A large scale genome simulation model incorporating patterns of linkage disequilibrium

Abstract

Evaluation of multiple hypotheses is a common problem, especially in genome wide association studies. False Discovery Rate control is often used to correct for multiple comparisons. However, this approach is influenced by linkage disequilibrium and needs to be evaluated. For such evaluation, first a model needs to be developed with a simulated linkage disequilibrium pattern that matches as closely as possible the observed linkage disequilibrium structure. This paper outlines the steps involved in the development of such a model, using mouse genome data as an example. References http://gscan.well.ox.ac.uk/ K. G. Ardlie, L. Kruglyak, and M. Seielstad. Patterns of linkage disequilibrium in the human genome. Nature Reviews Genetics, 3(4):299--309, 2002. doi:10.1038/nrg777 J. C. Barrett, B. Fry, J. Maller, and M. J. Daly. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics, 21(2):263, 2005. doi:10.1093/bioinformatics/bth457 Y. Benjamini and Y. Hochberg. Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society. Series B (Methodological), 57(1):289--300, 1995. http://www.jstor.org/pss/2346101 M. S. Khatkar, F. W. Nicholas, A. R. Collins, K. R. Zenger, J. A. L. Cavanagh, W. Barris, R. D. Schnabel, J. F. Taylor, and H. W. Raadsma. Extent of genome-wide linkage disequilibrium in Australian Holstein--Friesian cattle based on a high-density SNP panel. BMC genomics, 9(1):187, 2008. doi:10.1186/1471-2164-9-187 L. Kruglyak. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nature genetics, 22:139--144, 1999. doi:10.1038/9642 C. C. Laurie, D. A. Nickerson, A. D. Anderson, B. S. Weir, R. J. Livingston, M. D. Dean, K. L. Smith, E. E. Schadt, and M. W. Nachman. Linkage disequilibrium in wild mice. PLoS Genetics, 3(8):e144, 2007. doi:10.1371/journal.pgen.0030144 W. Valdar, L. C. Solberg, D. Gauguier, S. Burnett, P. Klenerman, W. O. Cookson, M. S. Taylor, J. N. P. Rawlins, R. Mott, and J. Flint. Genome-wide genetic association of complex traits in heterogeneous stock mice. Nature genetics, 38(8):879--887, 2006. doi:10.1038/ng1840