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Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review


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  • Chenjie Zeng
  • Xingyi Guo
  • Jirong Long
  • Karoline B Kuchenbaecker
  • Arnaud Droit
  • Kyriaki Michailidou
  • Maya Ghoussaini
  • Siddhartha Kar
  • Adam Freeman
  • John L Hopper
  • Roger L Milne
  • Manjeet K Bolla
  • Qin Wang
  • Joe Dennis
  • Simona Agata
  • Shahana Ahmed
  • Kristiina Aittomäki
  • Irene L Andrulis
  • Hoda Anton-Culver
  • Natalia N Antonenkova
  • Adalgeir Arason
  • Volker Arndt
  • Banu K Arun
  • Brita Arver
  • Francois Bacot
  • Daniel Barrowdale
  • Caroline Baynes
  • Alicia Beeghly-Fadiel
  • Javier Benitez
  • Marina Bermisheva
  • Carl Blomqvist
  • William J Blot
  • Natalia V Bogdanova
  • Stig E Bojesen
  • Bernardo Bonanni
  • Anne-Lise Borresen-Dale
  • Judith S Brand
  • Hiltrud Brauch
  • Paul Brennan
  • Hermann Brenner
  • Annegien Broeks
  • Thomas Brüning
  • Barbara Burwinkel
  • Saundra S Buys
  • Qiuyin Cai
  • Trinidad Caldes
  • Ian Campbell
  • Bent Ejlertsen
  • Henrik Flyger
  • Thomas V O Hansen
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BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.

METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.

RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05.

CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.

TidsskriftBreast Cancer Research
Udgave nummer1
Sider (fra-til)64
StatusUdgivet - 21 jun. 2016

ID: 49773607