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Am J Hum Genet. May 1998; 62(5): 1077–1083.
PMCID: PMC1377089

Linkage-disequilibrium mapping of autistic disorder, with 15q11-13 markers.


Autistic disorder is a complex genetic disease. Because of previous reports of individuals with autistic disorder with duplications of the Prader-Willi/Angelman syndrome critical region, we screened several markers across the 15q11-13 region, for linkage disequilibrium. One hundred forty families, consisting predominantly of a child with autistic disorder and both parents, were studied. Genotyping was performed by use of multiplex PCR and capillary electrophoresis. Two children were identified who had interstitial chromosome 15 duplications and were excluded from further linkage-disequilibrium analysis. Use of the multiallelic transmission-disequilibrium test (MTDT), for nine loci on 15q11-13, revealed linkage disequilibrium between autistic disorder and a marker in the gamma-aminobutyric acidA receptor subunit gene, GABRB3 155CA-2 (MTDT 28.63, 10 df, P=.0014). No evidence was found for parent-of-origin effects on allelic transmission. The convergence of GABRB3 as a positional and functional candidate along with the linkage-disequilibrium data suggests the need for further investigation of the role of GABRB3 or adjacent genes in autistic disorder.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Albrecht U, Sutcliffe JS, Cattanach BM, Beechey CV, Armstrong D, Eichele G, Beaudet AL. Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. Nat Genet. 1997 Sep;17(1):75–78. [PubMed]
  • Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, Rutter M. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med. 1995 Jan;25(1):63–77. [PubMed]
  • Bailey A, Phillips W, Rutter M. Autism: towards an integration of clinical, genetic, neuropsychological, and neurobiological perspectives. J Child Psychol Psychiatry. 1996 Jan;37(1):89–126. [PubMed]
  • Baker P, Piven J, Schwartz S, Patil S. Brief report: duplication of chromosome 15q11-13 in two individuals with autistic disorder. J Autism Dev Disord. 1994 Aug;24(4):529–535. [PubMed]
  • Browne CE, Dennis NR, Maher E, Long FL, Nicholson JC, Sillibourne J, Barber JC. Inherited interstitial duplications of proximal 15q: genotype-phenotype correlations. Am J Hum Genet. 1997 Dec;61(6):1342–1352. [PMC free article] [PubMed]
  • Bundey S, Hardy C, Vickers S, Kilpatrick MW, Corbett JA. Duplication of the 15q11-13 region in a patient with autism, epilepsy and ataxia. Dev Med Child Neurol. 1994 Aug;36(8):736–742. [PubMed]
  • Byerley W, Bailey ME, Hicks AA, Riley BP, Darlison MG, Holik J, Hoff M, Umar F, Reimherr F, Wender P, et al. Schizophrenia and GABAA receptor subunit genes. Psychiatr Genet. 1995 Spring;5(1):23–29. [PubMed]
  • Chang CC, Luntz-Leybman V, Evans JE, Rotter A, Frostholm A. Developmental changes in the expression of gamma-aminobutyric acidA/benzodiazepine receptor subunit mRNAs in the murine inferior olivary complex. J Comp Neurol. 1995 Jun 12;356(4):615–628. [PubMed]
  • Christian SL, Bhatt NK, Martin SA, Sutcliffe JS, Kubota T, Huang B, Mutirangura A, Chinault AC, Beaudet AL, Ledbetter DH. Integrated YAC contig map of the Prader-Willi/Angelman region on chromosome 15q11-q13 with average STS spacing of 35 kb. Genome Res. 1998 Feb;8(2):146–157. [PMC free article] [PubMed]
  • Comings DE, Comings BG, Muhleman D, Dietz G, Shahbahrami B, Tast D, Knell E, Kocsis P, Baumgarten R, Kovacs BW, et al. The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders. JAMA. 1991 Oct 2;266(13):1793–1800. [PubMed]
  • Cook EH, Jr, Courchesne R, Lord C, Cox NJ, Yan S, Lincoln A, Haas R, Courchesne E, Leventhal BL. Evidence of linkage between the serotonin transporter and autistic disorder. Mol Psychiatry. 1997 May;2(3):247–250. [PubMed]
  • Cook EH, Jr, Lindgren V, Leventhal BL, Courchesne R, Lincoln A, Shulman C, Lord C, Courchesne E. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet. 1997 Apr;60(4):928–934. [PMC free article] [PubMed]
  • Coon H, Hicks AA, Bailey ME, Hoff M, Holik J, Harvey RJ, Johnson KJ, Darlison MG, Reimherr F, Wender P, et al. Analysis of GABAA receptor subunit genes in multiplex pedigrees with manic depression. Psychiatr Genet. 1994 Fall;4(3):185–191. [PubMed]
  • Courchesne E. Brainstem, cerebellar and limbic neuroanatomical abnormalities in autism. Curr Opin Neurobiol. 1997 Apr;7(2):269–278. [PubMed]
  • Crolla JA, Harvey JF, Sitch FL, Dennis NR. Supernumerary marker 15 chromosomes: a clinical, molecular and FISH approach to diagnosis and prognosis. Hum Genet. 1995 Feb;95(2):161–170. [PubMed]
  • Crowe RR, Wang Z, Noyes R, Jr, Albrecht BE, Darlison MG, Bailey ME, Johnson KJ, Zoëga T. Candidate gene study of eight GABAA receptor subunits in panic disorder. Am J Psychiatry. 1997 Aug;154(8):1096–1100. [PubMed]
  • Culiat CT, Stubbs LJ, Montgomery CS, Russell LB, Rinchik EM. Phenotypic consequences of deletion of the gamma 3, alpha 5, or beta 3 subunit of the type A gamma-aminobutyric acid receptor in mice. Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2815–2818. [PMC free article] [PubMed]
  • Curtis D, Sham PC. A note on the application of the transmission disequilibrium test when a parent is missing. Am J Hum Genet. 1995 Mar;56(3):811–812. [PMC free article] [PubMed]
  • DiLavore PC, Lord C, Rutter M. The pre-linguistic autism diagnostic observation schedule. J Autism Dev Disord. 1995 Aug;25(4):355–379. [PubMed]
  • Flejter WL, Bennett-Baker PE, Ghaziuddin M, McDonald M, Sheldon S, Gorski JL. Cytogenetic and molecular analysis of inv dup(15) chromosomes observed in two patients with autistic disorder and mental retardation. Am J Med Genet. 1996 Jan 11;61(2):182–187. [PubMed]
  • Folstein S, Rutter M. Infantile autism: a genetic study of 21 twin pairs. J Child Psychol Psychiatry. 1977 Sep;18(4):297–321. [PubMed]
  • Gillberg C, Steffenburg S, Wahlström J, Gillberg IC, Sjöstedt A, Martinsson T, Liedgren S, Eeg-Olofsson O. Autism associated with marker chromosome. J Am Acad Child Adolesc Psychiatry. 1991 May;30(3):489–494. [PubMed]
  • Glatt K, Glatt H, Lalande M. Structure and organization of GABRB3 and GABRA5. Genomics. 1997 Apr 1;41(1):63–69. [PubMed]
  • Glatt K, Sinnett D, Lalande M. The human gamma-aminobutyric acid receptor subunit beta 3 and alpha 5 gene cluster in chromosome 15q11-q13 is rich in highly polymorphic (CA)n repeats. Genomics. 1994 Jan 1;19(1):157–160. [PubMed]
  • Guipponi M, Thomas P, Girard-Reydet C, Feingold J, Baldy-Moulinier M, Malafosse A. Lack of association between juvenile myoclonic epilepsy and GABRA5 and GABRB3 genes. Am J Med Genet. 1997 Apr 18;74(2):150–153. [PubMed]
  • Hérault J, Perrot A, Barthélémy C, Büchler M, Cherpi C, Leboyer M, Sauvage D, Lelord G, Mallet J, Müh JP. Possible association of c-Harvey-Ras-1 (HRAS-1) marker with autism. Psychiatry Res. 1993 Mar;46(3):261–267. [PubMed]
  • Homanics GE, DeLorey TM, Firestone LL, Quinlan JJ, Handforth A, Harrison NL, Krasowski MD, Rick CE, Korpi ER, Mäkelä R, et al. Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):4143–4148. [PMC free article] [PubMed]
  • Hotopf M, Bolton P. A case of autism associated with partial tetrasomy 15. J Autism Dev Disord. 1995 Feb;25(1):41–49. [PubMed]
  • Jorde LB. Linkage disequilibrium as a gene-mapping tool. Am J Hum Genet. 1995 Jan;56(1):11–14. [PMC free article] [PubMed]
  • Jorde LB, Watkins WS, Carlson M, Groden J, Albertsen H, Thliveris A, Leppert M. Linkage disequilibrium predicts physical distance in the adenomatous polyposis coli region. Am J Hum Genet. 1994 May;54(5):884–898. [PMC free article] [PubMed]
  • Kirkness EF, Fraser CM. A strong promoter element is located between alternative exons of a gene encoding the human gamma-aminobutyric acid-type A receptor beta 3 subunit (GABRB3). J Biol Chem. 1993 Feb 25;268(6):4420–4428. [PubMed]
  • Kishino T, Lalande M, Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet. 1997 Jan;15(1):70–73. [PubMed]
  • Klauck SM, Poustka F, Benner A, Lesch KP, Poustka A. Serotonin transporter (5-HTT) gene variants associated with autism? Hum Mol Genet. 1997 Dec;6(13):2233–2238. [PubMed]
  • Laurie DJ, Wisden W, Seeburg PH. The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. J Neurosci. 1992 Nov;12(11):4151–4172. [PubMed]
  • Leana-Cox J, Jenkins L, Palmer CG, Plattner R, Sheppard L, Flejter WL, Zackowski J, Tsien F, Schwartz S. Molecular cytogenetic analysis of inv dup(15) chromosomes, using probes specific for the Prader-Willi/Angelman syndrome region: clinical implications. Am J Hum Genet. 1994 May;54(5):748–756. [PMC free article] [PubMed]
  • Lord C, Rutter M, Goode S, Heemsbergen J, Jordan H, Mawhood L, Schopler E. Autism diagnostic observation schedule: a standardized observation of communicative and social behavior. J Autism Dev Disord. 1989 Jun;19(2):185–212. [PubMed]
  • 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 Oct;24(5):659–685. [PubMed]
  • Martinsson T, Johannesson T, Vujic M, Sjöstedt A, Steffenburg S, Gillberg C, Wahlström J. Maternal origin of inv dup(15) chromosomes in infantile autism. Eur Child Adolesc Psychiatry. 1996 Dec;5(4):185–192. [PubMed]
  • Nadler LS, Guirguis ER, Siegel RE. GABAA receptor subunit polypeptides increase in parallel but exhibit distinct distributions in the developing rat cerebellum. J Neurobiol. 1994 Dec;25(12):1533–1544. [PubMed]
  • Pickles A, Bolton P, Macdonald H, Bailey A, Le Couteur A, Sim CH, Rutter M. 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 Sep;57(3):717–726. [PMC free article] [PubMed]
  • Piven J, Chase GA, Landa R, Wzorek M, Gayle J, Cloud D, Folstein S. Psychiatric disorders in the parents of autistic individuals. J Am Acad Child Adolesc Psychiatry. 1991 May;30(3):471–478. [PubMed]
  • Ritvo ER, Freeman BJ, Mason-Brothers A, Mo A, Ritvo AM. Concordance for the syndrome of autism in 40 pairs of afflicted twins. Am J Psychiatry. 1985 Jan;142(1):74–77. [PubMed]
  • Robinson WP, Binkert F, Giné R, Vazquez C, Müller W, Rosenkranz W, Schinzel A. Clinical and molecular analysis of five inv dup(15) patients. Eur J Hum Genet. 1993;1(1):37–50. [PubMed]
  • Robinson WP, Lalande M. Sex-specific meiotic recombination in the Prader--Willi/Angelman syndrome imprinted region. Hum Mol Genet. 1995 May;4(5):801–806. [PubMed]
  • Sander T, Kretz R, Williamson MP, Elmslie FV, Rees M, Hildmann T, Bianchi A, Bauer G, Sailer U, Scaramelli A, et al. Linkage analysis between idiopathic generalized epilepsies and the GABA(A) receptor alpha5, beta3 and gamma3 subunit gene cluster on chromosome 15. Acta Neurol Scand. 1997 Jul;96(1):1–7. [PubMed]
  • Schinzel AA, Brecevic L, Bernasconi F, Binkert F, Berthet F, Wuilloud A, Robinson WP. Intrachromosomal triplication of 15q11-q13. J Med Genet. 1994 Oct;31(10):798–803. [PMC free article] [PubMed]
  • Smalley SL. Genetic influences in childhood-onset psychiatric disorders: autism and attention-deficit/hyperactivity disorder. Am J Hum Genet. 1997 Jun;60(6):1276–1282. [PMC free article] [PubMed]
  • Smalley SL, McCracken J, Tanguay P. Autism, affective disorders, and social phobia. Am J Med Genet. 1995 Feb 27;60(1):19–26. [PubMed]
  • Smalley SL, Tanguay PE, Smith M, Gutierrez G. Autism and tuberous sclerosis. J Autism Dev Disord. 1992 Sep;22(3):339–355. [PubMed]
  • 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 Mar;52(3):506–516. [PMC free article] [PubMed]
  • Steffenburg S, Gillberg C, Hellgren L, Andersson L, Gillberg IC, Jakobsson G, Bohman M. A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry. 1989 May;30(3):405–416. [PubMed]
  • Sutcliffe JS, Jiang YH, Galijaard RJ, Matsuura T, Fang P, Kubota T, Christian SL, Bressler J, Cattanach B, Ledbetter DH, et al. The E6-Ap ubiquitin-protein ligase (UBE3A) gene is localized within a narrowed Angelman syndrome critical region. Genome Res. 1997 Apr;7(4):368–377. [PMC free article] [PubMed]
  • Warren RP, Odell JD, Warren WL, Burger RA, Maciulis A, Daniels WW, Torres AR. Strong association of the third hypervariable region of HLA-DR beta 1 with autism. J Neuroimmunol. 1996 Jul;67(2):97–102. [PubMed]
  • Wisden W, Laurie DJ, Monyer H, Seeburg PH. The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon. J Neurosci. 1992 Mar;12(3):1040–1062. [PubMed]

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