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Title Collaboration Motivated Methodological Research at VICTR
Year 2011
Contributor/Contact Chang Yu
CTSA Vanderbilt
Success Topic Methods papers, Software development
Description of Success In our collaboration with CTSA investigators, Hardy-Weinberg equilibrium (HWE) has been routinely tested in association studies, often case-control studies, to check for genotyping errors. Chang Yu recognized a critical flaw in this practice: when HWE is tested separately in cases and in controls, the very underlying association that the studies set out to detect might cause the genotype to deviate from HWE, especially in the cases. If one were to test HWE in case-control studies, such potential underlying association should be considered in the test. This led us to develop a likelihood ratio test for HWE in case-control studies (Yu, Zhang, Zhou, Sile, 2009). Our test extends the work of Wittke-Thompson, Pluzhnikov, Cox (2005). Together, the two works provide guidance to testing and interpreting a departure from HWE detected in cases and/or in controls. Our test uses cases and controls combined while considering the underlying association. The detected departure from HWE needs to be explained in the context of genotyping errors, population stratification, population selection, and the study sampling plan. If genotyping errors are ruled not likely to be the cause and the departure from HWE is plausible (probably due to the other causes listed above), then its impact on the estimate of the association needs to be evaluated. This can be done in our framework (Grover, et al., 2009). Our methods explicitly incorporate HWE or a departure from HWE into the model when we infer the underlying disease-genotype association. The R programs and examples for this test can be obtained from chang.yu@vanderbilt.edu. The programs are also included in the R package Genetics Analysis Package (GAP) (Zhao and Tan, 2006; Zhao, 2007).


References:

Grover, V.K., Cole, D.E.C., Hamilton, D.C. (2010). Attributing Hardy-Weinberg disequilibrium to population stratification and genetic association in case-control studies. Annals of Human Genetics, 74:77-87.

J.A. Phillips III, J.S. Poling, C.A. Phillips, K. C. Stanton, E.D. Austin, J.D. Cogan, L. Wheeler, C Yu, Dietz, H.C. and J. E. Loyd. Synergistic heterozygosity for TGFβ1 SNPs and BMPR2 mutations modulates the age at diagnosis and penetrance of Familial Pulmonary Arterial Hypertension (FPAH), Genetics in Medicine 10(5):359-65, 2008.

Sile S, Gillani NB, Velez DR, Vanoye CG, Yu C, Byrne LM, Gainer JV, Brown NJ, Williams SM, George AL Jr. Functional BSND variants in essential hypertension. American Journal of Hypertension 2007 Nov;20(11):1176-1182.

Wittke-Thompson, J. K., Pluzhnikov, A., Cox, N. J. (2005). Rational inference about departures from Hardy-Weinberg equilibrium. American Journal of Human Genetics, 76 967-986.

Yu, C., Zhang, S., Zhou, C., and Sile, S. (2009). A likelihood ratio test of population Hardy Weinberg equilibrium for case-control studies. Genetic Epidemiology 33:275-280.

Zhao, J.H. (2007). Gap: Genetic analysis package. Journal of Statistical Software 23:1-18.

Zhao, J.H. and Tan, Q. (2006). Integrated analysis of genetic data with R, Hum. Genomics 2: 258265.
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Topic revision: r2 - 13 Feb 2012 - 11:15:40 - ChangYu
 

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