Original Paper

Exploiting Hardy-Weinberg Equilibrium for Efficient Screening of Single SNP Associations from Case-Control Studies
Jinbo Chen^a, Nilanjan Chatterjee<sup>b

a</sup>Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pa., and
^bBiostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Md., USA

Address of Corresponding Author

Hum Hered 2007;63:196-204 (DOI: 10.1159/000099996)

  Key Words

• Association test
• Case-control study
• Genome scan
• Hardy-Weinberg equilibrium
• Retrospective likelihood

  Abstract

In case-control studies, the assessment of the association between a binary disease outcome and a single nucleotide polymorphism (SNP) is often based on comparing the observed genotype distribution for the cases against that for the controls. In this article, we investigate an alternative analytic strategy in which the observed genotype frequencies of cases are compared against the expected genotype frequencies of controls assuming Hardy-Weinberg Equilibrium (HWE). Assuming HWE for controls, we derive closed-form expressions for maximum likelihood estimates of the genotype-specific disease odds ratio (OR) parameters and related variance-covariances. Based on these estimates and their variance-covariance structure, we then propose a two-degree-of-freedom test for disease-SNP association. We show that the proposed test can have substantially higher power than a variety of existing methods, especially when the true effect of the SNP is recessive. We also obtain analytic expressions for the bias of the OR estimates when the underlying HWE assumption is violated. We conclude that the novel test would be particularly useful for analyzing data from the initial 'screening' stages of contemporary multi-stage association studies.

Copyright © 2007 S. Karger AG, Basel

  Author Contacts

Dr. Jinbo Chen
Department of Biostatistics and Epidemiology
University of Pennsylvania School of Medicine
423 Guardian Drive, Pennsylvania, PA 19104 (USA)
Tel. +1 215 746 3915, Fax +1 215 573 4865, E-Mail jchen@cceb.med.upenn.edu

  Article Information

Received: August 16, 2006
Accepted after revision: November 2, 2006
Published online: February 22, 2007
Number of Print Pages : 9
Number of Figures : 2, Number of Tables : 5, Number of References : 16