Application of a novel score test for genetic association incorporating gene-gene interaction suggests functionality for prostate cancer susceptibility regions

Julia Ciampa, Meredith Yeager, Kevin Jacobs, Michael J. Thun, Susan Gapstur, Demetrius Albanes, Jarmo Virtamo, Stephanie J. Weinstein, Edward Giovannucci, Walter C. Willett, Geraldine Cancel-Tassin, Olivier Cussenot, Antoine Valeri, David Hunter, Robert Hoover, Gilles Thomas, Stephen Chanock, Chris Holmes, Nilanjan Chatterjee

Research output: Contribution to journalArticle

Abstract

Aims: We introduce an innovative multilocus test for disease association. It is an extension of an existing score test that gains power over alternative methods by incorporating a parsimonious one-degree-of-freedom model for interaction. We use our method in applications designed to detect interactions that generate hypotheses about the functionality of prostate cancer (PRCA) susceptibility regions. Methods: Our proposed score test is designed to gain additional power through the use of a retrospective likelihood that exploits an assumption of independence between unlinked loci in the underlying population. Its performance is validated through simulation. The method is used in conditional scans with data from stage II of the Cancer Genetic Markers of Susceptibility PRCA genome-wide association study. Results: Our proposed method increases power to detect susceptibility loci in diverse settings. It identified two high-ranking, biologically interesting interactions: (1) rs748120 of NR2C2 and subregions of 8q24 that contain independent susceptibility loci specific to PRCA and (2) rs4810671 of SULF2 and both JAZF1 and HNF1B that are associated with PRCA and type 2 diabetes. Conclusions: Our score test is a promising multilocus tool for genetic epidemiology. The results of our applications suggest functionality for poorly understood PRCA susceptibility regions. They motivate replication study.

Original languageEnglish (US)
Pages (from-to)182-193
Number of pages12
JournalHuman Heredity
Volume72
Issue number3
DOIs
StatePublished - Nov 1 2011

Keywords

  • Gene-gene interaction
  • Prostate cancer
  • Score test

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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  • Cite this

    Ciampa, J., Yeager, M., Jacobs, K., Thun, M. J., Gapstur, S., Albanes, D., Virtamo, J., Weinstein, S. J., Giovannucci, E., Willett, W. C., Cancel-Tassin, G., Cussenot, O., Valeri, A., Hunter, D., Hoover, R., Thomas, G., Chanock, S., Holmes, C., & Chatterjee, N. (2011). Application of a novel score test for genetic association incorporating gene-gene interaction suggests functionality for prostate cancer susceptibility regions. Human Heredity, 72(3), 182-193. https://doi.org/10.1159/000331222