Cancer risk is determined by a complex interplay of genetic and environmental factors. To understand this interplay, epidemiologic studies need to consider the effects of gene-environment (GxE) interactions. In 2012, the Epidemiology and Genomics Research Program (EGRP) launched an ongoing effort to transform 21st century epidemiology. Studies of GxE interactions should be part of this transformation. In the current “post-GWAS” era, GxE interactions are a proposed source of the missing heritability of complex disease. Examination and understanding of GxE interactions can allow for identification of novel genetic and environmental risk factors; it also can allow for an increased understanding of the biology of disease and may impact risk stratification for public health screening and prevention efforts.
Unanswered Questions in GxE Research
The recently published summary of NCI’s 2012 Gene-Environment Think Tank focuses on contemporary approaches to the analysis of GxE interactions. Key unanswered questions for advancing research in GxE identified by Think Tank participants included:
- Considerations for characterization and discovery of GxE interactions
- Measurement error
- Significance testing
- Sample size and power
GxE research will be further facilitated by multilevel analysis at the individual and population levels, considerations of rare variants, and improved measures of exposure. Continued progress will require increased collaboration and data sharing, data pooling, big data science approaches, and integrative epidemiology, as well as considerations of translational applications, combined environmental exposures, and life-course epidemiology.
In addition, the April 2013 issue of Cancer Epidemiology, Biomarkers and Prevention features results from an NCI portfolio analysis on GxE interactions performed by EGRP staff. The findings from the portfolio analysis suggest that GxE studies are concentrated on specific cancer types and exposures, and focused on identification and characterization of GxE, rather than applications for clinical and public health prevention. There is room for EGRP to expand and broaden its portfolio of GxE research.
Research Opportunities for GxE
These unanswered questions and knowledge gaps suggest opportunities for further research in this arena. To this end, EGRP welcomes investigator-initiated R01, R21, and R03 grant applications focusing on the joint effects of genes and environmental factors.
Moreover, we encourage GxE analysis using existing data. As such, NCI is participating in a newly released trans-NIH Funding Opportunity Announcement (FOA), “Analysis of Genome-Wide Gene-Environment (G x E) Interactions (R21),” led by the National Institute of Environmental Health Sciences. The purpose of the FOA is to support re-analysis of existing large genomic data sets for the study of GxE interactions.
What Do You Think?
EGRP invites you to tell us about work you have done on GxE interactions, and issues you think are most important to facilitate GxE research and move the field forward. In addition, EGRP would like to hear your thoughts on current challenges and barriers to GxE interaction studies.
You Are Invited: GXE Research Discussion Forum
EGRP will be launching a Yammer site to facilitate on-line discussion in this area. Yammer is a social networking tool used by NIH to promote collaborations by forming groups focused on specific interest areas. We hope to develop a dynamic, collaborative workspace where investigators interested in GxE research can post and answer questions, participate in online discussions, and share information. Please contact Leah Mechanic if you would like to join this Yammer group.
Carolyn Hutter, Ph.D., is a Program Director in the National Human Genome Research Institute’s (NHGRI) Division of Genomic Medicine. She works on The Cancer Genome Atlas (TCGA) and the Clinical Sequencing Exploratory Research (CSER) programs. Previously, she was a Program Director in EGRP’s Host Susceptibility Factors Branch.
Leah Mechanic, Ph.D., M.P.H., is a Program Director in EGRP’s Host Susceptibility Factors Branch. Her responsibilities include managing a portfolio of grants related to factors that modulate susceptibility to cancer. Additionally, Dr. Mechanic has been involved in several trans-NIH activities designed to address the analytical challenges involved in studying gene-gene and gene-environment interactions, complex phenotypes, and next-generation sequencing.