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We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.

Original publication

DOI

10.1038/ng.3521

Type

Journal article

Journal

Nat Genet

Publication Date

04/2016

Volume

48

Pages

374 - 386

Keywords

Base Sequence, Breast Neoplasms, Carrier Proteins, Cell Cycle Proteins, Chromosomes, Human, Pair 6, Estrogen Receptor alpha, Female, Gene Expression, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Phenotype, Polymorphism, Single Nucleotide, Protein Binding, Risk Factors