Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci

Hongjie Chen; Shaoqi Fan; Jennifer Stone; Deborah J. Thompson; Julie Douglas; Shuai Li; Christopher Scott; Manjeet K. Bolla; Qin Wang; Joe Dennis; Kyriaki Michailidou; Christopher Li; Ulrike Peters; John L. Hopper; Melissa C. Southey; Tu Nguyen-dumont; Tuong L. Nguyen; Peter A. Fasching; Annika Behrens; Gemma Cadby; Rachel A. Murphy; Kristan Aronson; Anthony Howell; Susan Astley; Fergus Couch; Janet Olson; Roger L. Milne; Graham G. Giles; Christopher A. Haiman; Gertraud Maskarinec; Stacey Winham; Esther M. John; Allison Kurian; Heather Eliassen; Irene Andrulis; D. Gareth Evans; William G. Newman; Per Hall; Kamila Czene; Anthony Swerdlow; Michael Jones; Marina Pollan; Pablo Fernandez-navarro; Daniel S. Mcconnell; Vessela N. Kristensen; Joseph H. Rothstein; Pei Wang; Laurel A. Habel; Weiva Sieh; Alison M. Dunning; Paul D. P. Pharoah; Douglas F. Easton; Gretchen L. Gierach; Rulla M. Tamimi; Celine M. Vachon; Sara Lindström

doi:10.1186/s13058-022-01524-0

Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci

Hongjie Chen, Shaoqi Fan, Jennifer Stone, Deborah J. Thompson, Julie Douglas, Shuai Li, Christopher Scott, Manjeet K. Bolla, Qin Wang, Joe Dennis, Kyriaki Michailidou, Christopher Li, Ulrike Peters, John L. Hopper, Melissa C. Southey, Tu Nguyen-dumont, Tuong L. Nguyen, Peter A. Fasching, Annika Behrens, Gemma CadbyRachel A. Murphy, Kristan Aronson, Anthony Howell, Susan Astley, Fergus Couch, Janet Olson, Roger L. Milne, Graham G. Giles, Christopher A. Haiman, Gertraud Maskarinec, Stacey Winham, Esther M. John, Allison Kurian, Heather Eliassen, Irene Andrulis, D. Gareth Evans, William G. Newman, Per Hall, Kamila Czene, Anthony Swerdlow, Michael Jones, Marina Pollan, Pablo Fernandez-navarro, Daniel S. Mcconnell, Vessela N. Kristensen, Joseph H. Rothstein, Pei Wang, Laurel A. Habel, Weiva Sieh, Alison M. Dunning, Paul D. P. Pharoah, Douglas F. Easton, Gretchen L. Gierach, Rulla M. Tamimi, Celine M. Vachon, Sara Lindström

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Abstract

Background
Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants.

Methods
We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia.

Results
We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes.

Conclusions
Our findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.

Original language	English
Journal	Breast Cancer Research
Volume	24
Issue number	1
Early online date	12 Apr 2022
DOIs	https://doi.org/10.1186/s13058-022-01524-0
Publication status	Published - 12 Apr 2022

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

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https://breast-cancer-research.biomedcentral.com/articles/10.1186/s13058-022-01524-0

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Chen, H., Fan, S., Stone, J., Thompson, D. J., Douglas, J., Li, S., Scott, C., Bolla, M. K., Wang, Q., Dennis, J., Michailidou, K., Li, C., Peters, U., Hopper, J. L., Southey, M. C., Nguyen-dumont, T., Nguyen, T. L., Fasching, P. A., Behrens, A., ... Lindström, S. (2022). Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci. Breast Cancer Research, 24(1). Advance online publication. https://doi.org/10.1186/s13058-022-01524-0

@article{10b1e8da9d0c4ec0abcd7cbdd10bc737,

title = "Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci",

abstract = "BackgroundMammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants.MethodsWe conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia.ResultsWe identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes.ConclusionsOur findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.",

author = "Hongjie Chen and Shaoqi Fan and Jennifer Stone and Thompson, {Deborah J.} and Julie Douglas and Shuai Li and Christopher Scott and Bolla, {Manjeet K.} and Qin Wang and Joe Dennis and Kyriaki Michailidou and Christopher Li and Ulrike Peters and Hopper, {John L.} and Southey, {Melissa C.} and Tu Nguyen-dumont and Nguyen, {Tuong L.} and Fasching, {Peter A.} and Annika Behrens and Gemma Cadby and Murphy, {Rachel A.} and Kristan Aronson and Anthony Howell and Susan Astley and Fergus Couch and Janet Olson and Milne, {Roger L.} and Giles, {Graham G.} and Haiman, {Christopher A.} and Gertraud Maskarinec and Stacey Winham and John, {Esther M.} and Allison Kurian and Heather Eliassen and Irene Andrulis and Evans, {D. Gareth} and Newman, {William G.} and Per Hall and Kamila Czene and Anthony Swerdlow and Michael Jones and Marina Pollan and Pablo Fernandez-navarro and Mcconnell, {Daniel S.} and Kristensen, {Vessela N.} and Rothstein, {Joseph H.} and Pei Wang and Habel, {Laurel A.} and Weiva Sieh and Dunning, {Alison M.} and Pharoah, {Paul D. P.} and Easton, {Douglas F.} and Gierach, {Gretchen L.} and Tamimi, {Rulla M.} and Vachon, {Celine M.} and Sara Lindstr{\"o}m",

year = "2022",

month = apr,

day = "12",

doi = "10.1186/s13058-022-01524-0",

language = "English",

volume = "24",

journal = "Breast Cancer Research",

issn = "1465-5411",

publisher = "Springer Nature",

number = "1",

}

Chen, H, Fan, S, Stone, J, Thompson, DJ, Douglas, J, Li, S, Scott, C, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Li, C, Peters, U, Hopper, JL, Southey, MC, Nguyen-dumont, T, Nguyen, TL, Fasching, PA, Behrens, A, Cadby, G, Murphy, RA, Aronson, K, Howell, A , Astley, S, Couch, F, Olson, J, Milne, RL, Giles, GG, Haiman, CA, Maskarinec, G, Winham, S, John, EM, Kurian, A, Eliassen, H, Andrulis, I, Evans, DG , Newman, WG, Hall, P, Czene, K, Swerdlow, A, Jones, M, Pollan, M, Fernandez-navarro, P, Mcconnell, DS, Kristensen, VN, Rothstein, JH, Wang, P, Habel, LA, Sieh, W, Dunning, AM, Pharoah, PDP, Easton, DF, Gierach, GL, Tamimi, RM, Vachon, CM & Lindström, S 2022, 'Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci', Breast Cancer Research, vol. 24, no. 1. https://doi.org/10.1186/s13058-022-01524-0

TY - JOUR

T1 - Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci

AU - Chen, Hongjie

AU - Fan, Shaoqi

AU - Stone, Jennifer

AU - Thompson, Deborah J.

AU - Douglas, Julie

AU - Li, Shuai

AU - Scott, Christopher

AU - Bolla, Manjeet K.

AU - Wang, Qin

AU - Dennis, Joe

AU - Michailidou, Kyriaki

AU - Li, Christopher

AU - Peters, Ulrike

AU - Hopper, John L.

AU - Southey, Melissa C.

AU - Nguyen-dumont, Tu

AU - Nguyen, Tuong L.

AU - Fasching, Peter A.

AU - Behrens, Annika

AU - Cadby, Gemma

AU - Murphy, Rachel A.

AU - Aronson, Kristan

AU - Howell, Anthony

AU - Astley, Susan

AU - Couch, Fergus

AU - Olson, Janet

AU - Milne, Roger L.

AU - Giles, Graham G.

AU - Haiman, Christopher A.

AU - Maskarinec, Gertraud

AU - Winham, Stacey

AU - John, Esther M.

AU - Kurian, Allison

AU - Eliassen, Heather

AU - Andrulis, Irene

AU - Evans, D. Gareth

AU - Newman, William G.

AU - Hall, Per

AU - Czene, Kamila

AU - Swerdlow, Anthony

AU - Jones, Michael

AU - Pollan, Marina

AU - Fernandez-navarro, Pablo

AU - Mcconnell, Daniel S.

AU - Kristensen, Vessela N.

AU - Rothstein, Joseph H.

AU - Wang, Pei

AU - Habel, Laurel A.

AU - Sieh, Weiva

AU - Dunning, Alison M.

AU - Pharoah, Paul D. P.

AU - Easton, Douglas F.

AU - Gierach, Gretchen L.

AU - Tamimi, Rulla M.

AU - Vachon, Celine M.

AU - Lindström, Sara

PY - 2022/4/12

Y1 - 2022/4/12

N2 - BackgroundMammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants.MethodsWe conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia.ResultsWe identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes.ConclusionsOur findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.

AB - BackgroundMammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants.MethodsWe conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia.ResultsWe identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes.ConclusionsOur findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.

U2 - 10.1186/s13058-022-01524-0

DO - 10.1186/s13058-022-01524-0

M3 - Article

SN - 1465-5411

VL - 24

JO - Breast Cancer Research

JF - Breast Cancer Research

IS - 1

ER -

Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci

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