Power of genetic association studies in the presence of linkage disequilibrium and allelic heterogeneity

Objectives: The calculation of the power and sample size required for association studies is essential, particularly for follow-up of genome-wide association studies, where much genotyping is required to replicate the original finding and identify the true disease susceptibility mutation. Methods: In this paper, we derive equations for estimation of sample sizes for the transmission disequilibrium test (TDT) and for case-control studies, in the presence of allelic heterogeneity and indirect association -where the genotyped tagging SNP is in linkage disequilibrium (LD) with the true mutation. Using data from NOD2 and PTPN22, we show that the true sample sizes required to detect association may be incorrect when calculated under the assumption of a single mutation and complete LD with the genotyped marker. Results: The true sample sizes may be lower when allelic heterogeneity acts in a recessive model across mutations, or increased when mutations lie on different alleles of a common tagging SNP. Conclusion: Calculating power and sample size under a range of realistic models of LD and allelic heterogeneity is essential to ensure that association studies have sufficient power to detect mutations. Copyright (C) 2008 S. Karger AG, Basel