Selection of cases with additional affected relatives has been shown to increase the power of the case-control association design. We investigated whether this strategy can also improve the power of family-based association studies that use the transmission disequilibrium test (TDT), while accounting for the effects of residual polygenic and environmental factors on disease liability. Ascertainment of parent-offspring trios conditional on the proband having affected first-degree relatives almost always reduced the power of the TDT. For many disease models, this reduction was quite considerable. In contrast, for the same sample size, designs that analyzed more than one affected offspring per family often improved power when compared to the standard parent-offspring trio design. Together, our results suggest that (1) residual polygenic and environmental influences should be considered when estimating the power of the TDT for studies that ascertain families with multiple affected relatives; (2) if trios are selected conditional on having additional affected offspring, then it is important to genotype and include in the analysis the additional siblings; (3) the ascertainment strategy should be considered when interpreting results from TDT analyses. Our analytic approach to estimate the asymptotic power of the TDT is implemented online at http://pngu.mgh.harvard.edu/∼purcell/gpc/.
Association TDT Power Study design Complex disease Family history
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MARF was funded by Sidney Sax fellowship 389927 from the National Health and Medical Research Council of Australia. SP and PS acknowledge the Medical Research Council grant G9901258 and National Eye Institute grant EY-12562. We thank three anonymous reviewers for their comments and suggestions on an earlier version of this manuscript.
Abecasis GR, Cardon LR, Cookson WO (2000) A general test of association for quantitative traits in nuclear families. Am J Hum Genet 66:279–292PubMedCrossRefGoogle Scholar
Antoniou AC, Easton DF (2003) Polygenic inheritance of breast cancer: implications for design of association studies. Genet Epidemiol 25:190–202PubMedCrossRefGoogle Scholar
Chen WM, Deng HW (2001) A general and accurate approach for computing the statistical power of the transmission disequilibrium test for complex disease genes. Genet Epidemiol 21:53–67PubMedCrossRefGoogle Scholar
Falconer DS (1981) Introduction to quantitative genetics. Longman, New YorkGoogle Scholar
Fulker DW, Cherny SS, Sham PC, Hewitt JK (1999) Combined linkage and association sib-pair analysis for quantitative traits. Am J Hum Genet 64:259–267PubMedCrossRefGoogle Scholar
Howson JM, Barratt BJ, Todd JA, Cordell HJ (2005) Comparison of population- and family-based methods for genetic association analysis in the presence of interacting loci. Genet Epidemiol 29:51–67PubMedCrossRefGoogle Scholar