Genomics & Informatics

Korea Genome Organization (한국유전체학회)
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Replication of the Association between Copy Number Variation on 8p23.1 and Autism by Using ASD-specific BAC Array

  • Woo, Jung-Hoon (Macrogen, Inc.) ;
  • Yang, Song-Ju (Macrogen, Inc.) ;
  • Yim, Seon-Hee (Intergrated Research Center for Genome Polymorphism, Department of Microbiology, The Catholic University of Korea School of Medicine) ;
  • Hu, Hae-Jin (Intergrated Research Center for Genome Polymorphism, Department of Microbiology, The Catholic University of Korea School of Medicine) ;
  • Shin, Myung-Ju (Macrogen, Inc.) ;
  • Oh, Eun-Hee (Macrogen, Inc.) ;
  • Kang, Hyun-Woong (Macrogen, Inc.) ;
  • Park, Seon-Yang (Department of Internal Medicine, Seoul National University College of Medicine) ;
  • Chung, Yeun-Jun (Intergrated Research Center for Genome Polymorphism, Department of Microbiology, The Catholic University of Korea School of Medicine)
  • Published : 2010.03.31
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Abstract

To discover genetic markers for autism spectrum disorder (ASD), we previously applied genome-wide BAC array comparative genomic hybridization (array-CGH) to 28 autistic patients and 62 normal controls in Korean population, and identified that chromosomal losses on 8p23.1 and on 17p11.2 are significantly associated with autism. In this study, we developed an 8.5K ASD-specific BAC array covering 27 previously reported ASD-associated CNV loci including ours and examined whether the associations would be replicated in 8 ASD patient cell lines of four different ethnic groups and 10 Korean normal controls. As a result, a CNV-loss on 8p23.1 was found to be significantly more frequent in patients regardless of ethnicity (p<0.0001). This CNV region contains two coding genes, DEFA1 and DEFA3, which are members of DEFENSIN gene family. Two other CNVs on 17p11.2 and Xp22.31 were also distributed differently between ASDs and controls, but not significant (p=0.069 and 0.092, respectively). All the other loci did not show significant association. When these evidences are considered, the association between ASD and CNV of DEFENSIN gene seems worthy of further exploration to elucidate the pathogenesis of ASD. Validation studies with a larger sample size will be required to verify its biological implication.

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References

  1. Cho, S.C., Yim, S.H., Yoo, H.K., Kim, M.Y., Jung, G.Y., Shin, G.W., Kim, B.N., Hwang, J.W., Kang, J.J., Kim, T.M., and Chung, Y.J. (2009). Copy number variations associated with idiopathic autism identified by whole-genome microarray-based comparative genomic hybridization. Psychiatr. Genet. 19, 177-185. https://doi.org/10.1097/YPG.0b013e32832bdafa
  2. Chung, Y.J., Jonkers, J., Kitson, H., Fiegler, H., Humphray, S., Scott, C., Hunt, S., Yu, Y., Nishijima, I., Velds, A., Holstege, H., Carter, N., and Bradley, A. (2004). A whole-genome mouse BAC microarray with 1-Mb resolution for analysis of DNA copy number changes by array comparative genomic hybridization. Genome Res. 14, 188-196.
  3. Cook, E.H.Jr., and Scherer, S.W. (2008). Copy-number variations associated with neuropsychiatric conditions. Nature 455, 919-923. https://doi.org/10.1038/nature07458
  4. Folstein, S.E., and Rosen-Sheidley, B. (2001). Genetics of autism: complex aetiology for a heterogeneous disorder. Nat. Rev. Genet. 2, 943-955. https://doi.org/10.1038/35103559
  5. Freeman, J.L., Perry, G.H., Feuk, L., Redon, R., McCarroll, S.A., Altshuler, D.M., Aburatani, H., Jones, K.W., Tyler-Smith, C., Hurles, M.E., Carter, N.P., Scherer, S.W., and Lee, C. (2006). Copy number variation: new insights in genome diversity. Genome Res. 16, 949-961. https://doi.org/10.1101/gr.3677206
  6. Ganz, T. (1999). Defensins and host defense. Science 286, 420-421. https://doi.org/10.1126/science.286.5439.420
  7. Glessner, J.T., Wang, K., Cai, G., Korvatska, O., Kim, C.E., Wood, S., Zhang, H., Estes, A., Brune, C.W., Bradfield, J.P., Imielinski, M., Frackelton, E.C., Reichert, J., Crawford, E.L., Munson, J., Sleiman, P.M., Chiavacci, R., Annaiah, K., Thomas, K., Hou, C., Glaberson, W., Flory, J., Otieno, F., Garris, M., Soorya, L., Klei, L., Piven, J,, Meyer, K.J., Anagnostou, E., Sakurai, T., Game, R.M., Rudd, D.S., Zurawiecki, D., McDougle, C.J., Davis, L.K., Miller, J., Posey, D.J., Michaels, S., Kolevzon, A., Silverman, J.M., Bernier, R., Levy, S.E., Schultz, R.T., Dawson, G., Owley, T., McMahon, W.M., Wassink, T.H., Sweeney, J.A., Nurnberger, J.I., Coon, H., Sutcliffe, J.S., Minshew, N.J., Grant, S.F., Bucan, M., Cook, E.H., Buxbaum, J.D., Devlin, B., Schellenberg, G.D., and Hakonarson, H. (2009). Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459, 569-573. https://doi.org/10.1038/nature07953
  8. Hollox, E.J. (2008b). Copy number variation of beta-defensins and relevance to disease. Cytogenet. Genome Res. 123, 148-155. https://doi.org/10.1159/000184702
  9. Hollox, E.J., Barber, J.C., Brookes, A.J., and Armour, J.A. (2008a). Defensins and the dynamic genome: what we can learn from structural variation at human chromosome band 8p23.1. Genome Res. 18, 1686-1697. https://doi.org/10.1101/gr.080945.108
  10. Hollox, E.J., Huffmeier, U., Zeeuwen, P.L., Palla, R., Lascorz, J., Rodijk-Olthuis, D., van de Kerkhof, P.C., Traupe, H., de Jongh, G., den Heijer, M., Reis, A., Armour, J.A., and Schalkwijk, J. (2008c). Psoriasis is associated with increased beta-defensin genomic copy number. Nat. Genet. 40, 23-25. https://doi.org/10.1038/ng.2007.48
  11. Iafrate, A.J., Feuk, L., Rivera, M.N., Listewnik, M.L., Donahoe, P.K., Qi, Y., Schererm S.W., and Lee, C. (2004). Detection of large-scale variation in the human genome. Nat. Genet. 36, 949-951. https://doi.org/10.1038/ng1416
  12. Jeong, Y.B., Kim, T.M., and Chung, Y.J. (2008). CGHscape: A Software Framework for the Detection and Visualization of Copy Number Alterations. Genomics Inform. 6, 126-129. https://doi.org/10.5808/GI.2008.6.3.126
  13. Joo, H.J., Jung, S.H., Yim, S.H., Kim, T.M., Xu, H.D., Shin, S.H., Kim, M.Y., Kang, H.M., and Chung, Y.J. (2008). Comparison of Non-amplified and Amplified DNA Preparation Methods for Array-comparative Gnomic Hybridization Analysis. Mol. Cell. Toxicol. 4, 246-252.
  14. Klauck, S.M. (2006). Genetics of autism spectrum disorder. Eur. J. Hum. Genet. 14, 714-720. https://doi.org/10.1038/sj.ejhg.5201610
  15. Marshall, C.R., Noor, A., Vincent, J.B., Lionel, A.C., Feuk, L., Skaug, J., Shago, M., Moessner, R., Pinto, D., Ren, Y., Thiruvahindrapduram, B., Fiebig, A., Schreiber, S., Friedman, J., Ketelaars, C.E., Vos, Y.J., Ficicioglu, C., Kirkpatrick, S., Nicolson, R., Sloman, L., Summers, A., Gibbons, C.A., Teebi, A., Chitayat, D., Weksberg, R., Thompson, A., Vardy, C., Crosbie, V., Luscombe, S., Baatjes, R., Zwaigenbaum, L., Roberts, W., Fernandez, B., Szatmari, P., and Scherer, S.W. (2008). Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477-488. https://doi.org/10.1016/j.ajhg.2007.12.009
  16. Pettenati, M.J., Rao, N., Johnson, C., Hayworth, R., Crandall, K., Huff, O., and Thomas, I.T. (1992). Molecular cytogenetic analysis of a familial 8p23.1 deletion associated with minimal dysmorphic features, seizures, and mild mental retardation. Hum. Genet. 89, 602-606.
  17. Rutter, M. (2005). Autism research: lessons from the past and prospects for the future. J. Autism. Dev. Disord. 35, 241-257. https://doi.org/10.1007/s10803-004-2003-9
  18. Schellenberg, G.D., Dawson, G., Sung, Y.J., Estes, A., Munson, J., Rosenthal, E., Rothstein, J., Flodman, P., Smith, M., Coon, H., Leong, L., Yu, C.E., Stodgell, C., Rodier, P.M., Spence, M.A., Minshew, N., McMahon, W.M., and Wijsman, E.M. (2006). Evidence for multiple loci from a genome scan of autism kindreds. Mol. Psychiatry 11, 1049-1160. https://doi.org/10.1038/sj.mp.4001874
  19. Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., Yamrom, B., Yoon, S., Krasnitz, A., Kendall, J., Leotta, A., Pai, D., Zhang, R., Lee, Y.H., Hicks, J., Spence, S.J., Lee, A.T., Puura, K., Lehtim-ki, T., Ledbetter, D., Gregersen, P.K., Bregman, J., Sutcliffe, J.S., Jobanputra, V., Chung, W., Warburton, D., King, M.C., Skuse, D., Geschwind, D.H., Gilliam, T.C., Ye, K., and Wigler, M. (2007). Strong association of de novo copy number mutations with autism. Science 316, 445-449. https://doi.org/10.1126/science.1138659
  20. Sebat, J., Lakshmi, B., Troge, J., Alexander, J., Young, J., Lundin, P., Maner, S., Massa, H., Walker, M., Chi, M., Navin, N., Lucito, R., Healy, J., Hicks, J., Ye, K., Reiner, A., Gilliam, T.C., Trask, B., Patterson, N., Zetterberg, A., and Wigler, M. (2004). Large-scale copy number polymorphism in the human genome. Science 305, 525-528. https://doi.org/10.1126/science.1098918
  21. Sultana, R., Yu, C.E., Yu, J., Munson, J., Chen, D., Hua, W., Estes, A., Cortes, F., de la Barra, F., Yu, D., Haider, S.T., Trask, B.J., Green, E.D., Raskind, W.H., Disteche, C.M., Wijsman, E., Dawson, G., Storm, D.R., Schellenberg, G.D., and Villacres, E.C. (2002). Identification of a novel gene on chromosome 7q11.2 interrupted by a translocation breakpoint in a pair of autistic twins. Genomics 80, 129-134. https://doi.org/10.1006/geno.2002.6810
  22. Veenstra-VanderWeele, J., and Cook, E.H.Jr. (2004). Molecular genetics of autism spectrum disorder. Mol. Psychiatry 9, 819-832. https://doi.org/10.1038/sj.mp.4001505
  23. Vorstman, J.A., Staal, W.G., van Daalen, E., van Engeland, H., Hochstenbach, P.F., and Franke, L. (2006). Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol. Psychiatry 11, 18-28. https://doi.org/10.1038/sj.mp.4001757