Genetically Predicted Body Mass Index and Breast Cancer Risk

Mendelian Randomization Analyses of Data from 145,000 Women of European Descent

Yan Guo, Shaneda Warren Andersen, Xiao Ou Shu, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang, Montserrat Garcia-Closas, Roger L. Milne, Marjanka K. Schmidt, Jenny Chang-Claude, Allison Dunning, Stig E. Bojesen, Habibul Ahsan, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Matthias W. Beckmann, Alicia Beeghly-Fadiel, Javier Benitez & 91 others Natalia V. Bogdanova, Bernardo Bonanni, Anne Lise Børresen-Dale, Judith Brand, Hiltrud Brauch, Hermann Brenner, Thomas Brüning, Barbara Burwinkel, Graham Casey, Georgia Chenevix-Trench, Fergus J Couch, Angela Cox, Simon S. Cross, Kamila Czene, Peter Devilee, Thilo Dörk, Martine Dumont, Peter A. Fasching, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, Florentia Fostira, Marilie Gammon, Graham G. Giles, Pascal Guénel, Christopher A. Haiman, Ute Hamann, Maartje J. Hooning, John L. Hopper, Anna Jakubowska, Farzana Jasmine, Mark Jenkins, Esther M. John, Nichola Johnson, Michael E. Jones, Maria Kabisch, Muhammad Kibriya, Julia A. Knight, Linetta B. Koppert, Veli Matti Kosma, Vessela Kristensen, Loic Le Marchand, Eunjung Lee, Jingmei Li, Annika Lindblom, Robert Luben, Jan Lubinski, Kathi E. Malone, Arto Mannermaa, Sara Margolin, Frederik Marme, Catriona McLean, Hanne Meijers-Heijboer, Alfons Meindl, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, Janet E Olson, Jose I A Perez, Barbara Perkins, Paolo Peterlongo, Kelly Anne Phillips, Katri Pylkäs, Anja Rudolph, Regina Santella, Elinor J. Sawyer, Rita K. Schmutzler, Caroline Seynaeve, Mitul Shah, Martha J. Shrubsole, Melissa C. Southey, Anthony J. Swerdlow, Amanda E. Toland, Ian Tomlinson, Diana Torres, Thérèse Truong, Giske Ursin, Rob B. Van Der Luijt, Senno Verhoef, Alice S. Whittemore, Robert Winqvist, Hui Zhao, Shilin Zhao, Per Hall, Jacques Simard, Peter Kraft, Paul Pharoah, David Hunter, Douglas F. Easton, Wei Zheng

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Background: Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors. Methods: We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively. Results: In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56–0.75, p = 3.32 × 10−10). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31–0.62, p = 9.91 × 10−8) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46–0.71, p = 1.88 × 10−8). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60–0.84, p = 1.64 × 10−7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk. Conclusions: BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.

Original languageEnglish (US)
Article numbere1002105
JournalPLoS Medicine
Volume13
Issue number8
DOIs
StatePublished - Aug 1 2016

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Mendelian Randomization Analysis
Body Mass Index
Breast Neoplasms
Odds Ratio
Confidence Intervals

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Genetically Predicted Body Mass Index and Breast Cancer Risk : Mendelian Randomization Analyses of Data from 145,000 Women of European Descent. / Guo, Yan; Warren Andersen, Shaneda; Shu, Xiao Ou; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Garcia-Closas, Montserrat; Milne, Roger L.; Schmidt, Marjanka K.; Chang-Claude, Jenny; Dunning, Allison; Bojesen, Stig E.; Ahsan, Habibul; Aittomäki, Kristiina; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W.; Beeghly-Fadiel, Alicia; Benitez, Javier; Bogdanova, Natalia V.; Bonanni, Bernardo; Børresen-Dale, Anne Lise; Brand, Judith; Brauch, Hiltrud; Brenner, Hermann; Brüning, Thomas; Burwinkel, Barbara; Casey, Graham; Chenevix-Trench, Georgia; Couch, Fergus J; Cox, Angela; Cross, Simon S.; Czene, Kamila; Devilee, Peter; Dörk, Thilo; Dumont, Martine; Fasching, Peter A.; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Fostira, Florentia; Gammon, Marilie; Giles, Graham G.; Guénel, Pascal; Haiman, Christopher A.; Hamann, Ute; Hooning, Maartje J.; Hopper, John L.; Jakubowska, Anna; Jasmine, Farzana; Jenkins, Mark; John, Esther M.; Johnson, Nichola; Jones, Michael E.; Kabisch, Maria; Kibriya, Muhammad; Knight, Julia A.; Koppert, Linetta B.; Kosma, Veli Matti; Kristensen, Vessela; Le Marchand, Loic; Lee, Eunjung; Li, Jingmei; Lindblom, Annika; Luben, Robert; Lubinski, Jan; Malone, Kathi E.; Mannermaa, Arto; Margolin, Sara; Marme, Frederik; McLean, Catriona; Meijers-Heijboer, Hanne; Meindl, Alfons; Neuhausen, Susan L.; Nevanlinna, Heli; Neven, Patrick; Olson, Janet E; Perez, Jose I A; Perkins, Barbara; Peterlongo, Paolo; Phillips, Kelly Anne; Pylkäs, Katri; Rudolph, Anja; Santella, Regina; Sawyer, Elinor J.; Schmutzler, Rita K.; Seynaeve, Caroline; Shah, Mitul; Shrubsole, Martha J.; Southey, Melissa C.; Swerdlow, Anthony J.; Toland, Amanda E.; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Ursin, Giske; Van Der Luijt, Rob B.; Verhoef, Senno; Whittemore, Alice S.; Winqvist, Robert; Zhao, Hui; Zhao, Shilin; Hall, Per; Simard, Jacques; Kraft, Peter; Pharoah, Paul; Hunter, David; Easton, Douglas F.; Zheng, Wei.

In: PLoS Medicine, Vol. 13, No. 8, e1002105, 01.08.2016.

Research output: Contribution to journalArticle

Guo, Y, Warren Andersen, S, Shu, XO, Michailidou, K, Bolla, MK, Wang, Q, Garcia-Closas, M, Milne, RL, Schmidt, MK, Chang-Claude, J, Dunning, A, Bojesen, SE, Ahsan, H, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bogdanova, NV, Bonanni, B, Børresen-Dale, AL, Brand, J, Brauch, H, Brenner, H, Brüning, T, Burwinkel, B, Casey, G, Chenevix-Trench, G, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dörk, T, Dumont, M, Fasching, PA, Figueroa, J, Flesch-Janys, D, Fletcher, O, Flyger, H, Fostira, F, Gammon, M, Giles, GG, Guénel, P, Haiman, CA, Hamann, U, Hooning, MJ, Hopper, JL, Jakubowska, A, Jasmine, F, Jenkins, M, John, EM, Johnson, N, Jones, ME, Kabisch, M, Kibriya, M, Knight, JA, Koppert, LB, Kosma, VM, Kristensen, V, Le Marchand, L, Lee, E, Li, J, Lindblom, A, Luben, R, Lubinski, J, Malone, KE, Mannermaa, A, Margolin, S, Marme, F, McLean, C, Meijers-Heijboer, H, Meindl, A, Neuhausen, SL, Nevanlinna, H, Neven, P, Olson, JE, Perez, JIA, Perkins, B, Peterlongo, P, Phillips, KA, Pylkäs, K, Rudolph, A, Santella, R, Sawyer, EJ, Schmutzler, RK, Seynaeve, C, Shah, M, Shrubsole, MJ, Southey, MC, Swerdlow, AJ, Toland, AE, Tomlinson, I, Torres, D, Truong, T, Ursin, G, Van Der Luijt, RB, Verhoef, S, Whittemore, AS, Winqvist, R, Zhao, H, Zhao, S, Hall, P, Simard, J, Kraft, P, Pharoah, P, Hunter, D, Easton, DF & Zheng, W 2016, 'Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent', PLoS Medicine, vol. 13, no. 8, e1002105. https://doi.org/10.1371/journal.pmed.1002105
Guo, Yan ; Warren Andersen, Shaneda ; Shu, Xiao Ou ; Michailidou, Kyriaki ; Bolla, Manjeet K. ; Wang, Qin ; Garcia-Closas, Montserrat ; Milne, Roger L. ; Schmidt, Marjanka K. ; Chang-Claude, Jenny ; Dunning, Allison ; Bojesen, Stig E. ; Ahsan, Habibul ; Aittomäki, Kristiina ; Andrulis, Irene L. ; Anton-Culver, Hoda ; Arndt, Volker ; Beckmann, Matthias W. ; Beeghly-Fadiel, Alicia ; Benitez, Javier ; Bogdanova, Natalia V. ; Bonanni, Bernardo ; Børresen-Dale, Anne Lise ; Brand, Judith ; Brauch, Hiltrud ; Brenner, Hermann ; Brüning, Thomas ; Burwinkel, Barbara ; Casey, Graham ; Chenevix-Trench, Georgia ; Couch, Fergus J ; Cox, Angela ; Cross, Simon S. ; Czene, Kamila ; Devilee, Peter ; Dörk, Thilo ; Dumont, Martine ; Fasching, Peter A. ; Figueroa, Jonine ; Flesch-Janys, Dieter ; Fletcher, Olivia ; Flyger, Henrik ; Fostira, Florentia ; Gammon, Marilie ; Giles, Graham G. ; Guénel, Pascal ; Haiman, Christopher A. ; Hamann, Ute ; Hooning, Maartje J. ; Hopper, John L. ; Jakubowska, Anna ; Jasmine, Farzana ; Jenkins, Mark ; John, Esther M. ; Johnson, Nichola ; Jones, Michael E. ; Kabisch, Maria ; Kibriya, Muhammad ; Knight, Julia A. ; Koppert, Linetta B. ; Kosma, Veli Matti ; Kristensen, Vessela ; Le Marchand, Loic ; Lee, Eunjung ; Li, Jingmei ; Lindblom, Annika ; Luben, Robert ; Lubinski, Jan ; Malone, Kathi E. ; Mannermaa, Arto ; Margolin, Sara ; Marme, Frederik ; McLean, Catriona ; Meijers-Heijboer, Hanne ; Meindl, Alfons ; Neuhausen, Susan L. ; Nevanlinna, Heli ; Neven, Patrick ; Olson, Janet E ; Perez, Jose I A ; Perkins, Barbara ; Peterlongo, Paolo ; Phillips, Kelly Anne ; Pylkäs, Katri ; Rudolph, Anja ; Santella, Regina ; Sawyer, Elinor J. ; Schmutzler, Rita K. ; Seynaeve, Caroline ; Shah, Mitul ; Shrubsole, Martha J. ; Southey, Melissa C. ; Swerdlow, Anthony J. ; Toland, Amanda E. ; Tomlinson, Ian ; Torres, Diana ; Truong, Thérèse ; Ursin, Giske ; Van Der Luijt, Rob B. ; Verhoef, Senno ; Whittemore, Alice S. ; Winqvist, Robert ; Zhao, Hui ; Zhao, Shilin ; Hall, Per ; Simard, Jacques ; Kraft, Peter ; Pharoah, Paul ; Hunter, David ; Easton, Douglas F. ; Zheng, Wei. / Genetically Predicted Body Mass Index and Breast Cancer Risk : Mendelian Randomization Analyses of Data from 145,000 Women of European Descent. In: PLoS Medicine. 2016 ; Vol. 13, No. 8.
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title = "Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent",
abstract = "Background: Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors. Methods: We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively. Results: In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95{\%} confidence interval [CI]: 0.56–0.75, p = 3.32 × 10−10). The associations were similar for both premenopausal (OR = 0.44, 95{\%} CI:0.31–0.62, p = 9.91 × 10−8) and postmenopausal breast cancer (OR = 0.57, 95{\%} CI: 0.46–0.71, p = 1.88 × 10−8). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95{\%} CI: 0.60–0.84, p = 1.64 × 10−7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk. Conclusions: BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.",
author = "Yan Guo and {Warren Andersen}, Shaneda and Shu, {Xiao Ou} and Kyriaki Michailidou and Bolla, {Manjeet K.} and Qin Wang and Montserrat Garcia-Closas and Milne, {Roger L.} and Schmidt, {Marjanka K.} and Jenny Chang-Claude and Allison Dunning and Bojesen, {Stig E.} and Habibul Ahsan and Kristiina Aittom{\"a}ki and Andrulis, {Irene L.} and Hoda Anton-Culver and Volker Arndt and Beckmann, {Matthias W.} and Alicia Beeghly-Fadiel and Javier Benitez and Bogdanova, {Natalia V.} and Bernardo Bonanni and B{\o}rresen-Dale, {Anne Lise} and Judith Brand and Hiltrud Brauch and Hermann Brenner and Thomas Br{\"u}ning and Barbara Burwinkel and Graham Casey and Georgia Chenevix-Trench and Couch, {Fergus J} and Angela Cox and Cross, {Simon S.} and Kamila Czene and Peter Devilee and Thilo D{\"o}rk and Martine Dumont and Fasching, {Peter A.} and Jonine Figueroa and Dieter Flesch-Janys and Olivia Fletcher and Henrik Flyger and Florentia Fostira and Marilie Gammon and Giles, {Graham G.} and Pascal Gu{\'e}nel and Haiman, {Christopher A.} and Ute Hamann and Hooning, {Maartje J.} and Hopper, {John L.} and Anna Jakubowska and Farzana Jasmine and Mark Jenkins and John, {Esther M.} and Nichola Johnson and Jones, {Michael E.} and Maria Kabisch and Muhammad Kibriya and Knight, {Julia A.} and Koppert, {Linetta B.} and Kosma, {Veli Matti} and Vessela Kristensen and {Le Marchand}, Loic and Eunjung Lee and Jingmei Li and Annika Lindblom and Robert Luben and Jan Lubinski and Malone, {Kathi E.} and Arto Mannermaa and Sara Margolin and Frederik Marme and Catriona McLean and Hanne Meijers-Heijboer and Alfons Meindl and Neuhausen, {Susan L.} and Heli Nevanlinna and Patrick Neven and Olson, {Janet E} and Perez, {Jose I A} and Barbara Perkins and Paolo Peterlongo and Phillips, {Kelly Anne} and Katri Pylk{\"a}s and Anja Rudolph and Regina Santella and Sawyer, {Elinor J.} and Schmutzler, {Rita K.} and Caroline Seynaeve and Mitul Shah and Shrubsole, {Martha J.} and Southey, {Melissa C.} and Swerdlow, {Anthony J.} and Toland, {Amanda E.} and Ian Tomlinson and Diana Torres and Th{\'e}r{\`e}se Truong and Giske Ursin and {Van Der Luijt}, {Rob B.} and Senno Verhoef and Whittemore, {Alice S.} and Robert Winqvist and Hui Zhao and Shilin Zhao and Per Hall and Jacques Simard and Peter Kraft and Paul Pharoah and David Hunter and Easton, {Douglas F.} and Wei Zheng",
year = "2016",
month = "8",
day = "1",
doi = "10.1371/journal.pmed.1002105",
language = "English (US)",
volume = "13",
journal = "PLoS Medicine",
issn = "1549-1277",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - Genetically Predicted Body Mass Index and Breast Cancer Risk

T2 - Mendelian Randomization Analyses of Data from 145,000 Women of European Descent

AU - Guo, Yan

AU - Warren Andersen, Shaneda

AU - Shu, Xiao Ou

AU - Michailidou, Kyriaki

AU - Bolla, Manjeet K.

AU - Wang, Qin

AU - Garcia-Closas, Montserrat

AU - Milne, Roger L.

AU - Schmidt, Marjanka K.

AU - Chang-Claude, Jenny

AU - Dunning, Allison

AU - Bojesen, Stig E.

AU - Ahsan, Habibul

AU - Aittomäki, Kristiina

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Beckmann, Matthias W.

AU - Beeghly-Fadiel, Alicia

AU - Benitez, Javier

AU - Bogdanova, Natalia V.

AU - Bonanni, Bernardo

AU - Børresen-Dale, Anne Lise

AU - Brand, Judith

AU - Brauch, Hiltrud

AU - Brenner, Hermann

AU - Brüning, Thomas

AU - Burwinkel, Barbara

AU - Casey, Graham

AU - Chenevix-Trench, Georgia

AU - Couch, Fergus J

AU - Cox, Angela

AU - Cross, Simon S.

AU - Czene, Kamila

AU - Devilee, Peter

AU - Dörk, Thilo

AU - Dumont, Martine

AU - Fasching, Peter A.

AU - Figueroa, Jonine

AU - Flesch-Janys, Dieter

AU - Fletcher, Olivia

AU - Flyger, Henrik

AU - Fostira, Florentia

AU - Gammon, Marilie

AU - Giles, Graham G.

AU - Guénel, Pascal

AU - Haiman, Christopher A.

AU - Hamann, Ute

AU - Hooning, Maartje J.

AU - Hopper, John L.

AU - Jakubowska, Anna

AU - Jasmine, Farzana

AU - Jenkins, Mark

AU - John, Esther M.

AU - Johnson, Nichola

AU - Jones, Michael E.

AU - Kabisch, Maria

AU - Kibriya, Muhammad

AU - Knight, Julia A.

AU - Koppert, Linetta B.

AU - Kosma, Veli Matti

AU - Kristensen, Vessela

AU - Le Marchand, Loic

AU - Lee, Eunjung

AU - Li, Jingmei

AU - Lindblom, Annika

AU - Luben, Robert

AU - Lubinski, Jan

AU - Malone, Kathi E.

AU - Mannermaa, Arto

AU - Margolin, Sara

AU - Marme, Frederik

AU - McLean, Catriona

AU - Meijers-Heijboer, Hanne

AU - Meindl, Alfons

AU - Neuhausen, Susan L.

AU - Nevanlinna, Heli

AU - Neven, Patrick

AU - Olson, Janet E

AU - Perez, Jose I A

AU - Perkins, Barbara

AU - Peterlongo, Paolo

AU - Phillips, Kelly Anne

AU - Pylkäs, Katri

AU - Rudolph, Anja

AU - Santella, Regina

AU - Sawyer, Elinor J.

AU - Schmutzler, Rita K.

AU - Seynaeve, Caroline

AU - Shah, Mitul

AU - Shrubsole, Martha J.

AU - Southey, Melissa C.

AU - Swerdlow, Anthony J.

AU - Toland, Amanda E.

AU - Tomlinson, Ian

AU - Torres, Diana

AU - Truong, Thérèse

AU - Ursin, Giske

AU - Van Der Luijt, Rob B.

AU - Verhoef, Senno

AU - Whittemore, Alice S.

AU - Winqvist, Robert

AU - Zhao, Hui

AU - Zhao, Shilin

AU - Hall, Per

AU - Simard, Jacques

AU - Kraft, Peter

AU - Pharoah, Paul

AU - Hunter, David

AU - Easton, Douglas F.

AU - Zheng, Wei

PY - 2016/8/1

Y1 - 2016/8/1

N2 - Background: Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors. Methods: We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively. Results: In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56–0.75, p = 3.32 × 10−10). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31–0.62, p = 9.91 × 10−8) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46–0.71, p = 1.88 × 10−8). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60–0.84, p = 1.64 × 10−7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk. Conclusions: BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.

AB - Background: Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors. Methods: We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively. Results: In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56–0.75, p = 3.32 × 10−10). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31–0.62, p = 9.91 × 10−8) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46–0.71, p = 1.88 × 10−8). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60–0.84, p = 1.64 × 10−7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk. Conclusions: BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.

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U2 - 10.1371/journal.pmed.1002105

DO - 10.1371/journal.pmed.1002105

M3 - Article

VL - 13

JO - PLoS Medicine

JF - PLoS Medicine

SN - 1549-1277

IS - 8

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ER -