Combining identity by descent and association in genetic case-control studies
1 Beijing Institute of Genomics, Chinese Academy of Sciences, No. 7 Bei Tu Cheng West Road, Beijing 100029, PR China
2 Department of Biostatistics, Mailman School of Public Health, 722 West 168th Street, Columbia University, New York, NY 10032, USA
3 Rockefeller University, Laboratory of Statistical Genetics, 1230 York Avenue, New York, NY 10065, USA
BMC Genetics 2008, 9:42 doi:10.1186/1471-2156-9-42Published: 5 July 2008
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.
Imposing 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.
For 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.