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

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. GoodeJulie 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

Research output: Contribution to journal › Article › peer-review

74 Scopus citations

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.

Original language	English (US)
Article number	5303
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms6303
State	Published - Oct 24 2014

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

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10.1038/ncomms6303

Cite this

Lindström, S., Thompson, D. J., Paterson, A. D., Li, J., Gierach, G. L., Scott, C., Stone, J., Douglas, J. A., Dos-Santos-Silva, I., Fernandez-Navarro, P., Verghase, J., Smith, P., Brown, J., Luben, R., Wareham, N. J., Loos, R. J. F., Heit, J. A., Shane Pankratz, V., Norman, A., ... Tamimi, R. M. (2014). Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk. Nature communications, 5, [5303]. https://doi.org/10.1038/ncomms6303

Lindström, S, Thompson, DJ, Paterson, AD, Li, J, Gierach, GL, Scott, C, Stone, J, Douglas, JA, Dos-Santos-Silva, I, Fernandez-Navarro, P, Verghase, J, Smith, P, Brown, J, Luben, R, Wareham, NJ, Loos, RJF, Heit, JA, Shane Pankratz, V, Norman, A, Goode, EL , Cunningham, JM , DeAndrade, M, Vierkant, RA, Czene, K, Fasching, PA, Baglietto, L, Southey, MC, Giles, GG, Shah, KP, Chan, HP, Helvie, MA, Beck, AH, Knoblauch, NW, Hazra, A, Hunter, DJ, Kraft, P, Pollan, M, Figueroa, JD, Couch, FJ, Hopper, JL, Hall, P, Easton, DF, Boyd, NF, Vachon, CM & Tamimi, RM 2014, 'Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk', Nature communications, vol. 5, 5303. https://doi.org/10.1038/ncomms6303

@article{c2b421a67d0c44d2bae6456ee52480fc,

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.",

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

note = "Funding Information: This study was supported by CA131332, CA087969, CA049449, CA128931, CA116201, CA075016, CA122340, CA122844, CA15083, CA089393, K22LM011931 and X01 HG005954 from NIH; genotyping services for the OOA study were provided by the Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096; The Breast Cancer Research Foundation, Breast Cancer Research Fund; Cancer Research UK; M{\"a}rit & Hans Rausing{\textquoteright}s Initiative against Breast Cancer; Susan Komen Foundation; Agency for Science, Technology and Research of Singapore (A*STAR); David F. and Margaret T. Grohne Family Foundation; Campbell Family Institute for Breast Cancer Research; David F. and Margaret T. Grohne Family Foundation; Ontario Ministry of Health and Long Term Care; Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale; FIS PI060386 from the Spain{\textquoteright}s Health Research Fund and EPY 1306/06 Collaboration Agreement between Astra-Zeneca and the Carlos III Institute of Health; Elizabeth C. Crosby Research Award, Gladys E. Davis Endowed Fund and the Office for Vice President of Research at the University of Michigan. EPIC-Norfolk was funded by research programme grant funding from Cancer Research UK and the Medical Research Council with additional support from the Stroke Association, British Heart Foundation, Department of Health, Research into Ageing and Academy of Medical Sciences. The SIBS study was supported by programme grant C1287/A10118 and project grants from Cancer Research UK (grant numbers C1287/8459). SEARCH is funded by a programme grant from Cancer Research UK (C490/A10124). The Polish Breast Cancer Study was supported (in part) by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The breast cancer meta-analysis is supported by the GAME-ON DRIVE (CA148065) and BCAC initiatives. We thank the BCAC, GAME-ON and DRIVE initiatives for generously sharing breast cancer association results for selected SNPs. We also thank the investigators in BCAC, PRACTICAL, CIMBA and OCAC for access to the iCOGS data for the replication analysis. BBCC was funded in part by the ELAN Programme of the Medical Faculty, Friedrich-Alexander University Erlangen-Nuremberg. We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. The OOA study investigators thank the members of the Amish community for their generous support and participation, the staff at the Amish Research Clinic for their dedicated recruitment and fieldwork efforts, the members of Dr Margarita Shultz{\textquoteright}s radiology clinic for their expert mammography services, the staff at the Center for Inherited Disease Research for their exceptional genotyping services, Drs Alan Shuldiner and Braxton Mitchell at the University of Maryland for their guidance and help with our fieldwork, and Terry Gliedt, Jennifer Greene Nidetz, Kristen Maas, Cris Van Hout, James MacDonald, Chris Plotts, Lubomir Hadjiiski and Chuan Zhou at the University of Michigan for their technical assistance with data management, entry and analysis and film digitization and scoring. The PBCS would like to thank Pei Chao and Michael Stagner from Information Management Services (Silver Spring, MD) for data management support; Laurie Burdette, Amy Hutchinson and Jeff Yuenger from the NCI Core Genotyping facility for genotyping support; the participants, physicians, pathologists, nurses and interviewers from participating centres in Poland for their efforts during fieldwork; Drs Jola Lissowska and Ewa Wesolowska from the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland for their assistance with mammogram retrieval; Dr Norman Boyd from the University of Toronto for providing the mammographic density assessments; and Drs. Louise Brinton, Montserrat Garcia-Closas, Beata Peplonska and Mark Sherman for their contributions to the study design. We thank Paul Pharoah and the SEARCH and EPIC teams. The iCOGS project would not have been possible without the contributions of the following: Paul Pharoah, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang (BCAC), Andrew Berchuck (OCAC), Rosalind A. Eeles, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Georgia Chenevix-Trench, Antonis Antoniou, Lesley McGuffog and Ken Offit (CIMBA), Joe Dennis, Alison M. Dunning, Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Javier Benitez, Anna Gonzalez-Neira and the staff of the CNIO genotyping unit, Jacques Simard and Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissi{\`e}re and Frederic Robidoux and the staff of the McGill University and G{\'e}nome Qu{\'e}bec Innovation Centre, Stig E. Bojesen, Sune F. Nielsen, Borge G. Nordestgaard and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility. The iCOGS infrastructure was funded by the following: the European Community{\textquoteright}s Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2–2009–223175; COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112—the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund. The results published here are in part based upon data generated by The Cancer Genome Atlas project established by the NCI and NHGRI (dbGaP Study Accession: phs000178.v8.p7). Information about TCGA and the investigators and institutions who constitute the TCGA research network can be found at http://cancergenome.nih.gov/. Publisher Copyright: {\textcopyright} 2014 Macmillan Publishers Limited. All rights reserved.",

year = "2014",

month = oct,

day = "24",

doi = "10.1038/ncomms6303",

language = "English (US)",

volume = "5",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk

AU - Lindström, Sara

AU - Thompson, Deborah J.

AU - Paterson, Andrew D.

AU - Li, Jingmei

AU - Gierach, Gretchen L.

AU - Scott, Christopher

AU - Stone, Jennifer

AU - Douglas, Julie A.

AU - Dos-Santos-Silva, Isabel

AU - Fernandez-Navarro, Pablo

AU - Verghase, Jajini

AU - Smith, Paula

AU - Brown, Judith

AU - Luben, Robert

AU - Wareham, Nicholas J.

AU - Loos, Ruth J.F.

AU - Heit, John A.

AU - Shane Pankratz, V.

AU - Norman, Aaron

AU - Goode, Ellen L.

AU - Cunningham, Julie M.

AU - DeAndrade, Mariza

AU - Vierkant, Robert A.

AU - Czene, Kamila

AU - Fasching, Peter A.

AU - Baglietto, Laura

AU - Southey, Melissa C.

AU - Giles, Graham G.

AU - Shah, Kaanan P.

AU - Chan, Heang Ping

AU - Helvie, Mark A.

AU - Beck, Andrew H.

AU - Knoblauch, Nicholas W.

AU - Hazra, Aditi

AU - Hunter, David J.

AU - Kraft, Peter

AU - Pollan, Marina

AU - Figueroa, Jonine D.

AU - Couch, Fergus J.

AU - Hopper, John L.

AU - Hall, Per

AU - Easton, Douglas F.

AU - Boyd, Norman F.

AU - Vachon, Celine M.

AU - Tamimi, Rulla M.

N1 - Funding Information: This study was supported by CA131332, CA087969, CA049449, CA128931, CA116201, CA075016, CA122340, CA122844, CA15083, CA089393, K22LM011931 and X01 HG005954 from NIH; genotyping services for the OOA study were provided by the Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096; The Breast Cancer Research Foundation, Breast Cancer Research Fund; Cancer Research UK; Märit & Hans Rausing’s Initiative against Breast Cancer; Susan Komen Foundation; Agency for Science, Technology and Research of Singapore (A*STAR); David F. and Margaret T. Grohne Family Foundation; Campbell Family Institute for Breast Cancer Research; David F. and Margaret T. Grohne Family Foundation; Ontario Ministry of Health and Long Term Care; Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale; FIS PI060386 from the Spain’s Health Research Fund and EPY 1306/06 Collaboration Agreement between Astra-Zeneca and the Carlos III Institute of Health; Elizabeth C. Crosby Research Award, Gladys E. Davis Endowed Fund and the Office for Vice President of Research at the University of Michigan. EPIC-Norfolk was funded by research programme grant funding from Cancer Research UK and the Medical Research Council with additional support from the Stroke Association, British Heart Foundation, Department of Health, Research into Ageing and Academy of Medical Sciences. The SIBS study was supported by programme grant C1287/A10118 and project grants from Cancer Research UK (grant numbers C1287/8459). SEARCH is funded by a programme grant from Cancer Research UK (C490/A10124). The Polish Breast Cancer Study was supported (in part) by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The breast cancer meta-analysis is supported by the GAME-ON DRIVE (CA148065) and BCAC initiatives. We thank the BCAC, GAME-ON and DRIVE initiatives for generously sharing breast cancer association results for selected SNPs. We also thank the investigators in BCAC, PRACTICAL, CIMBA and OCAC for access to the iCOGS data for the replication analysis. BBCC was funded in part by the ELAN Programme of the Medical Faculty, Friedrich-Alexander University Erlangen-Nuremberg. We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. The OOA study investigators thank the members of the Amish community for their generous support and participation, the staff at the Amish Research Clinic for their dedicated recruitment and fieldwork efforts, the members of Dr Margarita Shultz’s radiology clinic for their expert mammography services, the staff at the Center for Inherited Disease Research for their exceptional genotyping services, Drs Alan Shuldiner and Braxton Mitchell at the University of Maryland for their guidance and help with our fieldwork, and Terry Gliedt, Jennifer Greene Nidetz, Kristen Maas, Cris Van Hout, James MacDonald, Chris Plotts, Lubomir Hadjiiski and Chuan Zhou at the University of Michigan for their technical assistance with data management, entry and analysis and film digitization and scoring. The PBCS would like to thank Pei Chao and Michael Stagner from Information Management Services (Silver Spring, MD) for data management support; Laurie Burdette, Amy Hutchinson and Jeff Yuenger from the NCI Core Genotyping facility for genotyping support; the participants, physicians, pathologists, nurses and interviewers from participating centres in Poland for their efforts during fieldwork; Drs Jola Lissowska and Ewa Wesolowska from the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland for their assistance with mammogram retrieval; Dr Norman Boyd from the University of Toronto for providing the mammographic density assessments; and Drs. Louise Brinton, Montserrat Garcia-Closas, Beata Peplonska and Mark Sherman for their contributions to the study design. We thank Paul Pharoah and the SEARCH and EPIC teams. The iCOGS project would not have been possible without the contributions of the following: Paul Pharoah, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang (BCAC), Andrew Berchuck (OCAC), Rosalind A. Eeles, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Georgia Chenevix-Trench, Antonis Antoniou, Lesley McGuffog and Ken Offit (CIMBA), Joe Dennis, Alison M. Dunning, Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Javier Benitez, Anna Gonzalez-Neira and the staff of the CNIO genotyping unit, Jacques Simard and Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissière and Frederic Robidoux and the staff of the McGill University and Génome Québec Innovation Centre, Stig E. Bojesen, Sune F. Nielsen, Borge G. Nordestgaard and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility. The iCOGS infrastructure was funded by the following: the European Community’s Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2–2009–223175; COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112—the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund. The results published here are in part based upon data generated by The Cancer Genome Atlas project established by the NCI and NHGRI (dbGaP Study Accession: phs000178.v8.p7). Information about TCGA and the investigators and institutions who constitute the TCGA research network can be found at http://cancergenome.nih.gov/. Publisher Copyright: © 2014 Macmillan Publishers Limited. All rights reserved.

PY - 2014/10/24

Y1 - 2014/10/24

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84923349434&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84923349434&partnerID=8YFLogxK

U2 - 10.1038/ncomms6303

DO - 10.1038/ncomms6303

M3 - Article

C2 - 25342443

AN - SCOPUS:84923349434

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 5303

ER -

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

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