Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

GENICA Network, Nick Orr, Frank Dudbridge, Nicola Dryden, Sarah Maguire, Daniela Novo, Eleni Perrakis, Nichola Johnson, Maya Ghoussaini, John L Hopper, Melissa C Southey, Carmel Apicella, Jennifer Stone, Marjanka K Schmidt, Annegien Broeks, Laura J Van't Veer, Frans B Hogervorst, Peter A Fasching, Lothar Haeberle, Arif B EkiciMatthias W Beckmann, Lorna Gibson, Zoe Aitken, Helen Warren, Elinor Sawyer, Ian Tomlinson, Michael J Kerin, Nicola Miller, Barbara Burwinkel, Frederik Marme, Andreas Schneeweiss, Chistof Sohn, Pascal Guénel, Thérèse Truong, Emilie Cordina-Duverger, Marie Sanchez, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Javier Benitez, Maria Pilar Zamora, Jose Ignacio Arias Perez, Primitiva Menéndez, Hoda Anton-Culver, Susan L Neuhausen, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Jonine Figueroa

Research output: Contribution to journalArticlepeer-review


We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.

Original languageEnglish
Pages (from-to)2966-84
Number of pages19
JournalHuman Molecular Genetics
Issue number10
Publication statusPublished - 15 May 2015


  • Adult
  • Aged
  • Asian Continental Ancestry Group
  • Breast Neoplasms
  • Chromosome Mapping
  • Chromosomes, Human, Pair 9
  • Enhancer Elements, Genetic
  • Estrogen Receptor alpha
  • European Continental Ancestry Group
  • Female
  • GATA3 Transcription Factor
  • Genetic Association Studies
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Hepatocyte Nuclear Factor 3-alpha
  • Humans
  • Kruppel-Like Transcription Factors
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Risk


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