Abstract
BackgroundIn human case-control association studies, one of the chi-square tests typically carried out is based on a 2 × 3 table of genotypes (homogeneity of three genotype frequencies in case and control individuals). We formulate the two degrees of freedom associated with a given genotype distribution in terms of two biologically relevant parameters, (1) the probability F that an individual's two alleles are identical by descent (IBD) and (2) the frequency p of one of the alleles.ResultsImposing the restriction, F ≥ 0, makes some of the genotype frequencies invalid thereby reducing noise. We propose a new statistical association test, the FP test, by focusing on allele frequency differences between case and control individuals while allowing for suitable IBD probabilities. Power calculations show that (1) the practice of generally carrying out two association tests (allele and genotype test) has an increased type I error and (2) our test is more powerful than conventional genotype and allele tests under recessive trait inheritance, and at least as powerful as these conventional tests under dominant inheritance.ConclusionFor dominant and recessive modes of inheritance, any apparent power gain by an allele test when carried out in conjunction with a genotype test tends to be purchased entirely by an increased rate of false positive results due to omission of a multiple testing correction. As an alternative to these two standard association tests, our FP test represents a convenient and more powerful alternative.
Highlights
In human case-control association studies, one of the chi-square tests typically carried out is based on a 2 × 3 table of genotypes
The reason for this is not so much biological plausibility but rather statistical power: By disregarding parameter values that are unlikely to be of importance, we reduce the effect of statistical noise and thereby gain accuracy and power
Let F denote the probability that the two alleles in an individual are identical by descent (IBD) or autozygous or, equivalently, F = proportion of individuals who are IBD at that marker, where F is the inbreeding coefficient
Summary
In human case-control association studies, one of the chi-square tests typically carried out is based on a 2 × 3 table of genotypes (homogeneity of three genotype frequencies in case and control individuals). We formulate the two degrees of freedom associated with a given genotype distribution in terms of two biologically relevant parameters, (1) the probability F that an individual's two alleles are identical by descent (IBD) and (2) the frequency p of one of the alleles In their well-known paper on homozygosity mapping published 20 years ago, Lander and Botstein [1] showed that fewer than a dozen unrelated inbred children should suffice to map a recessive trait given a dense map of genetic markers. They recommended that one should search for extended regions of homozygosity shared by a set of inbred individuals. It will be seen below that our approach is somewhat analogous to the "possible triangle" method [8] in affected sib-pair linkage analysis and is expected to lead to similar increases in power
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