Identification of New Genetic Susceptibility Loci for Breast Cancer Through Consideration of Gene‐Environment Interactions
Authors: 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 
Published: November 2013

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.