A genome-wide gene-based gene-environment interaction study of breast cancer in more than 90,000 women.
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
- Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
- Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
- Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
- Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
- Division of Cancer Epidemiology and Genetic, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
- Genetic Epidemiology Group, School of Population and Global Health, University of Western Australia, Crawley, Australia.
- Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel.
- Cancer Control Research, BC Cancer and School of Population and Public Health, University of British Columbia, Vancouver, Canada.
- Public Health Sciences, Queen's University, Kingston, Canada.
- Université Paris-Saclay, Inserm, CESP, Team Exposome and Heredity, Villejuif, France.
- Department of Population Science, American Cancer Society, Atlanta, GA, USA.
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
- Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
- Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
- Genomics Center, Centre Hospitalier Universitaire de Québec-Université Laval Research Center, Québec City, Quebec, Canada.
- Department of Medicine, McGill University, Montréal, Quebec, Canada; Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, Quebec, Canada.
- Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, USA.
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Channing Division of Network Medicine, Department of Medicine, Brigham & Women's Hospital, Boston, MA, USA.
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA.
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Usher Institute of Population Health Sciences and Informatics, University of Edinburgh Medical School, Edinburgh, UK.
- Division of Evolution and Genomic Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
- Division of Cancer Sciences, University of Manchester, Manchester, UK.
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
- Epidemiology Branch, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC, USA.
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
- Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
- Departments of Oncology and Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
BACKGROUND: Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene-environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this.
METHODS: We obtained genotype and risk factor data from 46,060 cases and 47,929 controls of European ancestry from population-based studies within the Breast Cancer Association Consortium (BCAC). We built gene expression prediction models for 4,864 genes with a significant (P<0.01) heritable component using the transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project. We leveraged predicted gene expression information to investigate the interactions between gene-centric genetic variation and 14 established risk factors in association with breast cancer risk, using a mixed-effects score test.
RESULTS: After adjusting for number of tests using Bonferroni correction, no interaction remained statistically significant. The strongest interaction observed was between the predicted expression of the C13orf45 gene and age at first full-term pregnancy (PGXE=4.44×10-6).
CONCLUSION: In this transcriptome-informed genome-wide gene-environment interaction study of breast cancer, we found no strong support for the role of gene expression in modifying the associations between established risk factors and breast cancer risk.
IMPACT: Our study suggests a limited role of gene-environment interactions in breast cancer risk.