Association tests through combining p-values for case control genome-wide association studies

To detect single nucleotide polymorphisms (SNPs) that are associated with a common disease in a case control genome-wide association study (GWAS), powerful yet robust tests are desirable. Current available robust approaches in this area are mainly based on the optimal trend tests for some specific genetic models, such as recessive, additive, multiplicative, and dominant models. In this paper, we propose a class of robust association tests through combining p-values obtained by partitioning the 2 by 3 contingency table of the SNP data. Through simulation study and application to real data, we show that the proposed tests are powerful and robust. They provide alternative association tests for GWAS.

[1]  Xavier Estivill,et al.  Maximizing association statistics over genetic models , 2008, Genetic epidemiology.

[2]  M. Province,et al.  Avoiding the high Bonferroni penalty in genome‐wide association studies , 2009, Genetic epidemiology.

[3]  D. Walkup,et al.  Association of Random Variables, with Applications , 1967 .

[4]  Art B. Owen,et al.  Karl Pearson’s meta analysis revisited , 2009, 0911.3531.

[5]  Min-Jeong Kwak,et al.  Improving Power for Testing Genetic Association in Case–Control Studies by Reducing the Alternative Space , 2010, Biometrics.

[6]  Joseph L. Gastwirth,et al.  The Use of Maximin Efficiency Robust Tests in Combining Contingency Tables and Survival Analysis , 1985 .

[7]  P. Armitage.  Tests for Linear Trends in Proportions and Frequencies , 1955 .

[8]  Hon Keung Tony Ng,et al.  Design and analysis of multiple diseases genome-wide association studies without controls. , 2012, Gene.

[9]  D. Schaid,et al.  Case-Control Studies of Genetic Markers: Power and Sample Size Approximations for Armitage’s Test for Trend , 2001, Human Heredity.

[10]  J. Li,et al.  Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix , 2005, Heredity.

[11]  Gang Zheng,et al.  Genetic model selection in two-phase analysis for case-control association studies. , 2008, Biostatistics.

[12]  Z Chen,et al.  Is the weighted z‐test the best method for combining probabilities from independent tests? , 2011, Journal of evolutionary biology.

[13]  D. Balding.  A tutorial on statistical methods for population association studies , 2006, Nature Reviews Genetics.

[14]  Qingzhong Liu,et al.  A New Approach to Account for the Correlations among Single Nucleotide Polymorphisms in Genome-Wide Association Studies , 2011, Human Heredity.

[15]  M J Podgor,et al.  Efficiency Robust Tests for Survival or Ordered Categorical Data , 1999, Biometrics.

[16]  Kai Wang,et al.  A constrained-likelihood approach to marker-trait association studies. , 2005, American journal of human genetics.

[17]  Zhongxue Chen.  A new association test based on Chi‐square partition for case‐control GWA studies , 2011, Genetic epidemiology.

[18]  Qingzhong Liu,et al.  A new statistical approach to detecting differentially methylated loci for case control Illumina array methylation data , 2012, Bioinform..

[19]  J. Cheverud,et al.  A simple correction for multiple comparisons in interval mapping genome scans , 2001, Heredity.

[20]  P. Sasieni.  From genotypes to genes: doubling the sample size. , 1997, Biometrics.

[21]  Joseph L. Gastwirth,et al.  Comparison of robust tests for genetic association using case-control studies , 2006, math/0611179.

[22]  R. Fisher,et al.  Statistical Methods for Research Workers , 1930, Nature.

[23]  Min-Jeong Kwak,et al.  A Robust Test for Two‐Stage Design in Genome‐Wide Association Studies , 2009, Biometrics.

[24]  Joseph L. Gastwirth,et al.  Trend Tests for Case-Control Studies of Genetic Markers: Power, Sample Size and Robustness , 2002, Human Heredity.

[25]  Hon Keung Tony Ng,et al.  A Robust Method for Testing Association in Genome-Wide Association Studies , 2011, Human Heredity.

[26]  Joseph L. Gastwirth,et al.  Choice of scores in trend tests for case-control studies of candidate-gene associations , 2003 .

[27]  W. G. Cochran.  Some Methods for Strengthening the Common χ 2 Tests , 1954 .

[28]  J. Gastwirth.  ON ROBUST PROCEDURES , 1966 .

[29]  Simon C. Potter,et al.  Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants , 2007, Nature Genetics.

[30]  R. Elston,et al.  A powerful method of combining measures of association and Hardy–Weinberg disequilibrium for fine‐mapping in case‐control studies , 2006, Statistics in medicine.

[31]  W. Fung,et al.  Simple algorithms to calculate asymptotic null distributions of robust tests in case-control genetic association studies in R , 2010 .