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1.  Sample Size Requirements to Detect Gene-Environment Interactions in Genome-wide Association Studies 
Genetic epidemiology  2011;35(3):201-210.
Many complex diseases are likely to be a result of the interplay of genes and environmental exposures. The standard analysis in a genome-wide association study (GWAS) scans for main effects and ignores the potentially useful information in the available exposure data. Two recently proposed methods that exploit environmental exposure information involve a two-step analysis aimed at prioritizing the large number of SNPs tested to highlight those most likely to be involved in a G×E interaction. For example, Murcray et al (2009) proposed screening on a test that models the G-E association induced by an interaction in the combined case-control sample. Alternatively, Kooperberg et al (2008) suggested screening on genetic marginal effects. In both methods, SNPs that pass the respective screening step at a pre-specified significance threshold are followed up with a formal test of interaction in the second step. We propose a hybrid method that combines these two screening approaches by allocating a proportion of the overall genomewide significance level to each test. We show that the Murcray et al. approach is often the most efficient method, but that the hybrid approach is a powerful and robust method for nearly any underlying model. As an example, for a GWAS of 1 million markers including a single true disease SNP with minor allele frequency of 0.15, and a binary exposure with prevalence 0.3, the Murcray, Kooperberg and hybrid methods are 1.90, 1.27, and 1.87 times as efficient, respectively, as the traditional case-control analysis to detect an interaction effect size of 2.0.
PMCID: PMC3076801  PMID: 21308767
G×E interaction; case-control; genome-wide association study; efficiency
2.  Gene-Environment Interaction in Genome-Wide Association Studies 
American Journal of Epidemiology  2008;169(2):219-226.
It is a commonly held belief that most complex diseases (e.g., diabetes, asthma, cancer) are affected in part by interactions between genes and environmental factors. However, investigators conducting genome-wide association studies typically test for only the marginal effects of each genetic marker on disease. In this paper, the authors propose an efficient and easily implemented 2-step analysis of genome-wide association study data aimed at identifying genes involved in a gene-environment interaction. The procedure complements screening for marginal genetic effects and thus has the potential to uncover new genetic signals that have not been identified previously.
PMCID: PMC2732981  PMID: 19022827
association; environment; genes; genetic markers; genetics; genome
3.  Invited Commentary: GE-Whiz! Ratcheting Gene-Environment Studies up to the Whole Genome and the Whole Exposome 
American Journal of Epidemiology  2011;175(3):203-207.
One goal in the post-genome-wide association study era is characterizing gene-environment interactions, including scanning for interactions with all available polymorphisms, not just those showing significant main effects. In recent years, several approaches to such “gene-environment-wide interaction studies” have been proposed. Two contributions in this issue of the American Journal of Epidemiology provide systematic comparisons of the performance of these various approaches, one based on simulation and one based on application to 2 real genome-wide association study scans for type 2 diabetes. The authors discuss some of the broader issues raised by these contributions, including the plausibility of the gene-environment independence assumption that some of these approaches rely upon, the need for replication, and various generalizations of these approaches.
PMCID: PMC3261438  PMID: 22199029
epidemiologic research design; genetic epidemiology; genome-wide association study; genotype-environment interaction; polymorphisms, single nucleotide
4.  Efficient Genome-Wide Association Testing of Gene-Environment Interaction in Case-Parent Trios 
American Journal of Epidemiology  2010;172(1):116-122.
Complex trait variation is likely to be explained by the combined effects of genes, environmental factors, and gene × environment (G × E) interaction. The authors introduce a novel 2-step method for detecting a G × E interaction in a genome-wide association study (GWAS) of case-parent trios. The method utilizes 2 sources of G × E information in a trio sample to construct a screening step and a testing step. Across a wide range of models, this 2-step procedure provides substantially greater power to detect G × E interaction than a standard test of G × E interaction applied genome-wide. For example, for a disease susceptibility locus with minor allele frequency of 15%, a binary exposure variable with 50% prevalence, and a GWAS scan of 1 million markers in 1,000 case-parent trios, the 2-step method provides 87% power to detect a G × E interaction relative risk of 2.3, as compared with only 25% power using a standard G × E test. The method is easily implemented using standard software. This 2-step scan for G × E interaction is independent of any prior scan that may have been conducted for genetic main effects, and thus has the potential to uncover new genes in a GWAS that have not been previously identified.
PMCID: PMC2915477  PMID: 20543031
environmental exposure; epidemiologic methods; genetic association studies; genetics; genome-wide association study; models, genetic
5.  Detecting Gene-Environment Interactions in Genome-Wide Association Data 
Genetic epidemiology  2009;33(Suppl 1):S68-S73.
Despite the importance of gene-environment (G×E) interactions in the etiology of common diseases, little work has been done to develop methods for detecting these types of interactions in genome-wide association study data. This was the focus of Genetic Analysis Workshop 16 Group 10 contributions, which introduced a variety of new methods for the detection of G×E interactions in both case-control and family-based data using both cross-sectional and longitudinal study designs. Many of these contributions detected significant G×E interactions. Although these interactions have not yet been confirmed, the results suggest the importance of testing for interactions. Issues of sample size, quantifying the environmental exposure, longitudinal data analysis, family-based analysis, selection of the most powerful analysis method, population stratification, and computational expense with respect to testing G×E interactions are discussed.
PMCID: PMC2924567  PMID: 19924704
GAW; case-control; family-based; cross-sectional; longitudinal; rheumatoid arthritis; Framingham Heart Study

Results 1-5 (5)