title: Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk.
abstract: Mammographic density reflects the amount of stromal and epithelial tissues in relation to adipose tissue in the breast and is a strong risk factor for breast cancer. Here we report the results from meta-analysis of genome-wide association studies (GWAS) of three mammographic density phenotypes: dense area, non-dense area and percent density in up to 7,916 women in stage 1 and an additional 10,379 women in stage 2. We identify genome-wide significant (P<5 × 10(-8)) loci for dense area (AREG, ESR1, ZNF365, LSP1/TNNT3, IGF1, TMEM184B and SGSM3/MKL1), non-dense area (8p11.23) and percent density (PRDM6, 8p11.23 and TMEM184B). Four of these regions are known breast cancer susceptibility loci, and four additional regions were found to be associated with breast cancer (P<0.05) in a large meta-analysis. These results provide further evidence of a shared genetic basis between mammographic density and breast cancer and illustrate the power of studying intermediate quantitative phenotypes to identify putative disease-susceptibility loci.
authors.affiliation: 1] Program in Genetic Epidemiology and Statistical Genetics, Harvard School Of Public Health, Boston, Massachusetts 02115, USA [2] Department of Epidemiology, Harvard School Of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Lindström
authors.affiliation: 1] Centre for Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK [2] Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Thompson
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
authors.forename: Jingmei
authors.initials: J
authors.lastname: Li
authors.affiliation: Hormonal and Reproductive Epidemiology Branch, National Cancer Institute, Bethesda, Maryland 20850, USA.
authors.forename: Gretchen L
authors.initials: GL
authors.lastname: Gierach
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Scott
authors.affiliation: Centre for Genetic Origins of Health and Disease, University of Western Australia, Perth, Western Australia 6009, Australia.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stone
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Douglas
authors.affiliation: Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
authors.forename: Isabel
authors.initials: I
authors.lastname: dos-Santos-Silva
authors.affiliation: 1] Cancer and Environmental Epidemiology Unit, National Center for Epidemiology, Carlos III Institute of Health, Madrid 28029, Spain [2] Consortium for Biomedical Research in Epidemiology and Public Health (CIBER en Epidemiología y Salud Pública-CIBERESP), Madrid 28029, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Fernandez-Navarro
authors.affiliation: 1] Centre for Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK [2] Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK [3] Plastic Surgery Unit, Royal Free Hospital, London NW3 2QG, UK.
authors.forename: Jajini
authors.initials: J
authors.lastname: Verghase
authors.affiliation: 1] Centre for Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK [2] Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
authors.forename: Paula
authors.initials: P
authors.lastname: Smith
authors.affiliation: 1] Centre for Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK [2] Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
authors.forename: Judith
authors.initials: J
authors.lastname: Brown
authors.affiliation: Centre for Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Luben
authors.affiliation: Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB1 8RN, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.affiliation: 1] Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB1 8RN, UK [2] The Icahn School of Medicine at Mount Sinai, The Charles Bronfman Institute for Personalized Medicine, The Mindich Child Health and Development Institute, New York, New York 10029, USA.
authors.forename: Ruth J F
authors.initials: RJ
authors.lastname: Loos
authors.affiliation: Division of Cardiovascular Disease, Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Heit
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: V Shane
authors.initials: VS
authors.lastname: Pankratz
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Norman
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Mariza
authors.initials: M
authors.lastname: deAndrade
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Vierkant
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
authors.forename: Kamila
authors.initials: K
authors.lastname: Czene
authors.affiliation: 1] Department of Gynecology and Obstetrics, Erlangen University Hospital, Friedrich Alexander University of Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 910 54 Erlangen, Germany [2] Division Hematology/Oncology, Department of Medicine, University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, California 90024, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fasching
authors.affiliation: 1] Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria 3004, Australia [2] Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Baglietto
authors.affiliation: Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.affiliation: 1] Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria 3004, Australia [2] Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Kaanan P
authors.initials: KP
authors.lastname: Shah
authors.affiliation: Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Heang-Ping
authors.initials: HP
authors.lastname: Chan
authors.affiliation: Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Helvie
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Beck
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Knoblauch
authors.affiliation: 1] Program in Genetic Epidemiology and Statistical Genetics, Harvard School Of Public Health, Boston, Massachusetts 02115, USA [2] Department of Epidemiology, Harvard School Of Public Health, Boston, Massachusetts 02115, USA [3] Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Aditi
authors.initials: A
authors.lastname: Hazra
authors.affiliation: 1] Program in Genetic Epidemiology and Statistical Genetics, Harvard School Of Public Health, Boston, Massachusetts 02115, USA [2] Department of Epidemiology, Harvard School Of Public Health, Boston, Massachusetts 02115, USA [3] Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.affiliation: 1] Program in Genetic Epidemiology and Statistical Genetics, Harvard School Of Public Health, Boston, Massachusetts 02115, USA [2] Department of Epidemiology, Harvard School Of Public Health, Boston, Massachusetts 02115, USA [3] Department of Biostatistics, Harvard School Of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.affiliation: 1] Cancer and Environmental Epidemiology Unit, National Center for Epidemiology, Carlos III Institute of Health, Madrid 28029, Spain [2] Consortium for Biomedical Research in Epidemiology and Public Health (CIBER en Epidemiología y Salud Pública-CIBERESP), Madrid 28029, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Pollan
authors.affiliation: Hormonal and Reproductive Epidemiology Branch, National Cancer Institute, Bethesda, Maryland 20850, USA.
authors.forename: Jonine D
authors.initials: JD
authors.lastname: Figueroa
authors.affiliation: 1] Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA [2] Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Hall
authors.affiliation: 1] Centre for Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK [2] Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK [3] Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada M5G 2M9.
authors.forename: Norman F
authors.initials: NF
authors.lastname: Boyd
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Celine M
authors.initials: CM
authors.lastname: Vachon
authors.affiliation: 1] Program in Genetic Epidemiology and Statistical Genetics, Harvard School Of Public Health, Boston, Massachusetts 02115, USA [2] Department of Epidemiology, Harvard School Of Public Health, Boston, Massachusetts 02115, USA [3] Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Rulla M
authors.initials: RM
authors.lastname: Tamimi
mesh_terms: D000071060:Breast Density; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D042361:Mammary Glands, Human / Q000002:abnormalities*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011859:Radiography