Utilization of Lymphoblastoid Cell Lines as a System for the Molecular Modeling of Autism
- 322 Downloads
In order to provide an alternative approach for understanding the biology and genetics of autism, we performed statistical analysis of gene expression profiles of lymphoblastoid cell lines derived from children with autism and their families. The goal was to assess the feasibility of using this model in identifying autism-associated genes. Replicate microarray experiments demonstrated that expression data from the cell lines were consistent and highly reproducible. Further analyses identified differentially expressed genes between cell lines derived from children with autism and those derived from their normally developing siblings. These genes were then used to identify biochemical pathways potentially involved in autism. This study suggests that lymphoblastoid cell lines may be a viable tool for identifying genes associated with autism.
KeywordsAutism Lymphoblastoid cell lines Gene expression Microarray Blood genomics PathwayAssist
This work was supported by the MIND Institute Biomarkers Initiative, MIND Institute Genomics Core, and grant number PO1 ES 11269 from the NIEHS and US EPA. The authors would like to thank AGRE for providing cells lines and information on families used in this study. The authors express their appreciation to Zeljka Smit-McBride for culturing the AGRE cell lines, to Dawn Milliken for performing the gene expression microarray work, and to Clifford Tepper and Wenting Zhang for helpful commentary during manuscript preparation. We gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families. The Autism Genetic Resource Exchange is a program of Cure Autism Now and is supported, in part, by grant MH64547 from the National Institute of Mental Health to Daniel H. Geschwind (PI).
- American Psychiatric Association (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC.Google Scholar
- Buxbaum, J. D., Silverman, J. M., Smith, C. J., Kilifarski, M., Reichert, J., Hollander, E., Lawlor, B. A., Fitzgerald, M., Greenberg, D. A., & Davis, K. L. (2001). Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity. American Journal of Human Genetics, 68, 1514–1520.PubMedCrossRefGoogle Scholar
- Geschwind, D. H., & Gregg, J. P. (2002). Microarrays for the Neurosciences: An Essential Guide. Cambridge, MA: The MIT Press.Google Scholar
- Geschwind, D. H., Sowinski, J., Lord, C., Iversen, P., Shestack, J., Jones, P., Ducat, L., & Spence, S. J. (2001). The autism genetic resource exchange: a resource for the study of autism and related neuropsychiatric conditions. American Journal of Human Genetics, 69, 463–466.PubMedCrossRefGoogle Scholar
- Lord, C., Risi, S., Lambrecht, L., Cook, E., Leventhal, B., DiLavore, P., Pickles, A., & Rutter, M. (2000). The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. Journal of Autism and Developmental Disorders, 30, 205–223.PubMedCrossRefGoogle Scholar
- Luiselli, J. K., Blew, P., Keane, J., Thibadeau, S., & Holzman, T. (2000). Pharmacotherapy for severe aggression in a child with autism: “open label” evaluation of multiple medications on response frequency and intensity of behavioral intervention. Journal of Behavior Therapy and Experimental Psychiatry, 31, 219–230.PubMedCrossRefGoogle Scholar
- Philippe, A., Guilloud-Bataille, M., Martinez, M., Gillberg, C., Rastam, M., Sponheim, E., Coleman, M., Zappella, M., Aschauer, H., Penet, C., Feingold, J., Brice, A., & Leboyer, M. (2002). Analysis of ten candidate genes in autism by association and linkage. American Journal of Medical Genetics, 114, 125–128.PubMedCrossRefGoogle Scholar
- Pickles, A., Bolton, P., Macdonald, H., Bailey, A., Le Couteur, A., Sim, C., & Rutter M. (1995). Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism. American Journal of Human Genetics, 57, 717–726.PubMedGoogle Scholar
- Schadt, E. E., Monks, S. A., Drake, T. A., Lusis, A. J., Che, N., Colinayo, V., Ruff, T. G., Milligan, S. B., Lamb, J. R., Cavet, G., Linsley, P. S., Mao, M., Stoughton, R. B., & Friend, S. H. (2003). Genetics of gene expression surveyed in maize, mouse and man. Nature, 422, 297–302.PubMedCrossRefGoogle Scholar
- World Health Organization (1993). The ICD-10 classification for mental and behavioral disorders: diagnostic criteria for research ed. Geneva, Switzerland: World Health Organization.Google Scholar
- Yonan, A. L., Alarcon, M., Cheng, R., Magnusson, P. K., Spence, S. J., Palmer, A. A., Grunn, A., Juo, S. H., Terwilliger, J. D., Liu, J., Cantor, R. M., Geschwind, D. H., & Gilliam, T. C. (2003). A genomewide screen of 345 families for autism-susceptibility loci. American Journal of Human Genetics, 73, 886–897.PubMedCrossRefGoogle Scholar