对超过12万名个体进行的全基因组关联分析确定了15个新的乳腺癌易感基因座。
Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer.
作者信息
Michailidou Kyriaki, Beesley Jonathan, Lindstrom Sara, Canisius Sander, Dennis Joe, Lush Michael J, Maranian Mel J, Bolla Manjeet K, Wang Qin, Shah Mitul, Perkins Barbara J, Czene Kamila, Eriksson Mikael, Darabi Hatef, Brand Judith S, Bojesen Stig E, Nordestgaard Børge G, Flyger Henrik, Nielsen Sune F, Rahman Nazneen, Turnbull Clare, Fletcher Olivia, Peto Julian, Gibson Lorna, dos-Santos-Silva Isabel, Chang-Claude Jenny, Flesch-Janys Dieter, Rudolph Anja, Eilber Ursula, Behrens Sabine, Nevanlinna Heli, Muranen Taru A, Aittomäki Kristiina, Blomqvist Carl, Khan Sofia, Aaltonen Kirsimari, Ahsan Habibul, Kibriya Muhammad G, Whittemore Alice S, John Esther M, Malone Kathleen E, Gammon Marilie D, Santella Regina M, Ursin Giske, Makalic Enes, Schmidt Daniel F, Casey Graham, Hunter David J, Gapstur Susan M, Gaudet Mia M, Diver W Ryan, Haiman Christopher A, Schumacher Fredrick, Henderson Brian E, Le Marchand Loic, Berg Christine D, Chanock Stephen J, Figueroa Jonine, Hoover Robert N, Lambrechts Diether, Neven Patrick, Wildiers Hans, van Limbergen Erik, Schmidt Marjanka K, Broeks Annegien, Verhoef Senno, Cornelissen Sten, Couch Fergus J, Olson Janet E, Hallberg Emily, Vachon Celine, Waisfisz Quinten, Meijers-Heijboer Hanne, Adank Muriel A, van der Luijt Rob B, Li Jingmei, Liu Jianjun, Humphreys Keith, Kang Daehee, Choi Ji-Yeob, Park Sue K, Yoo Keun-Young, Matsuo Keitaro, Ito Hidemi, Iwata Hiroji, Tajima Kazuo, Guénel Pascal, Truong Thérèse, Mulot Claire, Sanchez Marie, Burwinkel Barbara, Marme Frederik, Surowy Harald, Sohn Christof, Wu Anna H, Tseng Chiu-chen, Van Den Berg David, Stram Daniel O, González-Neira Anna, Benitez Javier, Zamora M Pilar, Perez Jose Ignacio Arias, Shu Xiao-Ou, Lu Wei, Gao Yu-Tang, Cai Hui, Cox Angela, Cross Simon S, Reed Malcolm W R, Andrulis Irene L, Knight Julia A, Glendon Gord, Mulligan Anna Marie, Sawyer Elinor J, Tomlinson Ian, Kerin Michael J, Miller Nicola, Lindblom Annika, Margolin Sara, Teo Soo Hwang, Yip Cheng Har, Taib Nur Aishah Mohd, Tan Gie-Hooi, Hooning Maartje J, Hollestelle Antoinette, Martens John W M, Collée J Margriet, Blot William, Signorello Lisa B, Cai Qiuyin, Hopper John L, Southey Melissa C, Tsimiklis Helen, Apicella Carmel, Shen Chen-Yang, Hsiung Chia-Ni, Wu Pei-Ei, Hou Ming-Feng, Kristensen Vessela N, Nord Silje, Alnaes Grethe I Grenaker, Giles Graham G, Milne Roger L, McLean Catriona, Canzian Federico, Trichopoulos Dimitrios, Peeters Petra, Lund Eiliv, Sund Malin, Khaw Kay-Tee, Gunter Marc J, Palli Domenico, Mortensen Lotte Maxild, Dossus Laure, Huerta Jose-Maria, Meindl Alfons, Schmutzler Rita K, Sutter Christian, Yang Rongxi, Muir Kenneth, Lophatananon Artitaya, Stewart-Brown Sarah, Siriwanarangsan Pornthep, Hartman Mikael, Miao Hui, Chia Kee Seng, Chan Ching Wan, Fasching Peter A, Hein Alexander, Beckmann Matthias W, Haeberle Lothar, Brenner Hermann, Dieffenbach Aida Karina, Arndt Volker, Stegmaier Christa, Ashworth Alan, Orr Nick, Schoemaker Minouk J, Swerdlow Anthony J, Brinton Louise, Garcia-Closas Montserrat, Zheng Wei, Halverson Sandra L, Shrubsole Martha, Long Jirong, Goldberg Mark S, Labrèche France, Dumont Martine, Winqvist Robert, Pylkäs Katri, Jukkola-Vuorinen Arja, Grip Mervi, Brauch Hiltrud, Hamann Ute, Brüning Thomas, Radice Paolo, Peterlongo Paolo, Manoukian Siranoush, Bernard Loris, Bogdanova Natalia V, Dörk Thilo, Mannermaa Arto, Kataja Vesa, Kosma Veli-Matti, Hartikainen Jaana M, Devilee Peter, Tollenaar Robert A E M, Seynaeve Caroline, Van Asperen Christi J, Jakubowska Anna, Lubinski Jan, Jaworska Katarzyna, Huzarski Tomasz, Sangrajrang Suleeporn, Gaborieau Valerie, Brennan Paul, McKay James, Slager Susan, Toland Amanda E, Ambrosone Christine B, Yannoukakos Drakoulis, Kabisch Maria, Torres Diana, Neuhausen Susan L, Anton-Culver Hoda, Luccarini Craig, Baynes Caroline, Ahmed Shahana, Healey Catherine S, Tessier Daniel C, Vincent Daniel, Bacot Francois, Pita Guillermo, Alonso M Rosario, Álvarez Nuria, Herrero Daniel, Simard Jacques, Pharoah Paul P D P, Kraft Peter, Dunning Alison M, Chenevix-Trench Georgia, Hall Per, Easton Douglas F
机构信息
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Department of Genetics, QIMR (Queensland Institute for Medical Research) Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
出版信息
Nat Genet. 2015 Apr;47(4):373-80. doi: 10.1038/ng.3242. Epub 2015 Mar 9.
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 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.
全基因组关联研究（GWAS）以及大规模重复研究已经在79个与乳腺癌相关的基因座中确定了常见变异，这些变异解释了该疾病约14%的家族性风险。为了确定新的易感基因座，我们对11项GWAS进行了荟萃分析，这些研究包括15748例乳腺癌病例和18084例对照，以及来自41项研究的46785例病例和42892例对照，这些研究在一个包含211155个标记的定制芯片（iCOGS）上进行基因分型。分析仅限于欧洲血统的女性。我们使用千人基因组计划参考面板通过插补生成了超过1100万个单核苷酸多态性（SNP）的基因型，并确定了15个与乳腺癌相关的新基因座，其P值小于5×10^(-8)。将关联分析与乳腺细胞系中的染色质免疫沉淀测序（ChIP-seq）染色质结合数据以及来自ENCODE的染色质相互作用分析技术（ChIA-PET）染色质相互作用数据相结合，我们在两个区域确定了可能的靶基因：18q12.3处的SETBP1以及1q2处的RNF115和PDZK1。一种关联似乎是由EXO1中编码的一个氨基酸替换所驱动。
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