TY - JOUR

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

N1 - © 2013 WILEY PERIODICALS, INC.

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/m(2) (OR = 1.26, 95% CI 1.15-1.38) but not in women with a BMI of 30 kg/m(2) 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/m(2) (OR = 1.26, 95% CI 1.15-1.38) but not in women with a BMI of 30 kg/m(2) 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 - Adolescent

KW - Body Height

KW - Body Mass Index

KW - Breast Neoplasms

KW - Chromosomes, Human, Pair 21

KW - Chromosomes, Human, Pair 6

KW - European Continental Ancestry Group

KW - Female

KW - Gene-Environment Interaction

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Humans

KW - Linkage Disequilibrium

KW - Menarche

KW - Middle Aged

KW - Parity

KW - Polymorphism, Single Nucleotide

KW - Postmenopause

U2 - 10.1002/gepi.21771

DO - 10.1002/gepi.21771

M3 - Journal article

C2 - 24248812

VL - 38

SP - 84

EP - 93

JO - Genetic Epidemiology

JF - Genetic Epidemiology

SN - 0741-0395

IS - 1

ER -