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  • Original Research Article
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Association between a GABRB3 polymorphism and autism

Abstract

Autistic disorder (OMIM 209850) is a disease with a significant genetic component of a complex nature.1 Cytogenetic abnormalities in the Prader-Willi/Angelman syndrome critical region (15q11–13) have been described in several individuals with autism.1 For this reason, markers across this region have been screened for evidence of linkage and association, and a marker (155CA-2) in the γ-aminobutyric acid type-A receptor β3 subunit gene (GABRB3) has been associated in one study2 but not others.3–5 We completed an association analysis with 155CA-2 using the transmission disequilibrium test (TDT) in a set of 80 autism families (59 multiplex and 21 trios). We also used four additional markers (69CA, 155CA-1, 85CA, and A55CA-1) localized within 150 kb of 155CA-2. The use of multi-allelic TDT (MTDT) (P < 0.002), as well as the TDT (P < 0.004), demonstrated an association between autistic disorder and 155CA-2 in these families. Meiotic segregation distortion could be excluded as a possible cause for these results since no disequilibrium was observed in unaffected siblings. These findings support a role for genetic variants within the GABA receptor gene complex in 15q11–13 in autistic disorder.

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References

  1. Tager-Flusberg H, Joseph R, Folstein S . Current directions in research on autism Ment Retard Dev Disabil Res Rev 2001 7: 21–29

    Article  CAS  PubMed  Google Scholar 

  2. Cook EH Jr, Courchesne RY, Cox NJ, Lord C, Gonen D, Guter SJ et al. Linkage-disequilibrium mapping of autistic disorder, with 15q11–13 markers Am J Hum Genet 1998 62: 1077–1083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Maestrini E, Lai C, Marlow A, Matthews A, Wallace S, Bailey A et al. Serotonin transporter (5-HTT) and (γ-aminobutyric acid receptor subunit β3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families Am J Med Genet 1999 88: 492–496

    Article  CAS  PubMed  Google Scholar 

  4. Salmon B, Hallmayer J, Rogers T, Kalaydjieva L, Peterson PB, Nicholas P et al. Absence of linkage and linkage disequilibrium to chromosome 15q11–13 markers in 139 multiplex families with autism Am J Med Genet 1999 88: 551–556

    Article  CAS  PubMed  Google Scholar 

  5. Martin ER, Menold MM, Wolpert CM, Bass MP, Donnelly SL, Ravan SA et al. Analysis of linkage disequilibrium in γ-aminobutyric acid receptor subunit genes in autistic disorder Am J Med Genet 2000 96: 43–48

    Article  PubMed  Google Scholar 

  6. Pickles A, Bolton P, Macdonald H, Bailey A, Le Couteur A, Sim CH et al. Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism Am J Hum Genet 1995 57: 717–726

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J et al. A genomic screen of autism: evidence for a multilocus etiology Am J Hum Genet 1999 65: 493–507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Philippe A, Martinez M, Guilloud-Bataille M, Gillberg C, Rastam M, Sponheim E et al. Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study Hum Mol Genet 1998 8: 805–812

    Article  Google Scholar 

  9. Bass MP, Menold MM, Wolpert CM, Donnelly SL, Ravan SA, Hauser ER et al. Genetic studies in autistic disorder and chromosome 15 Neurogenetics 2000 2: 219–226

    Article  CAS  PubMed  Google Scholar 

  10. IMGSAC. A full genome screen for autism with evidence for linkage to a region on chromosome 7q. International Molecular Genetic Study of Autism Consortium Hum Mol Genet 1998 7: 571–578

  11. Glatt K, Sinnett D, Lalande M . The human γ-aminobutyric acid receptor subunit β3 and α5 gene cluster in chromosome 15q11–q13 is rich in highly polymorphic (CA)n repeats Genomics 1994 19: 157–160

    Article  CAS  PubMed  Google Scholar 

  12. Spielman RS, Ewens WJ . The TDT and other family-based tests for linkage disequilibrium and association Am J Hum Genet 1996 59: 983–989

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Spielman RS, McGinnis RE, Ewens WJ . Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM) Am J Hum Genet 1993 52: 506–516

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Feucht M, Fuchs K, Pichlbauer E, Hornik K, Scharfetter J, Goessler R et al. Possible association between childhood absence epilepsy and the gene encoding GABRB3 Biol Psychiatry 1999 46: 997–1002

    Article  CAS  PubMed  Google Scholar 

  15. Sterkers G, Zeliszewski D, Chaussee AM, Deschamps I, Font MP, Freidel C et al. HLA-DQ rather than HLA-DR region might be involved in dominant nonsusceptibility to diabetes Proc Natl Acad Sci U S A 1988 85: 6473–6477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rubinsztein DC, Hanlon CS, Irving RM, Goodburn S, Evans DG, Kellar-Wood H et al. Apo E genotypes in multiple sclerosis, Parkinson's disease, schwannomas and late-onset Alzheimer's disease Mol Cell Probes 1994 8: 519–525

    Article  CAS  PubMed  Google Scholar 

  17. Smith AD, Johnston C, Sim E, Nagy Z, Jobst KA, Hindley N et al. Protective effect of apo epsilon 2 in Alzheimer's disease. Oxford Project to Investigate Memory and Ageing (OPTIMA) Lancet 1994 344: 473–474

    CAS  PubMed  Google Scholar 

  18. Piven J, Chase GA, Landa R, Wzorek M, Gayle J, Cloud D et al. Psychiatric disorders in the parents of autistic individuals J Am Acad Child Adolesc Psychiatry 1991 30: 471–478

    Article  CAS  PubMed  Google Scholar 

  19. Smalley SL, McCracken J, Tanguay P . Autism, affective disorders, and social phobia Am J Med Genet 1995 60: 19–26

    Article  CAS  PubMed  Google Scholar 

  20. DeLorey TM, Handforth A, Anagnostaras SG, Homanics GE, Minassian BA, Asatourian A et al. Mice lacking the β3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome J Neurosci 1998 18: 8505–8514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Homanics GE, DeLorey TM, Firestone LL, Quinlan JJ, Handforth A, Harrison NL et al. Mice devoid of γ-aminobutyrate type A receptor β3 subunit have epilepsy, cleft palate, and hypersensitive behavior Proc Natl Acad Sci U S A 1997 94: 4143–4148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Krasowski MD, Rick CE, Harrison NL, Firestone LL, Homanics GE . A deficit of functional GABA(A) receptors in neurons of β3 subunit knockout mice Neurosci Lett 1998 240: 81–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Abecasis GR, Noguchi E, Heinzmann A, Traherne JA, Bhattacharyya S, Leaves NI et al. Extent and distribution of linkage disequilibrium in three genomic regions Am J Hum Genet 2000 68: 191–197

    Article  PubMed  PubMed Central  Google Scholar 

  24. Dunning AM, Durocher F, Healey CS, Teare MD, McBride SE, Carlomagno F et al. The extent of linkage disequilibrium in four populations with distinct demographic histories Am J Hum Genet 2000 67: 1544–1554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Roman SH, Greenberg D, Rubinstein P, Wallenstein S, Davies TF . Genetics of autoimmune thyroid disease: lack of evidence for linkage to HLA within families J Clin Endocrinol Metab 1992 74: 496–503

    CAS  PubMed  Google Scholar 

  26. Greenberg DA . Linkage analysis of ‘necessary’ disease loci versus ‘susceptibility’ loci Am J Hum Genet 1993 52: 135–143

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Geschwind DH, Sowinski J, Lord C, Iversen P, Shestack J, Jones P et al. The Autism Genetic Resource Exchange: a resource for the study of autism and related neuropsychiatric conditions Am J Hum Genet 2001 68: 1514–1520

    Article  Google Scholar 

  28. Lord C, Rutter M, Le Couteur A . Autism Diagnostic Interview–Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders J Autism Dev Disord 1994 24: 659–685

    Article  CAS  PubMed  Google Scholar 

  29. Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES . Parametric and nonparametric linkage analysis: a unified multipoint approach Am J Hum Genet 1996 58: 1347–1363

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Greenberg DA, Abreu P, Hodge SE . The power to detect linkage in complex disease by means of simple LOD score analyses Am J Hum Genet 1998 63: 870–879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

These studies were supported by grants from the Seaver Autism Research Center and Cure Autism Now. We acknowledge support from Cure Autism Now and the Autism Genetic Resource Exchange (AGRE27) and we gratefully acknowledge the resources provided by the AGRE consortium27 and the participating AGRE families.

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Correspondence to J D Buxbaum.

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Buxbaum, J., Silverman, J., Smith, C. et al. Association between a GABRB3 polymorphism and autism. Mol Psychiatry 7, 311–316 (2002). https://doi.org/10.1038/sj.mp.4001011

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