TY - JOUR
T1 - Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170
AU - Dunning, Alison M.
AU - Michailidou, Kyriaki
AU - Kuchenbaecker, Karoline B.
AU - Thompson, Deborah
AU - French, Juliet D.
AU - Beesley, Jonathan
AU - Healey, Catherine S.
AU - Kar, Siddhartha
AU - Pooley, Karen A.
AU - Lopez-Knowles, Elena
AU - Dicks, Ed
AU - Barrowdale, Daniel
AU - Sinnott-Armstrong, Nicholas A.
AU - Sallari, Richard C.
AU - Hillman, Kristine M.
AU - Kaufmann, Susanne
AU - Sivakumaran, Haran
AU - Marjaneh, Mahdi Moradi
AU - Lee, Jason S.
AU - Hills, Margaret
AU - Jarosz, Monika
AU - Drury, Suzie
AU - Canisius, Sander
AU - Bolla, Manjeet K.
AU - Dennis, Joe
AU - Wang, Qin
AU - Hopper, John L.
AU - Southey, Melissa C.
AU - Broeks, Annegien
AU - Schmidt, Marjanka K.
AU - Lophatananon, Artitaya
AU - Muir, Kenneth
AU - Beckmann, Matthias W.
AU - Fasching, Peter A.
AU - dos-Santos-Silva, Isabel
AU - Peto, Julian
AU - Sawyer, Elinor J.
AU - Tomlinson, Ian
AU - Burwinkel, Barbara
AU - Marme, Frederik
AU - Guenel, Pascal
AU - Truong, Therese
AU - Bojesen, Stig E.
AU - Flyger, Henrik
AU - Gonzalez-Neira, Anna
AU - Perez, Jose I. A.
AU - Mensenkamp, Arjen R.
AU - EMBRACE
AU - GEMO Study Collaborators
AU - HEBON
AU - kConFab Investigators
AU - Ligtenberg, J. J. M.
AU - Oosterwijk, J. C.
AU - van der Hout, A. H.
PY - 2016/4
Y1 - 2016/4
N2 - We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor a) 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.
AB - We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor a) 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.
KW - GENOME-WIDE ASSOCIATION
KW - BRCA2 MUTATION CARRIERS
KW - BONE-MINERAL DENSITY
KW - MAMMOGRAPHIC DENSITY
KW - SUSCEPTIBILITY LOCUS
KW - METAANALYSIS
KW - EXPRESSION
KW - MODIFIERS
KW - REVEALS
KW - DISEASE
U2 - 10.1038/ng.3521
DO - 10.1038/ng.3521
M3 - Article
VL - 48
SP - 374-+
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 4
ER -