A test for genetic association that incorporates information about deviation from Hardy-Weinberg proportions in cases

Am J Hum Genet. 2008 Jul;83(1):53-63. doi: 10.1016/j.ajhg.2008.06.010. Epub 2008 Jun 26.

Abstract

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.

MeSH terms

  • Alleles
  • Carcinoma, Squamous Cell / genetics
  • Case-Control Studies*
  • Computer Simulation
  • Gene Frequency
  • Genetic Predisposition to Disease*
  • Genetics, Population
  • Head and Neck Neoplasms / genetics
  • Humans
  • Logistic Models
  • Lung Neoplasms / genetics
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Models, Genetic
  • Odds Ratio
  • Polymorphism, Single Nucleotide*
  • Probability
  • Prostatic Neoplasms / genetics
  • Research Design*
  • Risk Factors
  • Sampling Studies
  • Smoking / epidemiology
  • Toll-Like Receptor 4 / metabolism

Substances

  • Toll-Like Receptor 4
  • Methylenetetrahydrofolate Reductase (NADPH2)