Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Research Article
  • Published:

Linkage and association of the glutamate receptor 6 gene with autism

Molecular Psychiatry volume 7, pages 302–310 (2002)Cite this article

Abstract

A genome scan was previously performed and pointed to chromosome 6q21 as a candidate region for autism. This region contains the glutamate receptor 6 (GluR6 or GRIK2) gene, a functional candidate for the syndrome. Glutamate is the principal excitatory neurotransmitter in the brain and is directly involved in cognitive functions such as memory and learning. We used two different approaches, the affected sib-pair (ASP) method and the transmission disequilibrium test (TDT), to investigate the linkage and association between GluR6 and autism. The ASP method, conducted with additional markers on the 51 original families and in eight new sibling pairs, showed a significant excess of allele sharing, generating an elevated multipoint maximum LOD score (ASPEX MLS = 3.28). TDT analysis, performed in the ASP families and in an independent data set of 107 parent-offspring trios, indicated a significant maternal transmission disequilibrium (TDTall P = 0.0004). Furthermore, TDT analysis (with only one affected proband per family) showed significant association between GluR6 and autism (TDT association P = 0.008). In contrast to maternal transmission, paternal transmission of GluR6 alleles was as expected in the absence of linkage, suggesting a maternal effect such as imprinting. Mutation screening was performed in 33 affected individuals, revealing several nucleotide polymorphisms (SNPs), including one amino acid change (M867I) in a highly conserved domain of the intracytoplasmic C-terminal region of the protein. This change is found in 8% of the autistic subjects and in 4% of the control population and seems to be more maternally transmitted than expected to autistic males (P = 0.007). Taken together, these data suggest that GluR6 is in linkage disequilibrium with autism.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Kanner L . Autistic disturbances of affective contact Nerv Child 1943 2: 217–250

    Google Scholar 

  2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn American Psychiatric Press: Washington DC 1994

  3. Gillberg C, Wing L . Autism: not an extremely rare disorder Acta Psychiatr Scand 1999 99: 399–406

    Article  CAS  PubMed  Google Scholar 

  4. Miles JH, Hillman RE . Value of a clinical morphology examination in autism Am J Med Genet 2000 91: 245–253

    Article  CAS  PubMed  Google Scholar 

  5. Ritvo ER, Jorde LB, Mason-Brothers A, Freeman BJ, Pingree C, Jones MB et al. The UCLA-University of Utah epidemiologic survey of autism: recurrence risk estimates and genetic counseling Am J Psychiatry 1989 146: 1032–1036

    Article  CAS  PubMed  Google Scholar 

  6. Steffenburg S, Gillberg C, Hellgren L, Andersson L, Gillberg IC, Jakobsson G et al. A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden J Child Psychol Psychiatry 1989 30: 405–416

    Article  CAS  PubMed  Google Scholar 

  7. Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E et al. Autism as a strongly genetic disorder: evidence from a British twin study Psychol Med 1995 25: 63–77

    Article  CAS  PubMed  Google Scholar 

  8. International Molecular Genetic Study of Autism Consortium. 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

  9. 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 1999 8: 805–812

    Article  CAS  PubMed  Google Scholar 

  10. 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 

  11. Barrett S, Beck JC, Bernier R, Bisson E, Braun TA, Casavant TL et al. An autosomal genomic screen for autism. Collaborative Linkage Study of Autism Am J Med Genet 1999 88: 609–615

    Article  CAS  PubMed  Google Scholar 

  12. Buxbaum JD, Silverman JM, Smith CJ, Kilifarski M, Reichert J, Hollander E et al. Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity Am J Hum Genet 2001 68: 1514–1520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hollmann M, Heinemann S . Cloned glutamate receptors Annu Rev Neurosci 1994 17: 31–108

    Article  CAS  PubMed  Google Scholar 

  14. Dingledine R, Borges K, Bowie D, Traynelis SF . The glutamate receptor ion channels Pharmacol Rev 1999 51: 7–61

    CAS  PubMed  Google Scholar 

  15. Shimizu E, Tang YP, Rampon C, Tsien JZ . NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation Science 2000 290: 1170–1174

    Article  CAS  PubMed  Google Scholar 

  16. Meldrum BS . Glutamate as a neurotransmitter in the brain: review of physiology and pathology J Nutr 2000 130: 1007S–1015S

    Article  CAS  PubMed  Google Scholar 

  17. Carlsson ML . Hypothesis: is infantile autism a hypoglutamatergic disorder? Relevance of glutamate – serotonin interactions for pharmacotherapy J Neural Transm 1998 105: 525–535

    Article  CAS  PubMed  Google Scholar 

  18. Moreno-Fuenmayor H, Borjas L, Arrieta A, Valera V, Socorro-Candanoza L . Plasma excitatory amino acids in autism Invest Clin 1996 37: 113–128

    CAS  PubMed  Google Scholar 

  19. Rolf LH, Haarmann FY, Grotemeyer KH, Kehrer H . Serotonin and amino acid content in platelets of autistic children Acta Psychiatr Scand 1993 87: 312–316

    Article  CAS  PubMed  Google Scholar 

  20. 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 

  21. Hinds D, Risch N . The ASPEX package: affected sib-pair mapping ftp://lahmed.stanford.edu/pub/aspex 1996

  22. 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 

  23. Kong A, Cox NJ . Allele-sharing models: LOD scores and accurate linkage tests Am J Hum Genet 1997 61: 1179–1188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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 

  25. 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 

  26. Paschen W, Blackstone CD, Huganir RL, Ross CA . Human GluR6 kainate receptor (GRIK2): molecular cloning, expression, polymorphism, and chromosomal assignment Genomics 1994 20: 435–440

    Article  CAS  PubMed  Google Scholar 

  27. Hauser ER, Boehnke M, Guo SW, Risch N . Affected-sib-pair interval mapping and exclusion for complex genetic traits: sampling considerations Genet Epidemiol 1996 13: 117–137

    Article  CAS  PubMed  Google Scholar 

  28. Kruglyak L, Lander ES . High-resolution genetic mapping of complex traits Am J Hum Genet 1995 56: 1212–1223

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Herb A, Higuchi M, Sprengel R, Seeburg PH . Q/R site editing in kainate receptor GluR5 and GluR6 pre-mRNAs requires distant intronic sequences Proc Natl Acad Sci USA 1996 93: 1875–1880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gregor P, O'Hara BF, Yang X, Uhl GR . Expression and novel subunit isoforms of glutamate receptor genes GluR5 and GluR6 Neuroreport 1993 4: 1343–1346

    Article  CAS  PubMed  Google Scholar 

  31. Lander E, Kruglyak L . Genetic dissection of complex traits – guidelines for interpreting and reporting linkage results Nat Genet 1995 11: 241–247

    Article  CAS  PubMed  Google Scholar 

  32. Lyttle TW . Cheaters sometimes prosper: distortion of mendelian segregation by meiotic drive Trends Genet 1993 9: 205–210

    Article  CAS  PubMed  Google Scholar 

  33. Ashley-Koch A, Wolpert CM, Menold MM, Zaeem L, Basu S, Donnelly SL et al. Genetic studies of autistic disorder and chromosome 7 Genomics 1999 61: 227–236

    Article  CAS  PubMed  Google Scholar 

  34. Wolpert CM, Menold MM, Bass MP, Qumsiyeh MB, Donnelly SL, Ravan SA et al. Three probands with autistic disorder and isodicentric chromosome 15 Am J Med Genet 2000 96: 365–372

    Article  CAS  PubMed  Google Scholar 

  35. Skuse DH . Imprinting, the X-chromosome, and the male brain: explaining sex differences in the liability to autism Pediatr Res 2000 47: 9–16

    Article  CAS  PubMed  Google Scholar 

  36. Gardner RJ, Mackay DJ, Mungall AJ, Polychronakos C, Siebert R, Shield JP et al. An imprinted locus associated with transient neonatal diabetes mellitus Hum Mol Genet 2000 9: 589–596

    Article  CAS  PubMed  Google Scholar 

  37. Schiffer HH, Swanson GT, Masliah E, Heinemann SF . Unequal expression of allelic kainate receptor GluR7 mRNAs in human brains J Neurosci 2000 20: 9025–9033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Garcia EP, Mehta S, Blair LA, Wells DG, Shang J, Fukushima T et al. SAP90 binds and clusters kainate receptors causing incomplete desensitization Neuron 1998 21: 727–739

    Article  CAS  PubMed  Google Scholar 

  39. Chittajallu R, Braithwaite SP, Clarke VR, Henley JM . Kainate receptors: subunits, synaptic localization and function Trends Pharmacol Sci 1999 20: 26–35

    Article  CAS  PubMed  Google Scholar 

  40. Contractor A, Swanson G, Heinemann SF . Kainate receptors are involved in short- and long-term plasticity at mossy fiber synapses in the hippocampus Neuron 2001 29: 209–216

    Article  CAS  PubMed  Google Scholar 

  41. Mulle C, Sailer A, Swanson GT, Brana C, O'Gorman S, Bettler B et al. Subunit composition of kainate receptors in hippocampal interneurons Neuron 2000 28: 475–484

    Article  CAS  PubMed  Google Scholar 

  42. Kidd FL, Isaac JT . Developmental and activity-dependent regulation of kainate receptors at thalamocortical synapses Nature 1999 400: 569–573

    Article  CAS  PubMed  Google Scholar 

  43. Wang LY, Taverna FA, Huang XP, MacDonald JF, Hampson DR . Phosphorylation and modulation of a kainate receptor (GluR6) by cAMP-dependent protein kinase Science 1993 259: 1173–1175

    Article  CAS  PubMed  Google Scholar 

  44. Mulle C, Sailer A, Perez-Otano I, Dickinson-Anson H, Castillo PE, Bureau I et al. Altered synaptic physiology and reduced susceptibility to kainate-induced seizures in GluR6-deficient mice Nature 1998 392: 601–605

    Article  CAS  PubMed  Google Scholar 

  45. Rapin I, Katzman R . Neurobiology of autism Ann Neurol 1998 43: 7–14

    Article  CAS  PubMed  Google Scholar 

  46. Ben-Ari Y, Cossart R . Kainate, a double agent that generates seizures: two decades of progress Trends Neurosci 2000 23: 580–587

    Article  CAS  PubMed  Google Scholar 

  47. Telfeian AE, Federoff HJ, Leone P, During MJ, Williamson A . Overexpression of GluR6 in rat hippocampus produces seizures and spontaneous nonsynaptic bursting in vitro Neurobiol Dis 2000 7: 362–374

    Article  CAS  PubMed  Google Scholar 

  48. Niswender CM . Recent advances in mammalian RNA editing Cell Mol Life Sci 1998 54: 946–964

    Article  CAS  PubMed  Google Scholar 

  49. Reenan RA . The RNA world meets behavior: A→I pre-mRNA editing in animals Trends Genet 2001 17: 53–56

    Article  CAS  PubMed  Google Scholar 

  50. Egebjerg J, Heinemann SF . Ca2+ permeability of unedited and edited versions of the kainate selective glutamate receptor GluR6 Proc Natl Acad Sci USA 1993 90: 755–759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Schmitt J, Dux E, Gissel C, Paschen W . Regional analysis of developmental changes in the extent of GluR6 mRNA editing in rat brain Dev Brain Res 1996 91: 153–157

    Article  CAS  Google Scholar 

  52. Grigorenko EV, Bell WL, Glazier S, Pons T, Deadwyler S . Editing status at the Q/R site of the GluR2 and GluR6 glutamate receptor subunits in the surgically excised hippocampus of patients with refractory epilepsy Neuroreport 1998 9: 2219–2224

    Article  CAS  PubMed  Google Scholar 

  53. Cao Q, Martinez M, Zhang J, Sanders AR, Badner JA, Cravchik A et al. Suggestive evidence for a schizophrenia susceptibility locus on chromosome 6q and a confirmation in an independent series of pedigrees Genomics 1997 43: 1–8

    Article  CAS  PubMed  Google Scholar 

  54. Martinez M, Goldin LR, Cao Q, Zhang J, Sanders AR, Nancarrow DJ et al. Follow-up study on a susceptibility locus for schizophrenia on chromosome 6q Am J Med Genet 1999 88: 337–343

    Article  CAS  PubMed  Google Scholar 

  55. Levinson DF, Holmans P, Straub RE, Owen MJ, Wildenauer DB, Gejman PV et al. Multicenter linkage study of schizophrenia candidate regions on chromosomes 5q, 6q, 10p, and 13q: schizophrenia linkage collaborative group III Am J Hum Genet 2000 67: 652–663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Meador-Woodruff JH, Healy DJ . Glutamate receptor expression in schizophrenic brain Brain Res Rev 2000 31: 288–294

    Article  CAS  PubMed  Google Scholar 

  57. Porter RH, Eastwood SL, Harrison PJ . Distribution of kainate receptor subunit mRNAs in human hippocampus, neocortex and cerebellum, and bilateral reduction of hippocampal GluR6 and KA2 transcripts in schizophrenia Brain Res 1997 751: 217–231

    Article  CAS  PubMed  Google Scholar 

  58. Rubinsztein DC, Leggo J, Chiano M, Dodge A, Norbury G, Rosser E et al. Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease Proc Natl Acad Sci USA 1997 94: 3872–3876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Walter AE, Turner DH, Kim J, Lyttle MH, Muller P, Mathews DH et al. Coaxial stacking of helixes enhances binding of oligoribonucleotides and improves predictions of RNA folding Proc Natl Acad Sci USA 1994 91: 9218–9222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the patients and their families who made this research possible, Dr Ken McElreavey and Dr Christophe Mulle for helpful discussions and comments during the writing of the manuscript, and Johann Tassin for technical assistance. Genotyping facilities were provided by the Centre National de Genotypage (CNG), Evry, France. This work was supported by the Délégation de la Recherche Clinique de l'Assistance Publique-Hôpitaux de Paris, the French Research Ministry (Actions Concertées Incitatives), France Télécom, and the Swedish Medical Research Council. CB was supported by a Cure Autism Now Foundation Award.

Author information

Author notes

  1. S Jamain, C Betancur, H Quach, A Philippe, M Fellous, B Giros, C Gillberg, M Leboyer and T Bourgeron: Paris Autism Research International Sibpair Study:

    Sweden. Department of Child and Adolescent Psychiatry, Göteborg University, Göteborg: Christopher Gillberg, Maria Rastam, Carina Gillberg, Agneta Nydén.

    France. Department of Psychiatry, Hôpital Albert Chenevier et Henri Mondor, Créteil: Marion Leboyer; INSERM U513, Faculté de Médecine, Créteil: Catalina Betancur, Bruno Giros, Anne Philippe; Service de Psychopathologie de l'Enfant et l'Adolescent, Hôpital Robert Debré, Paris: Nadia Chabane, Marie-Christine Mouren-Siméoni; INSERM U289, Hôpital de la Salpêtrière, Paris: Alexis Brice.

    Norway. Centre for Child and Adolescent Psychiatry, University of Oslo, Oslo: Eili Sponheim, Ingrid Spurkland; Department of Pediatrics, Rikshospitalet, University of Oslo, Oslo: Ola H Skjeldal.

    USA. Department of Pediatrics, Georgetown University School of Medicine, Washington DC: Mary Coleman; Children's National Medical Center, George Washington University School of Medicine, Washington, DC: Philip L Pearl; New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York: Ira L Cohen, John Tsiouris.

    Italy. Divisione di Neuropsichiatria Infantile, Azienda Ospedaliera Senese, Siena: Michele Zappella, Grazia Menchetti, Alfonso Pompella.

    Austria. Department of General Psychiatry, University Hospital, Vienna: Harald Aschauer.

    Belgium. Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gerpinnes, Loverval: Lionel Van Maldergem.

Authors and Affiliations

  1. Laboratoire d'Immunogénétique Humaine, INSERM E021, Institut Pasteur, Paris, 75015, France

    S Jamain, H Quach, M Fellous & T Bourgeron

  2. INSERM U513, Faculté de Médecine de Créteil, Créteil, 94000, France

    C Betancur, A Philippe, B Giros & M Leboyer

  3. Department of Child and Adolescent Psychiatry, Göteborg University, Göteborg, 41119, Sweden

    C Gillberg

  4. Department of Psychiatry, Hôpital Albert Chenevier et Henri Mondor, Créteil, 94000, France

    M Leboyer

Authors
  1. S Jamain
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Betancur
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Quach
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Philippe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Fellous
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B Giros
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C Gillberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Leboyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. T Bourgeron
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

and the Paris Autism Research International Sibpair (PARIS) Study

Corresponding author

Correspondence to T Bourgeron.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jamain, S., Betancur, C., Quach, H. et al. Linkage and association of the glutamate receptor 6 gene with autism. Mol Psychiatry 7, 302–310 (2002). https://doi.org/10.1038/sj.mp.4000979

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4000979

Keywords

This article is cited by

Search

Advanced search

Quick links