Original Paper

Power of Genetic Association Studies in the Presence of Linkage Disequilibrium and Allelic Heterogeneity
Sheila A. Fisher^a, Cathryn M. Lewis<sup>a, b

a</sup>Division of Genetics and Molecular Medicine and
^bSGDP Centre, Institute of Psychiatry, King's College London, London, UK

Address of Corresponding Author

Hum Hered 2008;66:210-222 (DOI: 10.1159/000143404)

  Key Words

• Allelic association
• Case-control study
• Heterogeneity
• Linkage disequilibrium
• Mutations
• Sample size
• Transmission disequilibrium test
• Allelic heterogeneity

  Abstract

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 © 2008 S. Karger AG, Basel

  Author Contacts

Dr. Cathryn M. Lewis
King's College London, Department of Medical and Molecular Genetics
8th Floor, Guy's Tower, Guy's Hospital
London SE1 9RT (UK)
Tel. +44 20 7188 2601, Fax +44 20 7188 2585, E-Mail cathryn.lewis@kcl.ac.uk

  Article Information

Received: July 13, 2007
Accepted after revision: October 30, 2007
Published online: July 9, 2008
Number of Print Pages : 13
Number of Figures : 2, Number of Tables : 6, Number of References : 31