A test for genetic association that incorporates information about deviation from Hardy-Weinberg proportions in cases.
For assessment of genetic association between single-nucleotide polymorphisms (SNPs) and disease status, the logistic-regression model or generalized linear model is typically employed. However, testing for deviation from Hardy-Weinberg proportion in a patient group could be another approach for genetic-association studies. The Hardy-Weinberg proportion is one of the most important principles in population genetics. Deviation from Hardy-Weinberg proportion among cases (patients) could provide additional evidence for the association between SNPs and diseases. To develop a more powerful statistical test for genetic-association studies, we combined evidence about deviation from Hardy-Weinberg proportion in case subjects and standard regression approaches that use case and control subjects. In this paper, we propose two approaches for combining such information: the mean-based tail-strength measure and the median-based tail-strength measure. These measures integrate logistic regression and Hardy-Weinberg-proportion tests for the study of the association between a binary disease outcome and an SNP on the basis of case- and control-subject data. For both mean-based and median-based tail-strength measures, we derived exact formulas to compute p values. We also developed an approach for obtaining empirical p values with the use of a resampling procedure. Results from simulation studies and real-disease studies demonstrate that the proposed approach is more powerful than the traditional logistic-regression model. The type I error probabilities of our approach were also well controlled.
Wang
Jian
J
Department of Epidemiology, M. D. Anderson Cancer Center, University of Texas, Houston, TX 77030, USA.
Shete
Sanjay
S
D000483:Alleles; D002294:Carcinoma, Squamous Cell / Q000235:genetics; D016022:Case-Control Studies; D003198:Computer Simulation; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D006258:Head and Neck Neoplasms / Q000235:genetics; D006801:Humans; D016015:Logistic Models; D008175:Lung Neoplasms / Q000235:genetics; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008957:Models, Genetic; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011336:Probability; D011471:Prostatic Neoplasms / Q000235:genetics; D012107:Research Design; D012307:Risk Factors; D012494:Sampling Studies; D012907:Smoking / Q000453:epidemiology; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D051197:Toll-Like Receptor 4; D042965:Methylenetetrahydrofolate Reductase (NADPH2)