Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk

Sara Lindström; Deborah J Thompson; Andrew D Paterson; Jingmei Li; Gretchen L Gierach; Christopher Scott; Jennifer Stone; Julie A Douglas; Isabel dos-Santos-Silva; Pablo Fernandez-Navarro; Jajini Verghase; Paula Smith; Judith Brown; Robert Luben; Nicholas J Wareham; Ruth J F Loos; John A Heit; V Shane Pankratz; Aaron Norman; Ellen L Goode; Julie M Cunningham; Mariza deAndrade; Robert A Vierkant; Kamila Czene; Peter A Fasching; Laura Baglietto; Melissa C Southey; Graham G Giles; Kaanan P Shah; Heang-Ping Chan; Mark A Helvie; Andrew H Beck; Nicholas W Knoblauch; Aditi Hazra; David J Hunter; Peter Kraft; Marina Pollan; Jonine D Figueroa; Fergus J Couch; John L Hopper; Per Hall; Douglas F Easton; Norman F Boyd; Celine M Vachon; Rulla M Tamimi

doi:10.1038/ncomms6303

Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk

Nat Commun. 2014 Oct 24:5:5303. doi: 10.1038/ncomms6303.

Authors

Sara Lindström¹, Deborah J Thompson², Andrew D Paterson³, Jingmei Li⁴, Gretchen L Gierach⁵, Christopher Scott⁶, Jennifer Stone⁷, Julie A Douglas⁸, Isabel dos-Santos-Silva⁹, Pablo Fernandez-Navarro¹⁰, Jajini Verghase¹¹, Paula Smith², Judith Brown², Robert Luben¹², Nicholas J Wareham¹³, Ruth J F Loos¹⁴, John A Heit¹⁵, V Shane Pankratz⁶, Aaron Norman⁶, Ellen L Goode⁶, Julie M Cunningham¹⁶, Mariza deAndrade⁶, Robert A Vierkant⁶, Kamila Czene⁴, Peter A Fasching¹⁷, Laura Baglietto¹⁸, Melissa C Southey¹⁹, Graham G Giles¹⁸, Kaanan P Shah⁸, Heang-Ping Chan²⁰, Mark A Helvie²⁰, Andrew H Beck²¹, Nicholas W Knoblauch²¹, Aditi Hazra²², David J Hunter²², Peter Kraft²³, Marina Pollan¹⁰, Jonine D Figueroa⁵, Fergus J Couch²⁴, John L Hopper²⁵, Per Hall⁴, Douglas F Easton²⁶, Norman F Boyd²⁷, Celine M Vachon⁶, Rulla M Tamimi²²

Affiliations

¹ 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.
² 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 Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
⁵ Hormonal and Reproductive Epidemiology Branch, National Cancer Institute, Bethesda, Maryland 20850, USA.
⁶ Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
⁷ Centre for Genetic Origins of Health and Disease, University of Western Australia, Perth, Western Australia 6009, Australia.
⁸ Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
⁹ Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
¹⁰ 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.
¹¹ 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.
¹² Centre for Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
¹³ Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB1 8RN, UK.
¹⁴ 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.
¹⁵ Division of Cardiovascular Disease, Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
¹⁶ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
¹⁷ 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.
¹⁸ 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.
¹⁹ Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia.
²⁰ Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
²¹ Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.
²² 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.
²³ 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.
²⁴ 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.
²⁵ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010, Australia.
²⁶ 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.
²⁷ Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada M5G 2M9.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Breast Density
Breast Neoplasms / diagnostic imaging*
Breast Neoplasms / genetics*
Case-Control Studies
Female
Genetic Loci*
Genetic Predisposition to Disease*
Genome-Wide Association Study*
Humans
Mammary Glands, Human / abnormalities*
Polymorphism, Single Nucleotide / genetics
Radiography

Abstract

Publication types

MeSH terms

Grants and funding