Journal of Autism and Developmental Disorders

, Volume 40, Issue 9, pp 1139–1145

Brief Report: Glutamate Transporter Gene (SLC1A1) Single Nucleotide Polymorphism (rs301430) and Repetitive Behaviors and Anxiety in Children with Autism Spectrum Disorder

  • Kenneth D. Gadow
  • Jasmin Roohi
  • Carla J. DeVincent
  • Sarah Kirsch
  • Eli Hatchwell
Brief Report

Abstract

Investigated association of single nucleotide polymorphism (SNP) rs301430 in glutamate transporter gene (SLC1A1) with severity of repetitive behaviors (obsessive–compulsive behaviors, tics) and anxiety in children with autism spectrum disorder (ASD). Mothers and/or teachers completed a validated DSM-IV-referenced rating scale for 67 children with autism spectrum disorder. Although analyses were not significant for repetitive behaviors, youths homozygous for the high expressing C allele had more severe anxiety than carriers of the T allele. Allelic variation in SLC1A1 may be a biomarker for or modifier of anxiety symptom severity in children with ASD, but study findings are best conceptualized as tentative pending replication with larger independent samples.

Keywords

Autism Autism spectrum disorder SLC1A1 Obsessive–compulsive behaviors Separation anxiety Generalized anxiety 

References

  1. Arnold, P. D., Sicard, T., Burroughs, E., Richter, M. A., & Kennedy, J. L. (2006). Glutamate transporter gene SLC1A1 associated with obsessive-compulsive disorder. Archives of General Psychiatry, 63, 769–776.CrossRefPubMedGoogle Scholar
  2. Belsky, J., Jonassaint, C., Pluess, M., Stanton, M., Brummett, B., & Williams, R. (2009). Vulnerability genes or plasticity genes. Molecular Genetics, 14, 746–754.Google Scholar
  3. Billstedt, E., Gillberg, I. C., & Gillberg, C. (2007). Autism in adult: Symptom patterns and early childhood predictors. Journal of Child Psychology and Psychiatry, 48, 1102–1110.CrossRefPubMedGoogle Scholar
  4. Bishop, S. L., Richler, J., Cain, A. C., & Lord, C. (2007). Predictors of perceived negative impact in moterhs of children with autism spectrum disorder. American Journal on Mental Retardation, 112, 450–461.CrossRefPubMedGoogle Scholar
  5. Bolton, P. F., Pickles, A., Murphy, M., & Rutter, M. (1998). Autism, affective and other psychiatric disorders: Patterns of familial aggregation. Psychological Medicine, 28, 385–395.CrossRefPubMedGoogle Scholar
  6. Brune, C. W., Kim, S.-J., Hanna, G. L., Courchesne, E., Lord, C., Leventhal, B. L., et al. (2008). Family-based association testing of OCD-associated SNPs of SLC1A1 in an autism sample. Autism Research, 1, 108–113.CrossRefPubMedGoogle Scholar
  7. Brune, C. W., Kim, S. J., Salt, J., Leventhal, B. L., Lord, C., & Cook, E. H. Jr. (2006). 5-HTTLPR genotype-specific phenotype in children and adolescents with autism. American Journal of Psychiatry, 163, 2148–2156.CrossRefPubMedGoogle Scholar
  8. Carcani-Rathwell, I., Rabe-Hasketh, S., & Santosh, P. J. (2006). Repetitive and stereotyped behaviours in pervasive developmental disorders. Journal of Child Psychology and Psychiatry, 47, 573–581.CrossRefPubMedGoogle Scholar
  9. Cath, D. C., Ran, N., Smit, J. H., van Balkom, A. J. L. M., & Comijs, H. C. (2008). Symptom overlap between autism spectrum disorder, generalized anxiety disorder and obsessive-compulsive disorder in adults: A preliminary case-controlled study. Psychopahtology, 41, 101–110.CrossRefGoogle Scholar
  10. Cohen, J. (1988). Statistical power analysis for the behavioral sciences (2nd ed.). Mahwah, NJ: Lawrence Erlbaum.Google Scholar
  11. Cohen, J. (1994). The earth is round (p < .05). American Psychologist, 49, 997–1003.CrossRefGoogle Scholar
  12. Cohen, I. L., Liu, X., Schultz, C., White, B. N., Jenkins, E. C., Brown, W. T., et al. (2003). Association of autism severity with a monoamine oxidase a functional polymorphism. Clinical Genetics, 64, 90–197.CrossRefGoogle Scholar
  13. Comings, D. E. (1990). Tourette syndrome and human behavior. Duarte, CA: Hope Press.Google Scholar
  14. Comings, D. E., Wu, S., Chiu, C., Ring, R. H., Gade, R., Ahn, C., et al. (1996). Polygenetic inheritance of Tourette syndrome, stuttering, attention deficit hyperactivity, conduct, and oppositional defiant disorder. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 67B, 264–288.Google Scholar
  15. Coon, H., Dunn, D., Lainhart, J., Miller, J., Hamil, C., Battaglia, A., et al. (2005). Possible association between autism and variants in the brain-expressed tryptophan hydroxylase gene (TPH2). American Journal of Medical Genetics Part B Neuropsychiatric Genetics, 135B, 42–46.CrossRefGoogle Scholar
  16. Cullen, B., Samuels, J., Grados, M., Landa, R., Bienvenu, O. J., Liang, K.-Y., et al. (2008). Social and communication difficulties and obsessive-compulsive disorder. Psychopathology, 41, 194–200.CrossRefPubMedGoogle Scholar
  17. Dickel, D. E., Veenstra-Vander Weele, J., Cox, N. J., Wu, X., Fischer, D. J., Van Etten-Lee, M., et al. (2006). Association testing of the positional and functional candidate gen SLOC1A1/EAAC1 in early-onset obsessive-compulsive disorder. Archives of General Psychiatry, 63, 778–785.CrossRefPubMedGoogle Scholar
  18. Feise, R. J. (2002). Do multiple outcome measures require p-value adjustment? BMC Medical Research Methodology, 2.Google Scholar
  19. Flint, J., & Mackay, T. F. C. (2009). Genetic architecture of quantitative traits in mice, flies, and humans. Genome Research, 19, 723–733.CrossRefPubMedGoogle Scholar
  20. Fong, L., Wilgosh, L., & Sobsey, D. (1993). The experience of parenting an adolescent with autism. International Journal of Disability, Development, and Education, 40, 105–113.CrossRefGoogle Scholar
  21. Gadow, K.D., DeVincent, C.J., Olvet, D.M., & Hatchwell, E. (2009a). Association of DRD4 polymorphism with severity oppositional defiant, separation anxiety, and repetitive behaviors in children with autism spectrum disorder. Manuscript submitted for publication.Google Scholar
  22. Gadow, K. D., DeVincent, C. J., Pomeroy, J., & Azizian, A. (2005). Comparison of DSM-IV symptoms in elementary school-aged children with PDD versus clinic and community samples. Autism, 9, 392–415.CrossRefPubMedGoogle Scholar
  23. Gadow, K. D., Nolan, E. E., Sprafkin, J., & Schwartz, J. (2002). Tics and psychiatric comorbidity in children and adolescents. Developmental Medicine and Child Neurology, 44, 330–338.CrossRefPubMedGoogle Scholar
  24. Gadow, K. D., Roohi, J., DeVincent, C. J., & Hatchwell, E. (2008a). Association of ADHD, tics, and anxiety with dopamine transporter (DAT1) genotype in autism spectrum disorder. Journal of Child Psychology and Psychiatry, 49, 1331–1338.CrossRefPubMedGoogle Scholar
  25. Gadow, K.D., Roohi, J., DeVincent, C.J., Kirsch, S., & Hatchwell, E. (2009b). Association of COMT (Val158Met) and BDNF (Val66Met) gene polymorphisms with anxiety, ADHD and tics in children with autism spectrum disorder. Journal of Autism and Developmental Disorders, 39, 67–74.Google Scholar
  26. Gadow, K. D., Schwartz, J., DeVincent, C., Strong, G., & Cuva, S. (2008b). Clinical utility of autism spectrum disorder scoring algorithms for the child symptom inventory. Journal of Autism and Developmental Disorders, 38, 419–427.CrossRefPubMedGoogle Scholar
  27. Gadow, K. D., & Sprafkin, J. (1986). Stony Brook Child Psychiatric Checklist-3. Stony Brook: Department of Psychiatry, State University of New York.Google Scholar
  28. Gadow, K. D., & Sprafkin, J. (2002). Child Symptom Inventory-4 Screening and Norms Manual. Checkmate Plus: Stony Brook, NY.Google Scholar
  29. Gadow, K. D, Sprafkin, J. (2008). The symptom inventories: An annotated bibliography [On-line]. Stony Brook, NY: Checkmate Plus. Available: www.checkmateplus.com.
  30. Grados, M. A., Mathews, C. A., & Tourette Syndrome Association International Consortium for Genetics. (2008). Latent class analysis of Gilles de la Tourette syndrome using comorbidities: Clinical and genetic implications. Biological Psychiatry, 64, 219–225.CrossRefPubMedGoogle Scholar
  31. Hollingshead, A. B. (1975). Four Factor Index of Social Status. Department of Sociology, Yale University: New Haven, CT.Google Scholar
  32. Howlin, P., Goode, S., Hutton, J., & Rutter, M. (2004). Adult outcome for children with autism. Journal of Child Psychology and Psychiatry, 45, 212–229.CrossRefPubMedGoogle Scholar
  33. Lam, K. S. L., Bodfish, J. W., & Piven, J. (2008). Evidence for three subtypes of repetitive behavior in autism that differ in familiarity and association with other symptoms. Journal of Child Psychology and Psychiatry, 49, 1193–1200.PubMedGoogle Scholar
  34. Lecavalier, L., Gadow, K. D., DeVincent, C. J., & Edwards, M. C. (2009a). Validation of DSM-IV model of psychiatric syndromes in children with autism spectrum disorder. Journal of Autism and Developmental Disorders, 39, 278–289.CrossRefPubMedGoogle Scholar
  35. Lecavalier, L., Gadow, K. D., DeVincent, C. J., Houts, C., & Edwards, M. C. (2009b). Deconstructing the PDD clinical phenotype: Internal validity of the DSM-IV. Journal of Child Psychology and Psychiatry, 50, 1246–1254.CrossRefPubMedGoogle Scholar
  36. Lecavalier, L., Leone, S., & Wiltz, J. (2006). The impact of behaviour problems on caregiver stress in young people with autism spectrum disorders. Journal of Intellectual Disability Research, 50, 172–183.CrossRefPubMedGoogle Scholar
  37. Lord, C., Risi, S., Lambrecht, L., Cook, E. H., Jr, Leventhal, B. L., DiLavore, P. C., et al. (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.CrossRefPubMedGoogle Scholar
  38. Mandy, W. P. L., & Skuse, D. H. (2008). Research review: What is the association between the social-communication element of autism and repetitive interests, behaviours and activities? Child Psychology and Psychiatry, 49, 795–808.CrossRefGoogle Scholar
  39. Matson, J. L., & Dempsey, T. (2009). The nature and treatment of compulsions, obsessions, and rituals in people with developmental disabilities. Research in Developmental Disabilities, 30, 603–611.CrossRefPubMedGoogle Scholar
  40. Moss, J., Oliver, C., Arron, K., Burbidge, C., & Berg, K. (2009). The prevelance and phenomenology of repetitive behavior in genetic syndromes. Journal of Autism and Developmental Disorders, 39, 572–588.CrossRefPubMedGoogle Scholar
  41. Mulder, E. J., Anderson, G. M., Kema, I. P., Brugman, A. M., Ketelaars, C. E. J., de Bildt, A., et al. (2005). Serotonin transporter intron 2 polymorphism associated with rigid-compulsive behaviors in Dutch individuals with pervasive developmental disorder. American Journal of Medical Genetics Part B Neuropsychiatric Genetics, B133, 93–96.CrossRefGoogle Scholar
  42. Perneger, T. V. (1998). What’s wrong with Bonferroni adjustments. BMJ, 316, 1236–1238.PubMedGoogle Scholar
  43. Piven, J., & Palmer, P. (1999). Psychiatric disorder and the broad autism phenotype: Evidence from family study of multiple-incidence autistic families. American Journal of Psychiatry, 156, 557–563.PubMedGoogle Scholar
  44. Roohi, J., DeVincent, C. J., Hatchwell, E., & Gadow, K. D. (2009). Association of a monoamine oxidase-A gene promoter polymorphism with ADHD and anxiety in boys with autism spectrum disorder. Journal of Autism and Developmental Disorders, 39, 67–74.CrossRefPubMedGoogle Scholar
  45. Rothman, K. (1990). No adjustments are needed for multiple comparisons. Epidemiology, 1, 43–46.CrossRefPubMedGoogle Scholar
  46. Rowe, D. C., Stever, C., Gard, J. M. C., Cleveland, H. H., Sanders, M. L., Abramowitz, A., et al. (1998). The relation of the dopamine transporter gene (DAT1) to symptoms of internalizing disorders in children. Behavior Genetics, 28, 215–225.CrossRefPubMedGoogle Scholar
  47. Rutter, M., LeCouteur, A., & Lord, C. (2003). Autism Diagnostic Interview-Revised. Western Psychological Services: Los Angeles, CA.Google Scholar
  48. Sacco, R., Papaleo, V., Hager, J., Rousseau, F., Moessner, R., Militerni, R., et al. (2007). Case-control and family-based association studies of candidate gene in autistic disorder and its endophenotypes: TPH2 and GLO1. BMC Medical Genetics, 8, 11.CrossRefPubMedGoogle Scholar
  49. Sakurai, T., Reichert, J., Hoffman, E. J., Cai, G., Jones, H. B., Faham, M., et al. (2008). A large-scale screen for coding variants in SERT/SLC6A4 in autism spectrum disorders. Autism Research, 1, 251–257.CrossRefPubMedGoogle Scholar
  50. Stewart, S. E., Fagerness, J. A., Platko, J., Smoller, J. W., Scharf, J. M., Illmann, C., et al. (2007). Association of the SLC1A1 glutamate transporter gene and obsessive-compulsive disorder. American Journal of Medical Genetics Part B Neurospychiatric Genetics, 144B, 1027–1033.CrossRefGoogle Scholar
  51. Sutcliffe, J. S., Delahanty, R. J., Prasad, H. C., McCauley, J. L., Han, Q., Jiang, L., et al. (2005). Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. American Journal of Human Genetics, 77, 265–279.CrossRefPubMedGoogle Scholar
  52. Tordjman, S., Gutknecht, L., Carlier, M., Spitz, E., Antoine, C., Slama, F., et al. (2001). Role of the serotonin transporter gene in the behavioral expression of autism. Molecular Psychiatry, 6, 434–439.CrossRefPubMedGoogle Scholar
  53. Wang, Y., Adamczyk, A., Shugart, Y.Y., Samuels, J.F., Grados, M.A., Greenberg, B.D., et al. (2009). A screen of SLC1A1 for OCD-related alleles. American Journal of Medical Genetics Part B. doi 10.1002/ajmg.b.31001.
  54. Wendland, J. R., Moya, P. R., Timpano, K. R., Anavitarte, A. P., Kruse, M. R., Wheaton, M. G., et al. (2009). A haplotype containing quantitative trait loci for SLC 1A1 gene expression and its association with obsessive-compulsive disorder. Archives of General Psychiatry, 66, 408–416.CrossRefPubMedGoogle Scholar
  55. White, S.W., Oswald, D., Ollendick, T., & Scahill, L. (2009). Anxiety in children and adolescents with autism spectrum disorders. Clinical Psychology Review, 29, 216–229.Google Scholar
  56. Wood, J.J., Drahota, A., Sze, K., Har, K., Chiu, A., & Langer, D.A. (2008). Cognitive behavioural therapy for anxiety in children with autism Spectrum disorders: a randomized, controlled trial. Journal of Child Psychology and Psychiatry, 50, 224–234.Google Scholar
  57. Zandt, F., Prior, M., & Kyrios, M. (2007). Repetitive behaviour in children with high functioning autism and obsessive compulsive disorder. Journal of Autism and Developmental Disorders, 37, 251–259.CrossRefPubMedGoogle Scholar
  58. Zhang, J., Quan, H., Ng, J., & Stepanavage, M. E. (1997). Some statistical methods for multiple endpoints in clinical trials. Controlled Clinical Trials, 18, 204–221.CrossRefPubMedGoogle Scholar
  59. Zhou, L., Myers, A. N., Vandersteen, J. G., Wang, L., & Wittwer, C. T. (2004). Closed-tube genotyping with unlabeled oligonucleotide probes and a saturating DNA dye. Clinical Chemistry, 50, 328–335. Epub 2004 May 27.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Kenneth D. Gadow
    • 1
    • 5
  • Jasmin Roohi
    • 2
  • Carla J. DeVincent
    • 3
  • Sarah Kirsch
    • 4
  • Eli Hatchwell
    • 4
  1. 1.Department of PsychiatryStony Brook UniversityNew YorkUSA
  2. 2.Department of GeneticsStony Brook UniversityStony BrookUSA
  3. 3.Department of PediatricsStony Brook UniversityStony BrookUSA
  4. 4.Department of PathologyStony Brook UniversityStony BrookUSA
  5. 5.Department of PsychiatryStony Brook UniversityStony BrookUSA

Personalised recommendations