WJNS  Vol.4 No.3 , June 2014
Identification of Genetic Variants Underlying Anxiety and Multiple Sclerosis in Heterogeneous Stock Rats

Identifying genetic variants that contribute to phenotypic variation is expected to provide insights into the etiology of complex traits. Here we show how combining genetic mapping in an outbred population of rats with sequence data from the progenitors of the population made it possible to identify causal variants and genes for a large number of phenotypes. We identified 355 genomic loci contributing to 122 measures relevant to six models of disease, including fear-related behaviors and experimental autoimmune encephalomyelitis. At 35 of those loci we identified the responsible gene, and in some cases, the responsible variant.

Cite this paper
Baud, A. , Flint, J. , Fernandez-Teruel, A. and Consortium, T. (2014) Identification of Genetic Variants Underlying Anxiety and Multiple Sclerosis in Heterogeneous Stock Rats. World Journal of Neuroscience, 4, 216-224. doi: 10.4236/wjns.2014.43025.
[1]   Baud, A., Hermsen, R., Guryev, V., Stridh, P., Graham, D., McBride, M.W., et al. (2013) Combined Sequence-Based and Genetic Mapping Analysis of Complex Traits in Outbred Rats. Nature Genetics, 45, 767-775.

[2]   Hansen, C. and Spuhler, K. (1984) Development of the National Institutes of Health Genetically Heterogeneous Rat Stock. Alcoholism: Clinical and Experimental Research, 8, 477-479.

[3]   Johannesson, M., Lopez-Aumatell, R., Stridh, P., Diez, M., Tuncel, J., Blazquez, G., et al. (2009) A Resource for the Simultaneous High-Resolution Mapping of Multiple Quantitative Trait Loci in Rats: The NIH Heterogeneous Stock. Genome Research, 19, 150-158. http://dx.doi.org/10.1101/gr.081497.108

[4]   Solberg, L.C., Valdar, W., Gauguier, D., Nunez, G., Taylor, A., Burnett, S., et al. (2006) A Protocol for HighThroughput Phenotyping, Suitable for Quantitative Trait Analysis in Mice. Mammalian Genome, 17, 129-146.

[5]   Kang, H.M., Zaitlen, N.A., Wade, C.M., Kirby, A., Heckerman, D., Daly, M.J., et al. (2008) Efficient Control of Population Structure in Model Organism Association Mapping. Genetics, 178, 1709-1723.

[6]   Mott, R., Talbot, C.J., Turri, M.G., Collins, A.C. and Flint, J. (2000) A Method for Fine Mapping Quantitative Trait Loci in Outbred Animal Stocks. Proceedings of the National Academy of Sciences of the United States of America, 97, 12649-12654.

[7]   Flint, J. (2011) Mapping Quantitative Traits and Strategies to Find Quantitative Trait Genes. Methods, 53, 163-174.

[8]   Yalcin, B., Flint, J. and Mott, R. (2005) Using Progenitor Strain Information to Identify Quantitative Trait Nucleotides in Outbred Mice. Genetics, 171, 673-681.

[9]   Diaz-Moran, S., Palencia, M., Mont-Cardona, C., Canete, T., Blazquez, G., Martinez-Membrives, E., et al. (2012) Coping Style and Stress Hormone Responses in Genetically Heterogeneous Rats: Comparison with the Roman Rat Strains. Behavioural Brain Research, 228, 203-210.

[10]   Fernandez-Teruel, A., Escorihuela, R.M., Nunez, J.F., Zapata, A., Boix, F., Salazar, W., et al. (1991) The Early Acquisition of Two-Way (Shuttle-Box) Avoidance as an Anxiety-Mediated Behavior: Psychopharmacological Validation. Brain Research Bulletin, 26, 173-176. http://dx.doi.org/10.1016/0361-9230(91)90205-X

[11]   Gray, J.A. (1982) The Neuropsychology of Anxiety: An Enquiry into the Functions of the Septo-Hippocampal System. Oxford University Press, Oxford, 548 p.

[12]   Lopez-Aumatell, R., Vicens-Costa, E., Guitart-Masip, M., Martinez-Membrives, E., Valdar, W., Johannesson, M., et al. (2009) Unlearned Anxiety Predicts Learned Fear: A Comparison among Heterogeneous Rats and the Roman Rat Strains. Behavioural Brain Research, 202, 92-101.

[13]   Vicens-Costa, E., Martinez-Membrives, E., Lopez-Aumatell, R., Guitart-Masip, M., Canete, T., Blazquez, G., et al. (2011) Two-Way Avoidance Acquisition Is Negatively Related to Conditioned Freezing and Positively Associated with Startle Reactions: A Dissection of Anxiety and Fear In Genetically Heterogeneous Rats. Physiology & Behavior, 103, 148-156. http://dx.doi.org/10.1016/j.physbeh.2010.12.009

[14]   Israely, I., Costa, R.M., Xie, C.W., Silva, A.J., Kosik, K.S. and Liu, X. (2004) Deletion of the neuron-Specific Protein Delta-Catenin Leads to Severe Cognitive and Synaptic Dysfunction. Current Biology, 14, 1657-1663.

[15]   Shirihai, O.S., Gregory, T., Yu, C., Orkin, S.H. and Weiss, M.J. (2000) ABC-me: A Novel Mitochondrial Transporter Induced by GATA-1 during Erythroid Differentiation. The EMBO Journal, 19, 2492-2502.

[16]   Hyde, B.B., Liesa, M., Elorza, A.A., Qiu, W., Haigh, S.E., Richey, L., et al. (2012) The Mitochondrial Transporter ABC-me (ABCB10), a Downstream Target of GATA-1, Is Essential for Erythropoiesis in Vivo. Cell Death & Differentiation, 19, 1117-1126.

[17]   Veyrieras, J.B., Kudaravalli, S., Kim, S.Y., Dermitzakis, E.T., Gilad, Y., Stephens, M., et al. (2008) High-Resolution Mapping of Expression-QTLs Yields Insight into Human Gene Regulation. PLOS Genetics, 4, Article ID: e1000214.

[18]   Wallstrom, E. and Olsson, T. (2008) Rat Models of Experimental Autoimmune Encephalomyelitis. In: Conn, P.M., Ed., Sourcebook of Models for Biomedical Research, Humana Press, Totowa, 547-556.

[19]   Baud, A., Guryev, V., Hummel, O. and Johannesson, M., The Rat Genome Sequencing and Mapping Consortium and Flint, J. (2014) Genomes and Phenomes of a Population of Outbred Rats and Its Progenitors. Scientific Data, 1, Article ID: 140011.