Identification of new genetic susceptibility loci for breast cancer through consideration of gene-environment interactions

Anja Schoeps; Anja Rudolph; Petra Seibold; Alison M. Dunning; Roger L. Milne; Stig E. Bojesen; Anthony Swerdlow; Irene Andrulis; Hermann Brenner; Sabine Behrens; Nicholas Orr; Michael Jones; Alan Ashworth; Jingmei Li; Helen Cramp; Dan Connley; Kamila Czene; Hatef Darabi; Stephen J. Chanock; Jolanta Lissowska; Jonine D. Figueroa; Julia Knight; Gord Glendon; Anna M. Mulligan; Martine Dumont; Gianluca Severi; Laura Baglietto; Janet Olson; Celine Vachon; Kristen Purrington; Matthieu Moisse; Patrick Neven; Hans Wildiers; Amanda Spurdle; Veli Matti Kosma; Vesa Kataja; Jaana M. Hartikainen; Ute Hamann; Yon Dschun Ko; Aida K. Dieffenbach; Volker Arndt; Christa Stegmaier; Núria Malats; José I. Arias Perez; Javier Benítez; Henrik Flyger; Børge G. Nordestgaard; Thérèse Truong; Emilie Cordina-Duverger; Florence Menegaux; Isabel dos Santos Silva; Olivia Fletcher; Nichola Johnson; Lothar Häberle; Matthias W. Beckmann; Arif B. Ekici; Linde Braaf; Femke Atsma; Alexandra J. van den Broek; Enes Makalic; Daniel F. Schmidt; Melissa C. Southey; Angela Cox; Jacques Simard; Graham G. Giles; Diether Lambrechts; Arto Mannermaa; Hiltrud Brauch; Pascal Guénel; Julian Peto; Peter A. Fasching; John Hopper; Dieter Flesch-Janys; Fergus Couch; Georgia Chenevix-Trench; Paul D.P. Pharoah; Montserrat Garcia-Closas; Marjanka K. Schmidt; Per Hall; Douglas F. Easton; Jenny Chang-Claude

doi:10.1002/gepi.21771

Identification of new genetic susceptibility loci for breast cancer through consideration of gene-environment interactions

Anja Schoeps, Anja Rudolph, Petra Seibold, Alison M. Dunning, Roger L. Milne, Stig E. Bojesen, Anthony Swerdlow, Irene Andrulis, Hermann Brenner, Sabine Behrens, Nicholas Orr, Michael Jones, Alan Ashworth, Jingmei Li, Helen Cramp, Dan Connley, Kamila Czene, Hatef Darabi, Stephen J. Chanock, Jolanta LissowskaJonine D. Figueroa, Julia Knight, Gord Glendon, Anna M. Mulligan, Martine Dumont, Gianluca Severi, Laura Baglietto, Janet Olson, Celine Vachon, Kristen Purrington, Matthieu Moisse, Patrick Neven, Hans Wildiers, Amanda Spurdle, Veli Matti Kosma, Vesa Kataja, Jaana M. Hartikainen, Ute Hamann, Yon Dschun Ko, Aida K. Dieffenbach, Volker Arndt, Christa Stegmaier, Núria Malats, José I. Arias Perez, Javier Benítez, Henrik Flyger, Børge G. Nordestgaard, Thérèse Truong, Emilie Cordina-Duverger, Florence Menegaux, Isabel dos Santos Silva, Olivia Fletcher, Nichola Johnson, Lothar Häberle, Matthias W. Beckmann, Arif B. Ekici, Linde Braaf, Femke Atsma, Alexandra J. van den Broek, Enes Makalic, Daniel F. Schmidt, Melissa C. Southey, Angela Cox, Jacques Simard, Graham G. Giles, Diether Lambrechts, Arto Mannermaa, Hiltrud Brauch, Pascal Guénel, Julian Peto, Peter A. Fasching, John Hopper, Dieter Flesch-Janys, Fergus Couch, Georgia Chenevix-Trench, Paul D.P. Pharoah, Montserrat Garcia-Closas, Marjanka K. Schmidt, Per Hall, Douglas F. Easton, Jenny Chang-Claude

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

22 Scopus citations

Abstract

Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10^-07), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m² (OR = 1.26, 95% CI 1.15-1.38) but not in women with a BMI of 30 kg/m² or higher (OR = 0.89, 95% CI 0.72-1.11, P for interaction = 3.2 × 10^-05). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci.

Original language	English (US)
Pages (from-to)	84-93
Number of pages	10
Journal	Genetic epidemiology
Volume	38
Issue number	1
DOIs	https://doi.org/10.1002/gepi.21771
State	Published - Jan 2014

Keywords

Body mass index
Breast cancer risk
Case-control study
Gene-environment interaction
Polymorphisms

ASJC Scopus subject areas

Epidemiology
Genetics(clinical)

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10.1002/gepi.21771

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Schoeps, A., Rudolph, A., Seibold, P., Dunning, A. M., Milne, R. L., Bojesen, S. E., Swerdlow, A., Andrulis, I., Brenner, H., Behrens, S., Orr, N., Jones, M., Ashworth, A., Li, J., Cramp, H., Connley, D., Czene, K., Darabi, H., Chanock, S. J., ... Chang-Claude, J. (2014). Identification of new genetic susceptibility loci for breast cancer through consideration of gene-environment interactions. Genetic epidemiology, 38(1), 84-93. https://doi.org/10.1002/gepi.21771

Schoeps, A, Rudolph, A, Seibold, P, Dunning, AM, Milne, RL, Bojesen, SE, Swerdlow, A, Andrulis, I, Brenner, H, Behrens, S, Orr, N, Jones, M, Ashworth, A, Li, J, Cramp, H, Connley, D, Czene, K, Darabi, H, Chanock, SJ, Lissowska, J, Figueroa, JD, Knight, J, Glendon, G, Mulligan, AM, Dumont, M, Severi, G, Baglietto, L, Olson, J , Vachon, C, Purrington, K, Moisse, M, Neven, P, Wildiers, H, Spurdle, A, Kosma, VM, Kataja, V, Hartikainen, JM, Hamann, U, Ko, YD, Dieffenbach, AK, Arndt, V, Stegmaier, C, Malats, N, Arias Perez, JI, Benítez, J, Flyger, H, Nordestgaard, BG, Truong, T, Cordina-Duverger, E, Menegaux, F, dos Santos Silva, I, Fletcher, O, Johnson, N, Häberle, L, Beckmann, MW, Ekici, AB, Braaf, L, Atsma, F, van den Broek, AJ, Makalic, E, Schmidt, DF, Southey, MC, Cox, A, Simard, J, Giles, GG, Lambrechts, D, Mannermaa, A, Brauch, H, Guénel, P, Peto, J, Fasching, PA, Hopper, J, Flesch-Janys, D, Couch, F, Chenevix-Trench, G, Pharoah, PDP, Garcia-Closas, M, Schmidt, MK, Hall, P, Easton, DF & Chang-Claude, J 2014, 'Identification of new genetic susceptibility loci for breast cancer through consideration of gene-environment interactions', Genetic epidemiology, vol. 38, no. 1, pp. 84-93. https://doi.org/10.1002/gepi.21771

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title = "Identification of new genetic susceptibility loci for breast cancer through consideration of gene-environment interactions",

abstract = "Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10-07), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m2 (OR = 1.26, 95% CI 1.15-1.38) but not in women with a BMI of 30 kg/m2 or higher (OR = 0.89, 95% CI 0.72-1.11, P for interaction = 3.2 × 10-05). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci.",

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author = "Anja Schoeps and Anja Rudolph and Petra Seibold and Dunning, {Alison M.} and Milne, {Roger L.} and Bojesen, {Stig E.} and Anthony Swerdlow and Irene Andrulis and Hermann Brenner and Sabine Behrens and Nicholas Orr and Michael Jones and Alan Ashworth and Jingmei Li and Helen Cramp and Dan Connley and Kamila Czene and Hatef Darabi and Chanock, {Stephen J.} and Jolanta Lissowska and Figueroa, {Jonine D.} and Julia Knight and Gord Glendon and Mulligan, {Anna M.} and Martine Dumont and Gianluca Severi and Laura Baglietto and Janet Olson and Celine Vachon and Kristen Purrington and Matthieu Moisse and Patrick Neven and Hans Wildiers and Amanda Spurdle and Kosma, {Veli Matti} and Vesa Kataja and Hartikainen, {Jaana M.} and Ute Hamann and Ko, {Yon Dschun} and Dieffenbach, {Aida K.} and Volker Arndt and Christa Stegmaier and N{\'u}ria Malats and {Arias Perez}, {Jos{\'e} I.} and Javier Ben{\'i}tez and Henrik Flyger and Nordestgaard, {B{\o}rge G.} and Th{\'e}r{\`e}se Truong and Emilie Cordina-Duverger and Florence Menegaux and {dos Santos Silva}, Isabel and Olivia Fletcher and Nichola Johnson and Lothar H{\"a}berle and Beckmann, {Matthias W.} and Ekici, {Arif B.} and Linde Braaf and Femke Atsma and {van den Broek}, {Alexandra J.} and Enes Makalic and Schmidt, {Daniel F.} and Southey, {Melissa C.} and Angela Cox and Jacques Simard and Giles, {Graham G.} and Diether Lambrechts and Arto Mannermaa and Hiltrud Brauch and Pascal Gu{\'e}nel and Julian Peto and Fasching, {Peter A.} and John Hopper and Dieter Flesch-Janys and Fergus Couch and Georgia Chenevix-Trench and Pharoah, {Paul D.P.} and Montserrat Garcia-Closas and Schmidt, {Marjanka K.} and Per Hall and Easton, {Douglas F.} and Jenny Chang-Claude",

year = "2014",

month = jan,

doi = "10.1002/gepi.21771",

language = "English (US)",

volume = "38",

pages = "84--93",

journal = "Genetic epidemiology",

issn = "0741-0395",

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T1 - Identification of new genetic susceptibility loci for breast cancer through consideration of gene-environment interactions

AU - Schoeps, Anja

AU - Rudolph, Anja

AU - Seibold, Petra

AU - Dunning, Alison M.

AU - Milne, Roger L.

AU - Bojesen, Stig E.

AU - Swerdlow, Anthony

AU - Andrulis, Irene

AU - Brenner, Hermann

AU - Behrens, Sabine

AU - Orr, Nicholas

AU - Jones, Michael

AU - Ashworth, Alan

AU - Li, Jingmei

AU - Cramp, Helen

AU - Connley, Dan

AU - Czene, Kamila

AU - Darabi, Hatef

AU - Chanock, Stephen J.

AU - Lissowska, Jolanta

AU - Figueroa, Jonine D.

AU - Knight, Julia

AU - Glendon, Gord

AU - Mulligan, Anna M.

AU - Dumont, Martine

AU - Severi, Gianluca

AU - Baglietto, Laura

AU - Olson, Janet

AU - Vachon, Celine

AU - Purrington, Kristen

AU - Moisse, Matthieu

AU - Neven, Patrick

AU - Wildiers, Hans

AU - Spurdle, Amanda

AU - Kosma, Veli Matti

AU - Kataja, Vesa

AU - Hartikainen, Jaana M.

AU - Hamann, Ute

AU - Ko, Yon Dschun

AU - Dieffenbach, Aida K.

AU - Arndt, Volker

AU - Stegmaier, Christa

AU - Malats, Núria

AU - Arias Perez, José I.

AU - Benítez, Javier

AU - Flyger, Henrik

AU - Nordestgaard, Børge G.

AU - Truong, Thérèse

AU - Cordina-Duverger, Emilie

AU - Menegaux, Florence

AU - dos Santos Silva, Isabel

AU - Fletcher, Olivia

AU - Johnson, Nichola

AU - Häberle, Lothar

AU - Beckmann, Matthias W.

AU - Ekici, Arif B.

AU - Braaf, Linde

AU - Atsma, Femke

AU - van den Broek, Alexandra J.

AU - Makalic, Enes

AU - Schmidt, Daniel F.

AU - Southey, Melissa C.

AU - Cox, Angela

AU - Simard, Jacques

AU - Giles, Graham G.

AU - Lambrechts, Diether

AU - Mannermaa, Arto

AU - Brauch, Hiltrud

AU - Guénel, Pascal

AU - Peto, Julian

AU - Fasching, Peter A.

AU - Hopper, John

AU - Flesch-Janys, Dieter

AU - Couch, Fergus

AU - Chenevix-Trench, Georgia

AU - Pharoah, Paul D.P.

AU - Garcia-Closas, Montserrat

AU - Schmidt, Marjanka K.

AU - Hall, Per

AU - Easton, Douglas F.

AU - Chang-Claude, Jenny

PY - 2014/1

Y1 - 2014/1

N2 - Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10-07), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m2 (OR = 1.26, 95% CI 1.15-1.38) but not in women with a BMI of 30 kg/m2 or higher (OR = 0.89, 95% CI 0.72-1.11, P for interaction = 3.2 × 10-05). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci.

AB - Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10-07), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m2 (OR = 1.26, 95% CI 1.15-1.38) but not in women with a BMI of 30 kg/m2 or higher (OR = 0.89, 95% CI 0.72-1.11, P for interaction = 3.2 × 10-05). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci.

KW - Body mass index

KW - Breast cancer risk

KW - Case-control study

KW - Gene-environment interaction

KW - Polymorphisms

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Identification of new genetic susceptibility loci for breast cancer through consideration of gene-environment interactions

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