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Open Access Highly Accessed Methodology article

Calculation of exact p-values when SNPs are tested using multiple genetic models

Rajesh Talluri1, Jian Wang1 and Sanjay Shete12*

Author Affiliations

1 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

2 Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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BMC Genetics 2014, 15:75  doi:10.1186/1471-2156-15-75

Published: 20 June 2014

Abstract

Background

Several methods have been proposed to account for multiple comparisons in genetic association studies. However, investigators typically test each of the SNPs using multiple genetic models. Association testing using the Cochran-Armitage test for trend assuming an additive, dominant, or recessive genetic model, is commonly performed. Thus, each SNP is tested three times. Some investigators report the smallest p-value obtained from the three tests corresponding to the three genetic models, but such an approach inherently leads to inflated type 1 errors. Because of the small number of tests (three) and high correlation (functional dependence) among these tests, the procedures available for accounting for multiple tests are either too conservative or fail to meet the underlying assumptions (e.g., asymptotic multivariate normality or independence among the tests).

Results

We propose a method to calculate the exact p-value for each SNP using different genetic models. We performed simulations, which demonstrated the control of type 1 error and power gains using the proposed approach. We applied the proposed method to compute p-value for a polymorphism eNOS -786T>C which was shown to be associated with breast cancer risk.

Conclusions

Our findings indicate that the proposed method should be used to maximize power and control type 1 errors when analyzing genetic data using additive, dominant, and recessive models.

Keywords:
Genetic association; Multiple testing; Cochran-Armitage trend test; Genetic models; Exact p-value