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Fine mapping by composite genome-wide association analysis


Genome-wide association (GWA) studies play a key role in current genetics research, unravelling genomic regions linked to phenotypic traits of interest in multiple species. Nevertheless, the extent of linkage disequilibrium (LD) may provide confounding results when significant genetic markers span along several contiguous cM. In this study, we have adapted the composite interval mapping approach to the GWA framework (composite GWA), in order to evaluate the impact of including competing (possibly linked) genetic markers when testing for the additive allelic effect inherent to a given genetic marker. We tested model performance on simulated data sets under different scenarios (i.e., qualitative trait loci effects, LD between genetic markers and width of the genomic region involved in the analysis). Our results showed that the genomic region had a small impact on the number of competing single nucleotide polymorphisms (SNPs) as well as on the precision of the composite GWA analysis. A similar conclusion was derived from the preferable range of LD between the tested SNP and competing SNPs, although moderate-to-high LD seemed to attenuate the loss of statistical power. The composite GWA improved specificity and reduced the number of significant genetic markers. The composite GWA model contributes a novel point of view for GWA analyses where testing circumscribed to the genomic region flanking each SNP (delimited by the nearest competing SNPs) and conditioning on linked markers increases the precision to locate causal mutations, but possibly at the expense of power.

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Benjamini, Y. & Hochberg, Y. (1995). Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society B 57, 289290.
Benyamin, B., Visscher, P. M. & McRae, A. F. (2009). Family-based genome-wide association studies. Pharmacogenomics 10, 181190.
Bernardo, R. (2013). Genomewide markers as cofactors for precision mapping of quantitative trait loci. Theoretical and Applied Genetics 126, 9991009.
Bonferroni, C. E. (1936). Teoria statistica della classi a calcolo della probabilità. Pubblicasioni del R Instituto Superiore di Scienze Economiche e Commerciali di Firenze 8, 362.
Casellas, J. & Varona, L. (2011). Effect of mutation age on genomic prediction. Journal of Dairy Science 94, 42244229.
Gibbs, R. A., Weinstock, G. M., Metzker, M. L., Munzy, D. M., Sodergren, E. J., Scherer, S., Scott, G., Steffen, D., Worley, K. C., Burch, P. E., Okwuonu, G., Hines, S., Lewis, L., DeRamo, C., Delgado, O., Dugan-Rocha, S., Miner, G., Morgan, M., Hawes, A., Gill, R., Celera, , Holt, R. A., Adams, M. D., Amanatides, P. G., Baden-Tillson, H., Barnstead, M., Chin, S., Evans, C. A., Ferriera, S., Fosler, C., Glodek, A., Gu, Z., Jennings, D., Kraft, C. L., Nguyen, T., Pfannkoch, C. M., Sitter, C., Sutton, G. G., Venter, J. C., Woodage, T., Smith, D., Lee, H. M., Gustafson, E., Cahill, P., Kana, A., Doucette-Stamm, L., Weinstock, K., Fechtel, K., Weiss, R. B., Dunn, D. M., Green, E. D., Blakesley, R. W., Bouffard, G. G., De Jong, P. J., Osoegawa, K., Zhu, B., Marra, M., Schein, J., Bosdet, I., Fjell, C., Jones, S., Krzywinski, M., Mathewson, C., Siddiqui, A., Wye, N., McPherson, J., Zhao, S., Fraser, C. M., Shetty, J., Shatsman, S., Geer, K., Chen, Y., Abramzon, S., Nierman, W. C., Havlak, P. H., Chen, R., Durbin, K. J., Egan, A., Ren, Y., Song, X. Z., Li, B., Liu, Y., Qin, X., Cawley, S., Worley, K. C., Cooney, A. J., D'Souza, L. M., Martin, K., Wu, J. Q., Gonzalez-Garay, M. L., Jackson, A. R., Kalafus, K. J., McLeod, M. P., Milosavljevic, A., Virk, D., Volkov, A., Wheeler, D. A., Zhang, Z., Bailey, J. A., Eichler, E. E., Tuzun, E., Birney, E., Mongin, E., Ureta-Vidal, A., Woodwark, C., Zdobnov, E., Bork, P., Suyama, M., Torrents, D., Alexandersson, M., Trask, B. J., Young, J. M., Huang, H., Wang, H., Xing, H., Daniels, S., Gietzen, D., Schmidt, J., Stevens, K., Vitt, U., Wingrove, J., Camara, F., Mar Albà, M., Abril, J. F., Guigo, R., Smit, A., Dubchak, I., Rubin, E. M., Couronne, O., Poliakov, A., Hübner, N., Ganten, D., Goesele, C., Hummel, O., Kreitler, T., Lee, Y. A., Monti, J., Schulz, H., Zimdahl, H., Himmelbauer, H., Lehrach, H., Jacob, H. J., Bromberg, S., Gullings-Handley, J., Jensen-Seaman, M. I., Kwitek, A. E., Lazar, J., Pasko, D., Tonellato, P. J., Twigger, S., Ponting, C. P., Duarte, J. M., Rice, S., Goodstadt, L., Beatson, S. A., Emes, R. D., Winter, E. E., Webber, C., Brandt, P., Nyakatura, G., Adetobi, M., Chiaromonte, F., Elnitski, L., Eswara, P., Hardison, R. C., Hou, M., Kolbe, D., Makova, K., Miller, W., Nekrutenko, A., Riemer, C., Schwartz, S., Taylor, J., Yang, S., Zhang, Y., Lindpaintner, K., Andrews, T. D., Caccamo, M., Clamp, M., Clarke, L., Curwen, V., Durbin, R., Eyras, E., Searle, S. M., Cooper, G. M., Batzoglou, S., Brudno, M., Sidow, A., Stone, E. A., Venter, J. C., Payseur, B. A., Bourque, G., López-Otín, C., Puente, X. S., Chakrabarti, K., Chatterji, S., Dewey, C., Pachter, L., Bray, N., Yap, V. B., Caspi, A., Tesler, G., Pevzner, P. A., Haussler, D., Roskin, K. M., Baertsch, R., Clawson, H., Furey, T. S., Hinrichs, A. S., Karolchik, D., Kent, W. J., Rosenbloom, K. R., Trumbower, H., Weirauch, M., Cooper, D. N., Stenson, P. D., Ma, B., Brent, M., Arumugam, M., Shteynberg, D., Copley, R. R., Taylor, M. S., Riethman, H., Mudunuri, U., Peterson, J., Guyer, M., Felsenfeld, A., Old, S., Mockrin, S., Collins, F & Rat Genome Sequencing Project Consortium (2004). Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature 428, 493521.
Habier, D., Fernando, R. L. & Dekkers, J. C. M. (2009). Genomic selection using low-density marker panels. Genetics 182, 343353.
He, Q. & Lin, D.-Y. (2011). A variable selection method for genome-wide association studies. Bioinformatics 27, 18.
Hickey, J. M. & Gorjanc, G. (2012). Simulated data from genomic selection and genome-wide association studies using a combination of coalescent gene drop methods. G3 2, 425427.
Hill, W. G. & Robertson, A. (1968). Linkage disequilibrium in finite populations. Theoretical and Applied Genetics 38, 226231.
Ibáñez-Escriche, N., Fernando, R. L., Toosi, A. & Dekkers, J. C. M. (2009). Genomic selection of purebred for crossbred performance. Genetics, Selection, Evolution 41, 12.
International Chicken Genome Sequencing Consortium (2004). Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution. Nature 432, 695716.
International HapMap Consortium (2005). A haplotype map of the human genome. Nature 437, 12991320.
Jansen, R. C. & Stam, P. (1994). High resolution of quantitative traits into multiple loci via interval mapping. Genetics 136, 14471455.
Jensen, R. C. (1993). Interval mapping of multiple quantitative trait loci. Genetics 167, 19872002.
Kemper, K. E., Daetwyler, H. D., Visscher, P. M. & Goddard, M. E. (2012). Comparing linkage and association analyses in sheep points to a better way of doing GWAS. Genetics Research 94, 191203.
Klein, R. J., Zeiss, C., Chew, E. Y., Tsai, J. Y., Sackler, R. S., Haynes, C., Henning, A. K., SanGiovanni, J. P., Mane, S. M., Mayne, S. T., Bracken, M. B., Ferris, F. L., Ott, J., Barnstable, C. & Hoh, J. (2005). Complement factor H polymorphism in age-related macular degeneration. Science 308, 385389.
Kosambi, D. D. (1943). The estimation of map distances from recombination values. Annals of Eugenics 12, 172175.
Li, R., Fan, W., Tian, G., Zhu, H., He, L., Cai, J., Huang, Q., Cai, Q., Li, B., Bai, Y., Zhang, Z., Zhang, Y., Wang, W., Li, J., Wei, F., Li, H., Jian, M., Li, J., Zhang, Z., Nielsen, R., Li, D., Gu, W., Yang, Z., Xuan, Z., Ryder, O. A., Leung, F. C., Zhou, Y., Cao, J., Sun, X., Fu, Y., Fang, X., Guo, X., Wang, B., Hou, R., Shen, F., Mu, B., Ni, P., Lin, R., Qian, W., Wang, G., Yu, C., Nie, W., Wang, J., Wu, Z., Liang, H., Min, J., Wu, Q., Cheng, S., Ruan, J., Wang, M., Shi, Z., Wen, M., Liu, B., Ren, X., Zheng, H., Dong, D., Cook, K., Shan, G., Zhang, H., Kosiol, C., Xie, X., Lu, Z., Zheng, H., Li, Y., Steiner, C. C., Lam, T. T., Lin, S., Zhang, Q., Li, G., Tian, J., Gong, T., Liu, H., Zhang, D., Fang, L., Ye, C., Zhang, J., Hu, W., Xu, A., Ren, Y., Zhang, G., Bruford, M. W., Li, Q., Ma, L., Guo, Y., An, N., Hu, Y., Zheng, Y., Shi, Y., Li, Z., Liu, Q., Chen, Y., Zhao, J., Qu, N., Zhao, S., Tian, F., Wang, X., Wang, H., Xu, L., Liu, X., Vinar, T., Wang, Y., Lam, T. W., Yiu, S. M., Liu, S., Zhang, H., Li, D., Huang, Y., Wang, X., Yang, G., Jiang, Z., Wang, J., Qin, N., Li, L., Li, J., Bolund, L., Kristiansen, K., Wong, G. K., Olson, M., Zhang, X., Li, S., Yang, H., Wang, J. & Wang, J. (2010). The sequence and de novo assembly of the giant panda genome. Nature 463, 311317.
Meuwissen, T. H. E., Hayes, B. J. & Goddard, M. E. (2001). Prediction of total genetic value using genome-wide dense marker maps. Genetics 157, 18191829.
Mrode, R. A. (2005). Linear Models for the Prediction of Animal Breeding Values. CAB International, Oxon, UK.
Neyman, J., & Pearson, E. S. (1933). On the problem of the most efficient tests of statistical hypotheses. Philosophical Transaction of the Royal Society A 231, 289337.
Ødegård, J., Soneson, A. K., Yazdi, M. H. & Meuwissen, T. H. E. (2009). Introgression of a major QTL from an inferior into a superior population using genomic selection. Genetics, Selection, Evolution 41, 38.
Pearson, T. A. & Manolio, T. A. (2008). How to interpret a genome-wide association study. Journal of the American Medical Association 19, 13351344.
Rodolphe, F. & Lefort, M. (1993). A multi-marker model for detecting chromosomal segments displaying QTL activity. Genetics 134, 12771288.
Sachidanandam, R., Weissman, D., Schmidt, S. C., Kakol, J. M., Stein, L. D., Marth, G., Sherry, S., Mullikin, J. C., Mortimore, B. J., Willey, D. L., Hunt, S. E., Cole, C. G., Coggill, P. C., Rice, C. M., Ning, Z., Rogers, J., Bentley, D. R., Kwok, P. Y., Mardis, E. R., Yeh, R. T., Schultz, B., Cook, L., Davenport, R., Dante, M., Fulton, L., Hillier, L., Waterston, R. H., McPherson, J. D., Gilman, B., Schaffner, S., Van Etten, W. J., Reich, D., Higgins, J., Daly, M. J., Blumenstiel, B., Baldwin, J., Stange-Thomann, N., Zody, M. C., Linton, L., Lander, E. S., Altshuler, D & International SNP Map Working Group (2001). A map of human genome sequence variation containing 1·42 million single nucleotide polymorphisms. Nature 409, 928933.
Sargolzaei, M., Schenkel, F. S., Jansen, G. B. & Schaeffer, L. R. (2008). Extent of linkage disequilibrium in Holstein cattle in North America. Journal of Dairy Science 91, 21062117.
Scally, A., Dutheil, J. Y., Hillier, L. W., Jordan, G. E., Goodhead, I., Herrero, J., Hobolth, A., Lappalainen, T., Mailund, T., Marques-Bonet, T., McCarthy, S., Montgomery, S. H., Schwalie, P. C., Tang, Y. A., Ward, M. C., Xue, Y., Yngvadottir, B., Alkan, C., Andersen, L. N., Ayub, Q., Ball, E. V., Beal, K., Bradley, B. J., Chen, Y., Clee, C. M., Fitzgerald, S., Graves, T. A., Gu, Y., Heath, P., Heger, A., Karakoc, E., Kolb-Kokocinski, A., Laird, G. K., Lunter, G., Meader, S., Mort, M., Mullikin, J. C., Munch, K., O'Connor, T. D., Phillips, A. D., Prado-Martinez, J., Rogers, A. S., Sajjadian, S., Schmidt, D., Shaw, K., Simpson, J. T., Stenson, P. D., Turner, D. J., Vigilant, L., Vilella, A. J., Whitener, W., Zhu, B., Cooper, D. N., de Jong, P., Dermitzakis, E. T., Eichler, E. E., Flicek, P., Goldman, N., Mundy, N. I., Ning, Z., Odom, D. T., Ponting, C. P., Quail, M. A., Ryder, O. A., Searle, S. M., Warren, W. C., Wilson, R. K., Schierup, M. H., Rogers, J., Tyler-Smith, C. & Durbin, R. (2012). Insights into hominid evolution from the gorilla genome sequence. Nature 483, 169175.
Singer, J. B. (2009). Candidate gene association analysis. Methods in Molecular Biology 573, 223230.
Stam, P. (1991). Some aspects of QTL analysis. In Proceedings of the Eighth Meeting of the Eucarpia Section Biometrics in Plant Breeding. Brno, Czech Republic, July 1991. European Association for Research on Plant Breeding (EUCARPIA).
Tenesa, A., Wright, A. F., Knott, S. A., Carothers, A. D., Hayward, C., Angius, A., Maestrale, G., Hastie, N. D., Pirastu, M. & Visscher, P. M. (2004). Extent of linkage disequilibrium in a Sardinian sub-isolate: sampling and methodological considerations. Human Molecular Genetics 13, 2533.
Toosi, A., Fernando, R. L. & Dekkers, J. C. M. (2010). Genomic selection in admixed and crossbred populations. Journal of Animal Science 88, 3246.
Wang, K., Dickson, S. P., Stolle, C. A., Krantz, I. D., Goldstein, D. B. & Hakonarson, H. (2010). Interpretation of association signals and identification of causal variants from genome-wide association studies. American Journal of Human Genetics 86, 730742.
Wright, S. (1931). Evolution in Mendelian populations. Genetics 16, 97159.
Zeng, Z.-B. (1993). Theoretical basis of separation of multiple linked gene effects on mapping quantitative trait loci. Proceedings of the National Academy of Sciences of USA 90, 1097210976.
Zeng, Z.-B. (1994). Precision mapping of quantitative trait loci. Genetics 136, 14571468.
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