Marme F;Surowy H;Sohn C;Wu AH;Tseng CC;Van Den Berg D;Stram DO;González-Neira A;Benitez J;Zamora MP;Perez JI;Shu XO;Lu W;Gao YT;Cai H;Cox A;Cross SS;Reed MW;Andrulis IL;Knight JA;Glendon G;Mulligan AM;Sawyer EJ;Tomlinson I;Kerin MJ;Miller N;kConFab Investigators;AOCS Group;Lindblom A;Margolin S;Teo SH;Yip CH;Taib NA;Tan GH;Hooning MJ;Hollestelle A;Martens JW;Collée JM;Blot W;Signorello LB;Cai Q;Hopper JL;Southey MC;Tsimiklis H;Apicella C;Shen CY;Hsiung CN;Wu PE;Hou MF;Kristensen VN;Nord S;Alnaes GI;NBCS;Giles GG;Milne RL;McLean C;Canzian F;Trichopoulos D;Peeters P;Lund E;Sund M;Khaw KT;Gunter MJ;Palli D;Mortensen LM;Dossus L;Huerta JM;Meindl A;Schmutzler RK;Sutter C;Yang R;Muir K;Lophatananon A;Stewart-Brown S;Siriwanarangsan P;Hartman M;Miao H;Chia KS;Chan CW;Fasching PA;Hein A;Beckmann MW;Haeberle L;Brenner H;Dieffenbach AK;Arndt V;Stegmaier C;Ashworth A;Orr N;Schoemaker MJ;Swerdlow AJ;Brinton L;Garcia-Closas M;Zheng W;Halverson SL;Shrubsole M;Long J;Goldberg MS;Labrèche F;Dumont M;Winqvist R;Pylkäs K;Jukkola-Vuorinen A;Grip M;Brauch H;Hamann U;Brüning T;GENICA Network;Radice P;Peterlongo P;Manoukian S;Bernard L;Bogdanova NV;Dörk T;Mannermaa A;Kataja V;Kosma VM;Hartikainen JM;Devilee P;Tollenaar RA;Seynaeve C;Van Asperen CJ;Jakubowska A;Lubinski J;Jaworska K;Huzarski T;Sangrajrang S;Gaborieau V;Brennan P;McKay J;Slager S;Toland AE;Ambrosone CB;Yannoukakos D;Kabisch M;Torres D;Neuhausen SL;Anton-Culver H;Luccarini C;Baynes C;Ahmed S;Healey CS;Tessier DC;Vincent D;Bacot F;Pita G;Alonso MR;Álvarez N;Herrero D;Simard J;Pharoah PP;Kraft P;Dunning AM;Chenevix-Trench G;Hall P;Easton DF
全基因组关联研究和大规模复制研究已经在79个与乳腺癌相关的基因座上发现了常见的变异，解释了约14%的乳腺癌家族风险。为了确定新的易感基因，我们对11个GWA进行了荟萃分析，其中包括15,748例乳腺癌病例和18,084名对照，以及来自41项研究的46,785例病例和42,892名对照，这些研究在200K定制阵列(ICOGS)上进行了基因分型。分析仅限于欧洲血统的女性。超过1100万个SNPs的基因类型是通过使用1000基因组计划参考小组的推定产生的。我们在P<；5×10−8上发现了15个与乳腺癌相关的新基因。结合乳腺细胞系的芯片序列数据和Encode中的ChIA-PET染色质相互作用数据，我们在两个区域发现了可能的靶基因：18q12.3上的SETBP118q12.3和1q21.1上的RNF115和PDZK1。其中一个关联似乎是由EXO1中的氨基酸取代所驱动的。
Genome wide association studies (GWAS) and large scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ~14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS comprising of 15,748 breast cancer cases and 18,084 controls, and 46,785 cases and 42,892 controls from 41 studies genotyped on a 200K custom array (iCOGS). Analyses were restricted to women of European ancestry. Genotypes for more than 11M SNPs were generated by imputation using the 1000 Genomes Project reference panel. We identified 15 novel loci associated with breast cancer at P<5×10−8. Combining association analysis with ChIP-Seq data in mammary cell lines and ChIA-PET chromatin interaction data in ENCODE, we identified likely target genes in two regions: SETBP1 on 18q12.3 and RNF115 and PDZK1 on 1q21.1. One association appears to be driven by an amino-acid substitution in EXO1.