Constrained Score Statistics Identify Genetic Variants Interacting with Multiple Risk Factors in Barrett's Esophagus

James Y. Dai*, Jean de Dieu Tapsoba, Matthew F. Buas, BEACON Consortium, Harvey A. Risch, Thomas L. Vaughan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


Few gene-environment interactions (G × E) have been discovered in cancer epidemiology thus far, in part due to the large number of possible G × E to be investigated and inherent low statistical power of traditional analytic methods for discovering G × E. We consider simultaneously testing for interactions between several related exposures and a genetic variant in a genome-wide study. To improve power, constrained testing strategies are proposed for multivariate gene-environment interactions at two levels: interactions that have the same direction (one-sided or bidirectional hypotheses) or are proportional to respective exposure main effects (a variant of Tukey's one-degree test). Score statistics were developed to expedite the genome-wide computation. We conducted extensive simulations to evaluate validity and power performance of the proposed statistics, applied them to the genetic and environmental exposure data for esophageal adenocarcinoma and Barrett's esophagus from the Barretts Esophagus and Esophageal Adenocarcinoma Consortium (BEACON), and discovered three loci simultaneously interacting with gastresophageal reflux, obesity, and tobacco smoking with genome-wide significance. These findings deepen understanding of the genetic and environmental architecture of Barrett's esophagus and esophageal adenocarcinoma.

Original languageEnglish
Pages (from-to)352-365
Number of pages14
JournalAmerican Journal of Human Genetics
Issue number2
Early online date2 Aug 2016
Publication statusPublished - 4 Aug 2016

Bibliographical note

This work was supported in part by NIH grants R01 HL114901, R01 CA136725, R21 CA197502, and P01 CA53996. We thank Nilanjan Chatterjee for helpful comments.


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