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Large-scale genotyping identifies 41 new loci associated with breast cancer risk.

ABSTRACT: Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ?9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.

SUBMITTER: Michailidou K

PROVIDER: S-EPMC3771688 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Large-scale genotyping identifies 41 new loci associated with breast cancer risk.

Michailidou Kyriaki K Hall Per P Gonzalez-Neira Anna A Ghoussaini Maya M Dennis Joe J Milne Roger L RL Schmidt Marjanka K MK Chang-Claude Jenny J Bojesen Stig E SE Bolla Manjeet K MK Wang Qin Q Dicks Ed E Lee Andrew A Turnbull Clare C Rahman Nazneen N Fletcher Olivia O Peto Julian J Gibson Lorna L Dos Santos Silva Isabel I Nevanlinna Heli H Muranen Taru A TA Aittomäki Kristiina K Blomqvist Carl C Czene Kamila K Irwanto Astrid A Liu Jianjun J Waisfisz Quinten Q Meijers-Heijboer Hanne H Adank Muriel M van der Luijt Rob B RB Hein Rebecca R Dahmen Norbert N Beckman Lars L Meindl Alfons A Schmutzler Rita K RK Müller-Myhsok Bertram B Lichtner Peter P Hopper John L JL Southey Melissa C MC Makalic Enes E Schmidt Daniel F DF Uitterlinden Andre G AG Hofman Albert A Hunter David J DJ Chanock Stephen J SJ Vincent Daniel D Bacot François F Tessier Daniel C DC Canisius Sander S Wessels Lodewyk F A LF Haiman Christopher A CA Shah Mitul M Luben Robert R Brown Judith J Luccarini Craig C Schoof Nils N Humphreys Keith K Li Jingmei J Nordestgaard Børge G BG Nielsen Sune F SF Flyger Henrik H Couch Fergus J FJ Wang Xianshu X Vachon Celine C Stevens Kristen N KN Lambrechts Diether D Moisse Matthieu M Paridaens Robert R Christiaens Marie-Rose MR Rudolph Anja A Nickels Stefan S Flesch-Janys Dieter D Johnson Nichola N Aitken Zoe Z Aaltonen Kirsimari K Heikkinen Tuomas T Broeks Annegien A Veer Laura J Van't LJ van der Schoot C Ellen CE Guénel Pascal P Truong Thérèse T Laurent-Puig Pierre P Menegaux Florence F Marme Frederik F Schneeweiss Andreas A Sohn Christof C Burwinkel Barbara B Zamora M Pilar MP Perez Jose Ignacio Arias JI Pita Guillermo G Alonso M Rosario MR Cox Angela A Brock Ian W IW Cross Simon S SS Reed Malcolm W R MW Sawyer Elinor J EJ Tomlinson Ian I Kerin Michael J MJ Miller Nicola N Henderson Brian E BE Schumacher Fredrick F Le Marchand Loic L Andrulis Irene L IL Knight Julia A JA Glendon Gord G Mulligan Anna Marie AM Lindblom Annika A Margolin Sara S Hooning Maartje J MJ Hollestelle Antoinette A van den Ouweland Ans M W AM Jager Agnes A Bui Quang M QM Stone Jennifer J Dite Gillian S GS Apicella Carmel C Tsimiklis Helen H Giles Graham G GG Severi Gianluca G Baglietto Laura L Fasching Peter A PA Haeberle Lothar L Ekici Arif B AB Beckmann Matthias W MW Brenner Hermann H Müller Heiko H Arndt Volker V Stegmaier Christa C Swerdlow Anthony A Ashworth Alan A Orr Nick N Jones Michael M Figueroa Jonine J Lissowska Jolanta J Brinton Louise L Goldberg Mark S MS Labrèche France F Dumont Martine M Winqvist Robert R Pylkäs Katri K Jukkola-Vuorinen Arja A Grip Mervi M Brauch Hiltrud H Hamann Ute U Brüning Thomas T Radice Paolo P Peterlongo Paolo P Manoukian Siranoush S Bonanni Bernardo B Devilee Peter P Tollenaar Rob A E M RA Seynaeve Caroline C van Asperen Christi J CJ Jakubowska Anna A Lubinski Jan J Jaworska Katarzyna K Durda Katarzyna K Mannermaa Arto A Kataja Vesa V Kosma Veli-Matti VM Hartikainen Jaana M JM Bogdanova Natalia V NV Antonenkova Natalia N NN Dörk Thilo T Kristensen Vessela N VN Anton-Culver Hoda H Slager Susan S Toland Amanda E AE Edge Stephen S Fostira Florentia F Kang Daehee D Yoo Keun-Young KY Noh Dong-Young DY Matsuo Keitaro K Ito Hidemi H Iwata Hiroji H Sueta Aiko A Wu Anna H AH Tseng Chiu-Chen CC Van Den Berg David D Stram Daniel O DO Shu Xiao-Ou XO Lu Wei W Gao Yu-Tang YT Cai Hui H Teo Soo Hwang SH Yip Cheng Har CH Phuah Sze Yee SY Cornes Belinda K BK Hartman Mikael M Miao Hui H Lim Wei Yen WY Sng Jen-Hwei JH Muir Kenneth K Lophatananon Artitaya A Stewart-Brown Sarah S Siriwanarangsan Pornthep P Shen Chen-Yang CY Hsiung Chia-Ni CN Wu Pei-Ei PE Ding Shian-Ling SL Sangrajrang Suleeporn S Gaborieau Valerie V Brennan Paul P McKay James J Blot William J WJ Signorello Lisa B LB Cai Qiuyin Q Zheng Wei W Deming-Halverson Sandra S Shrubsole Martha M Long Jirong J Simard Jacques J Garcia-Closas Montse M Pharoah Paul D P PD Chenevix-Trench Georgia G Dunning Alison M AM Benitez Javier J Easton Douglas F DF

Nature genetics 20130401 4

Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European anc ...[more]

PMID: 23535729

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Project description:Background & aimsGenome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations.MethodsWe analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels.ResultsA meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10-8. We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%-75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci.ConclusionsWe showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to β-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.

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Large-scale genotyping identifies 41 new loci associated with breast cancer risk.

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Large-scale genotyping identifies 41 new loci associated with breast cancer risk.

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