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 & 61 others 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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)84-93
Number of pages10
JournalGenetic Epidemiology
Volume38
Issue number1
DOIs
StatePublished - Jan 2014
Externally publishedYes

Fingerprint

Gene-Environment Interaction
Genetic Loci
Genetic Predisposition to Disease
Single Nucleotide Polymorphism
Breast Neoplasms
Chromosomes, Human, Pair 21
Body Mass Index
Joints
Chromosomes, Human, Pair 6
Menarche
Linkage Disequilibrium
Environmental Exposure
Parity
Population
Genes

Keywords

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

ASJC Scopus subject areas

  • Genetics(clinical)
  • Epidemiology

Cite this

Schoeps, A., Rudolph, A., Seibold, P., Dunning, A. M., Milne, R. L., Bojesen, S. E., ... 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

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

In: Genetic Epidemiology, Vol. 38, No. 1, 01.2014, p. 84-93.

Research output: Contribution to journalArticle

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
Schoeps, Anja ; Rudolph, Anja ; Seibold, Petra ; Dunning, Alison M. ; Milne, Roger L. ; Bojesen, Stig E. ; Swerdlow, Anthony ; Andrulis, Irene ; Brenner, Hermann ; Behrens, Sabine ; Orr, Nicholas ; Jones, Michael ; Ashworth, Alan ; Li, Jingmei ; Cramp, Helen ; Connley, Dan ; Czene, Kamila ; Darabi, Hatef ; Chanock, Stephen J. ; Lissowska, Jolanta ; Figueroa, Jonine D. ; Knight, Julia ; Glendon, Gord ; Mulligan, Anna M. ; Dumont, Martine ; Severi, Gianluca ; Baglietto, Laura ; Olson, Janet ; Vachon, Celine ; Purrington, Kristen ; Moisse, Matthieu ; Neven, Patrick ; Wildiers, Hans ; Spurdle, Amanda ; Kosma, Veli Matti ; Kataja, Vesa ; Hartikainen, Jaana M. ; Hamann, Ute ; Ko, Yon Dschun ; Dieffenbach, Aida K. ; Arndt, Volker ; Stegmaier, Christa ; Malats, Núria ; Arias Perez, José I. ; Benítez, Javier ; Flyger, Henrik ; Nordestgaard, Børge G. ; Truong, Thérèse ; Cordina-Duverger, Emilie ; Menegaux, Florence ; dos Santos Silva, Isabel ; Fletcher, Olivia ; Johnson, Nichola ; Häberle, Lothar ; Beckmann, Matthias W. ; Ekici, Arif B. ; Braaf, Linde ; Atsma, Femke ; van den Broek, Alexandra J. ; Makalic, Enes ; Schmidt, Daniel F. ; Southey, Melissa C. ; Cox, Angela ; Simard, Jacques ; Giles, Graham G. ; Lambrechts, Diether ; Mannermaa, Arto ; Brauch, Hiltrud ; Guénel, Pascal ; Peto, Julian ; Fasching, Peter A. ; Hopper, John ; Flesch-Janys, Dieter ; Couch, Fergus ; Chenevix-Trench, Georgia ; Pharoah, Paul D P ; Garcia-Closas, Montserrat ; Schmidt, Marjanka K. ; Hall, Per ; Easton, Douglas F. ; Chang-Claude, Jenny. / Identification of new genetic susceptibility loci for breast cancer through consideration of gene-environment interactions. In: Genetic Epidemiology. 2014 ; Vol. 38, No. 1. pp. 84-93.
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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

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AU - Dumont, Martine

AU - Severi, Gianluca

AU - Baglietto, Laura

AU - Olson, Janet

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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

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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.

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KW - Polymorphisms

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