Objective: A simple method for accounting efficiently for multiple testing of many SNPs in an association study was recently proposed by Nyholt, but its performance was not extensively evaluated. The method involves estimating an ‘effective number’ of independent tests and then adjusting the smallest observed p value using Šidák’s formula based on this number of tests. We sought to carry out an empirical and theoretical evaluation of Nyholt’s method. Methods: Nyholt’s method was applied to a sample of 31 genes typed at a total of 291 SNPs and permutation used to determine the type-I error rate for each gene. Based on our empirical results, we algebraically investigated the effective number of independent tests for a simple model of haplotype block structure. Results: The nominal 5% type I error rate varied from under 3% to over 7%, and was dependent on linkage disequilibrium. Theoretical considerations show further that the method can be very conservative in the presence of haplotype block structure. Conclusion: Although Nyholt’s approach may be useful as an exploratory tool, it is not an adequate substitute for permutation tests.

Keywords:
Linkage disequilibrium, Case-control study, Spectral decomposition
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© 2005 S. Karger AG, Basel
2005
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