NeuroMolecular Medicine

, Volume 2, Issue 1, pp 11–28 | Cite as

Autism

In search of susceptibility genes
  • Janine A. Lamb
  • Jeremy R. Parr
  • Anthony J. Bailey
  • Anthony P. Monaco
Review Article

Abstract

Autism is a neurodevelopmental disorder of unknown etiology. There is convincing data for the involvement of genetic factors in the development of autism, and the absence of any consistent evidence for an environmental, neuroanatomical, or biochemical cause has led to an increasing number of genetic studies to determine the basis of this complex disorder. The results of recent genetic linkage and candidate gene studies are reviewed in relation to the challenge of clinical and genetic heterogeneity, and prospects for the future of genetic research in autism are considered.

Index Entries

Autism pervasive developmental disorder genetics linkage candidate gene chromosomal abnormality heterogeneity language 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Abecasis G. R., Noguchi E., Heinzmann A., Traherne J. A., Bhattacharyya S., Leaves N. I., et al. (2001) Extent and distribution of linkage disequilibrium in three genomic regions. Am. J. Hum. Genet. 68, 191–197.PubMedCrossRefGoogle Scholar
  2. Alarcon M., Cantor R. M., Liu J., Gilliam T. C., and Geschwind D. H. (2002) Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families. Am. J. Hum. Genet. 70, 60–71.PubMedCrossRefGoogle Scholar
  3. Amir R. E., Van den Veyver I. B., Wan M., Tran C. Q., Francke U., and Zoghbi H. Y. (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- CpG-binding protein 2. Nat. Genet. 23, 185–188.PubMedCrossRefGoogle Scholar
  4. Ashley-Koch A., Wolpert C. M., Menold M. M., Zaeem L., Basu S., Donnelly S. L., et al. (1999) Genetic studies of autistic disorder and chromosome 7. Genomics 61, 227–236.PubMedCrossRefGoogle Scholar
  5. Auranen M. P., Kempas E., Vanhala R., Varilo T., Ylisaukko-oja T., Peltonen L., and Jarvela I. (2001) A major susceptibility locus for autism spectrum disorders on chromosome 3q25–27 in the Finnish population. Paper presented at American Society of Human Genetics, San Diego, CA.Google Scholar
  6. Bailey A., Le Couteur A., Gottesman I., Bolton P., Simonoff E., Yuzda E., and Rutter M. (1995) Autism as a strongly genetic disorder: evidence from a British twin study. Psychol. Med. 25, 63–77.PubMedCrossRefGoogle Scholar
  7. Bailey A., Luthert P., Dean A., Harding B., Janota I., Montgomery M., et al. (1998a) A clinicopathological study of autism. Brain 121, 889–905.PubMedCrossRefGoogle Scholar
  8. Bailey A., Palferman S., Heavey L., and Le Couteur A. (1998b) Autism: the phenotype in relatives. J. Autism Dev. Disord. 28, 369–392.PubMedCrossRefGoogle Scholar
  9. Barrett S., Beck J. C., Bernier R., Bisson E., Braun T. A., Casavant T. L., et al. (1999) An autosomal genomic screen for autism. Am. J. Med. Genet. 88, 609–615.PubMedCrossRefGoogle Scholar
  10. Barton M. and Volkmar F. (1998) How commonly are known medical conditions associated with autism? J. Autism Dev. Disord. 28, 273–278.PubMedCrossRefGoogle Scholar
  11. Berney T. P. (2000) Autism—an evolving concept. Br. J. Psychiatry 176, 20–25.PubMedCrossRefGoogle Scholar
  12. Beyer K. S., Klauck S. M., Wiemann S., and Poustka A. (2001) Construction of a physical map of an autism susceptibility region in 7q32.3–q33. Gene 272, 85–91.PubMedCrossRefGoogle Scholar
  13. Blagitko N., Schulz U., Schinzel A. A., Ropers H. H., and Kalscheuer V. M. (1999) gamma2-COP, a novel imprinted gene on chromosome 7q32, defines a new imprinting cluster in the human genome. Hum. Mol. Genet. 8, 2387–2396.PubMedCrossRefGoogle Scholar
  14. Bolton P. F., Murphy M., Macdonald H., Whitlock B., Pickles A., and Rutter M. (1997) Obstetric complications in autism: consequences or causes of the condition? J. Am. Acad. Child Adolesc. Psychiatry 36, 272–281.PubMedCrossRefGoogle Scholar
  15. Bolton P.F., Roobol M., Allsopp L., and Pickles A. (2001) Association between idiopathic infantile macrocephaly and autism spectrum disorders. Lancet 358, 726–727.PubMedCrossRefGoogle Scholar
  16. Bonora E., Bacchelli E., Levy E. R., Blasi F., Marlow A., Monaco A. P., Maestrini E., and IMGSAC (2002) Mutation screening and imprinting analysis of four candidate genes for autism in the 7q32 region. Mol. Psychiatry, 7(3), 289–301.PubMedCrossRefGoogle Scholar
  17. Bottini N., De Luca D., Saccucci P., Fiumara A., Elia M., Porfirio M. C., et al. (2001) Autism: evidence of association with adenosine deaminase genetic polymorphism. Neurogenetics 3, 111–113.PubMedCrossRefGoogle Scholar
  18. Bradford Y., Haines J., Hutcheson H., Gardiner M., Braun T., Sheffield V., et al. (2001) Incorporating language phenotypes strengthens evidence of linkage to autism. Am. J. Med. Genet. 105, 539–547.PubMedCrossRefGoogle Scholar
  19. Brodkin E. S., McDougle C. J., Naylor S. T., Cohen D. J., and Price L. H. (1997) Clomipramine in adults with pervasive developmental disorders: a prospective open-label investigation. J. Child. Adolesc. Psychopharmacol. 7, 109–121.PubMedCrossRefGoogle Scholar
  20. Buitelaar J. K. and Willemsen-Swinkels S. H. (2000) Autism: current theories regarding its pathogenesis and implications for rational pharmacotherapy. Paediatr. Drugs 2, 67–81.PubMedCrossRefGoogle Scholar
  21. Buoni S., Sorrentino L., Farnetani M. A., Pucci L., and Fois A. (2000) The syndrome of inv dup (15): clinical, electroencephalographic, and imaging findings. J. Child. Neurol. 15, 380–385.PubMedGoogle Scholar
  22. Buxbaum J. D., Silverman J. M., Smith C. J., Kilifarski M., Reichert J., Hollander E., et al. (2001) Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity. Am. J. Hum. Genet. 68, 1514–1520.PubMedCrossRefGoogle Scholar
  23. Chakrabarti S. and Fombonne E. (2001) Pervasive developmental disorders in preschool children. JAMA 285, 3093–3099.PubMedCrossRefGoogle Scholar
  24. Collins F. S. (1995) Positional cloning moves from perditional to traditional. Nat. Genet. 9, 347–350.PubMedCrossRefGoogle Scholar
  25. Comings D. E., Wu S., Chiu C., Muhleman D., and Sverd J. (1996) Studies of the c-Harvey-Ras gene in psychiatric disorders. Psychiatry Res. 63, 25–32.PubMedCrossRefGoogle Scholar
  26. Cook E. H., Jr. (2001) Genetics of autism. Child. Adolesc. Psychiatr. Clin. North Am. 10, 333–350.Google Scholar
  27. Cook E. H., Jr., Courchesne R., Lord C., Cox N. J., Yan S., Lincoln A., et al. (1997a) Evidence of linkage between the serotonin transporter and autistic disorder. Mol. Psychiatry 2, 247–250.PubMedCrossRefGoogle Scholar
  28. Cook E. H., Jr., Courchesne R. Y., Cox N. J., Lord C., Gonen D., Guter S. J., et al. (1998) Linkage-disequilibrium mapping of autistic disorder, with 15q11–13 markers. Am. J. Hum. Genet. 62, 1077–1083.PubMedCrossRefGoogle Scholar
  29. Cook E. H., Jr., Lindgren V., Leventhal B. L., Courchesne R., Lincoln A., Shulman C., et al. (1997b) Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am. J. Hum. Genet. 60, 928–934.PubMedGoogle Scholar
  30. Cook, E. H. and Leventhal B. L. (1996) The serotonin system in autism. Curr. Opin. Pediatr. 8, 348–354.PubMedCrossRefGoogle Scholar
  31. Cook Jr. E. H., Kim S., Cox N., Courchesne R., Lord C., C., C., Akshoomoff N., et al. (2001) Transmission Disequilibrium Mapping in the Serotonin Transporter Gene (SLC6A4) Region in Autistic Disorder. Paper presented at American Society of Human Genetics, San Diego, CA.Google Scholar
  32. Cordell H. J., Wedig G. C., Jacobs K. B., and Elston R. C. (2000) Multilocus linkage tests based on affected relative pairs. Am. J. Hum. Genet. 66, 1273–1286.PubMedCrossRefGoogle Scholar
  33. Cox N. J., Frigge M., Nicolae D. L., Concannon P., Hanis C. L., Bell G. I., and Kong A. (1999) Loci on chromosomes 2 (NIDDM1) and 15 interact to increase susceptibility to diabetes in Mexican Americans. Nat. Genet. 21, 213–215.PubMedCrossRefGoogle Scholar
  34. Daly M. J., Rioux J. D., Schaffner S. F., Hudson T. J., and Lander E. S. (2001) High-resolution haplotype structure in the human genome. Nat. Genet. 29, 229–232.PubMedCrossRefGoogle Scholar
  35. Donnelly S. L., Wolpert C. M., Menold M. M., Bass M. P., Gilbert J. R., Cuccaro M. L., et al. (2000) Female with autistic disorder and monosomy X (Turner syndrome): parent- of-origin effect of the X chromosome. Am. J. Med. Genet. 96, 312–316.PubMedCrossRefGoogle Scholar
  36. Dowd M. F., Manoski R., Santangelo S., and Folstein S. (2001) Evidence of an Epistatic interaction in a Genetic Linkage Study of Autism. Paper presented at American Society of Human Genetics, San Diego, CA.Google Scholar
  37. Dunning A. M., Durocher F., Healey C. S., Teare M. D., McBride S. E., Carlomagno F., et al. (2000) The extent of linkage disequilibrium in four populations with distinct demographic histories. Am. J. Hum. Genet. 67, 1544–1554.PubMedCrossRefGoogle Scholar
  38. Dykens E. and Volkmar F. R. (1997) Medical conditions associated with autism, in Handbook of Autism and Pervasive Developmental Disorders (Volkmar C., ed.), Wiley, New York, pp. 388–410.Google Scholar
  39. Elliman D. A. and Bedford H. E. (2001) MMR vaccine: worries are not justified. Arch. Dis. Child. 85, 271–274.PubMedCrossRefGoogle Scholar
  40. Fatemi S. H., Realmuto G. M., Khan L., and Thuras P. (1998) Fluoxetine in treatment of adolescent patients with autism: a longitudinal open trial. J. Autism Dev. Disord. 28, 303–307.PubMedCrossRefGoogle Scholar
  41. Fatemi S. H., Stary J. M., Halt A. R., and Realmuto G. R. (2001) Dysregulation of Reelin and Bcl-2 Proteins in Autistic Cerebellum. J. Autism Dev. Disord. 31, 529–535.PubMedCrossRefGoogle Scholar
  42. Feinstein C. and Reiss A. L. (1998) Autism: the point of view from fragile X studies. J. Autism Dev. Disord. 28, 393–405.PubMedCrossRefGoogle Scholar
  43. Fisher S. E., Vargha-Khadem F., Watkins K. E., Monaco A. P., and Pembrey M. E. (1998) Localisation of a gene implicated in a severe speech and language disorder. Nat. Genet. 18, 168–170.PubMedCrossRefGoogle Scholar
  44. Folstein S. and Rutter M. (1977) Infantile autism: a genetic study of 21 twin pairs. J. Child Psychol. Psychiatry 18, 297–321.PubMedCrossRefGoogle Scholar
  45. Folstein S. E. and Mankoski R. E. (2000) Chromosome 7q: where autism meets language disorder? Am. J. Hum. Genet. 67, 278–281.PubMedCrossRefGoogle Scholar
  46. Fombonne E. (1999) The epidemiology of autism: a review. Psychol. Med. 29, 769–786.PubMedCrossRefGoogle Scholar
  47. Geschwind D. H., Sowinski J., Lord C., Iversen P., Shestack J., Jones P., et al. (2001) The autism genetic resource exchange: a resource for the study of autism and related neuropsychiatric conditions. Am. J. Hum. Genet. 69, 463–466.PubMedCrossRefGoogle Scholar
  48. Ghaziuddin M. and Burmeister M. (1999) Deletion of chromosome 2q37 and autism: a distinct subtype? J. Autism Dev. Disord. 29, 259–263.PubMedCrossRefGoogle Scholar
  49. Gillberg C. (1992) Subgroups in autism: are there behavioural phenotypes typical of underlying medical conditions? J. Intellect. Disabil. Res. 36, 201–214.PubMedCrossRefGoogle Scholar
  50. Gillberg C. (1998) Chromosomal disorders and autism. J. Autism Dev. Disord. 28, 415–425.PubMedCrossRefGoogle Scholar
  51. Gillberg C. and Coleman M. (1996) Autism and medical disorders: a review of the literature. Dev. Med. Child. Neurol. 38, 191–202.PubMedCrossRefGoogle Scholar
  52. Glatt C. E., DeYoung J. A., Delgado S., Service S. K., Giacomini K. M., Edwards R. H., et al. (2001) Screening a large reference sample to identify very low frequency sequence variants: comparisons between two genes. Nat. Genet. 27, 435–438.PubMedCrossRefGoogle Scholar
  53. Goodman R. (1990) Technical note: are perinatal complications causes or consequences of autism? J. Child. Psychol. Psychiatry 31, 809–812.PubMedCrossRefGoogle Scholar
  54. Guidotti A., Auta J., Davis J. M., Gerevini V. D., Dwivedi Y., Grayson D. R., et al. (2000) Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch. Gen. Psychiatry 57, 1061–1069.PubMedCrossRefGoogle Scholar
  55. Gutknecht L. (2001) Full-genome scans with autistic disorder: a review. Behav. Genet. 31, 113–123.PubMedCrossRefGoogle Scholar
  56. Hafeman L. and Tomblin J. B. (1999) Autism behaviours in the siblings of children with specific language impairment. Paper presented at The VIIth World Congress of Psychiatric Genetics, Monterey, CA.Google Scholar
  57. Hampe J., Cuthbert A., Croucher P. J., Mirza M. M., Mascheretti S., Fisher S., et al. (2001) Association between insertion mutation in NOD2 gene and Crohn’s disease in German and British populations. Lancet 357, 1925–1928.PubMedCrossRefGoogle Scholar
  58. Hayashida S., Yamasaki K., Asada Y., Soeda E., Niikawa N., and Kishino T. (2000) Construction of a physical and transcript map flanking the imprinted MEST/PEG1 region at 7q32. Genomics 66, 221–225.PubMedCrossRefGoogle Scholar
  59. Herault J., Perrot A., Barthelemy C., Buchler M., Cherpi C., Leboyer M., et al. (1993) Possible association of c-Harvey-Ras-1 (HRAS-1) marker with autism. Psychiatry Res. 46, 261–267.PubMedCrossRefGoogle Scholar
  60. Herault J., Petit E., Martineau J., Cherpi C., Perrot A., Barthelemy C., et al. (1996) Serotonin and autism: biochemical and molecular biology features. Psychiatry Res. 65, 33–43.PubMedCrossRefGoogle Scholar
  61. Hong S. E., Shugart Y. Y., Huang D. T., Shahwan S. A., Grant P. E., Hourihane J. O., et al. (2000) Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat. Genet. 26, 93–96.PubMedCrossRefGoogle Scholar
  62. Hugot J. P., Chamaillard M., Zouali H., Lesage S., Cezard J. P., Belaiche J., et al. (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411, 599–603.PubMedCrossRefGoogle Scholar
  63. Hunsinger D. M., Nguyen T., Zebraski S. E., and Raffa R. B. (2000) Is there a basis for novel pharmacotherapy of autism? Life Sci. 67, 1667–1682.PubMedCrossRefGoogle Scholar
  64. Hurst J. A., Baraitser M., Auger E., Graham F., and Norell S. (1990) An extended family with a dominantly inherited speech disorder. Dev. Med. Child. Neurol. 32, 352–355.PubMedCrossRefGoogle Scholar
  65. Impagnatiello F., Guidotti A. R., Pesold C., Dwivedi Y., Caruncho H., Pisu M. G., et al. (1998) A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc. Natl. Acad. Sci. USA 95, 15,718–15,723.CrossRefGoogle Scholar
  66. Ingram J. L., Stodgell C. J., Hyman S. L., Figlewicz D. A., Weitkamp L. R., and Rodier P. M. (2000) Discovery of allelic variants of HOXA1 and HOXB1: genetic susceptibility to autism spectrum disorders. Teratology 62, 393–405.PubMedCrossRefGoogle Scholar
  67. International Human Genome Sequencing Consortium. (2001) Initial sequencing and analysis of the human genome. Nature 409, 860–921.CrossRefGoogle Scholar
  68. International Molecular Genetic Study of Autism Consortium. (1998) A full genome screen for autism with evidence for linkage to a region on chromosome 7q. Hum. Mol. Genet. 7, 571–578.CrossRefGoogle Scholar
  69. International Molecular Genetic Study of Autism Consortium. (2001a) Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q. Hum. Mol. Genet. 10, 973–982.CrossRefGoogle Scholar
  70. International Molecular Genetic Study of Autism Consortium. (2001b) A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am. J. Hum. Genet. 69, 570–581.CrossRefGoogle Scholar
  71. Jeffreys A. J., Kauppi L., and Neumann R. (2001) Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat. Genet. 29, 217–222.PubMedCrossRefGoogle Scholar
  72. Johnson G. C., Esposito L., Barratt B. J., Smith A. N., Heward J., Di Genova G., et al. (2001) Haplotype tagging for the identification of common disease genes. Nat. Genet. 29, 233–237.PubMedCrossRefGoogle Scholar
  73. Keller F., Persico A. M., Zelante L., Gasparini P., D’Agruma L., Maiorano N., et al. (2000) Reelin gene alleles and haplotypes are associated with autistic disorder. Paper presented at Society for Neuroscience, New Orleans, LA.Google Scholar
  74. Kemper T. L. and Bauman M. (1998) Neuropathology of infantile autism. J. Neuropathol. Exp. Neurol. 57, 645–652.PubMedCrossRefGoogle Scholar
  75. Kim S.-J., Herzing L. B. K., Veenstra-VanderWeele J., Lord C., Courchesne R., Leventhal B. L., et al. (2002) Mutation screening and transmission disequilibrium study of ATP10C in autism. Am. J. Med. Genet. 114(2), 137–143.PubMedCrossRefGoogle Scholar
  76. Klauck S. M., Poustka F., Benner A., Lesch K. P., and Poustka A. (1997) Serotonin transporter (5-HTT) gene variants associated with autism? Hum. Mol. Genet. 6, 2233–2238.PubMedCrossRefGoogle Scholar
  77. Kobayashi S., Kohda T., Miyoshi N., Kuroiwa Y., Aisaka K., Tsutsumi O., et al. (1997) Human PEG1/MEST, an imprinted gene on chromosome 7. Hum. Mol. Genet. 6, 781–786.PubMedCrossRefGoogle Scholar
  78. Lai C. S., Fisher S. E., Hurst J. A., Levy E. R., Hodgson S., Fox M., et al. (2000) The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder. Am. J. Hum. Genet. 67, 357–368.PubMedCrossRefGoogle Scholar
  79. Lai C. S., Fisher S. E., Hurst J. A., Vargha-Khadem F., and Monaco A. P. (2001) A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 413, 519–523.PubMedCrossRefGoogle Scholar
  80. Lamb J. A., Moore J., Bailey A., and Monaco A. P. (2000) Autism: recent molecular genetic advances [published erratum appears in Hum. Mol. Genet. 2000 May 22;9(9):1461]. Hum. Mol. Genet. 9, 861–868.PubMedCrossRefGoogle Scholar
  81. Lander E. and Kruglyak L. (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat. Genet. 11, 241–247.PubMedCrossRefGoogle Scholar
  82. Lassig J. P., Vachirasomtoon K., Hartzell K., Leventhal M., Courchesne E., Courchesne R., et al. (1999) Physical mapping of the serotonin 5-HT(7) receptor gene (HTR7) to chromosome 10 and pseudogene (HTR7P) to chromosome 12, and testing of linkage disequilibrium between HTR7 and autistic disorder. Am. J. Med. Genet. 88, 472–475.PubMedCrossRefGoogle Scholar
  83. Le Couteur A., Bailey A., Goode S., Pickles A., Robertson S., Gottesman I., and Rutter M. (1996) Abroader phenotype of autism: the clinical spectrum in twins. J. Child. Psychol. Psychiatry 37, 785–801.PubMedCrossRefGoogle Scholar
  84. Leboyer M., Bellivier F., Nosten-Bertrand M., Jouvent R., Pauls D., and Mallet J. (1998) Psychiatric genetics: search for phenotypes. Trends Neurosci. 21, 102–105.PubMedCrossRefGoogle Scholar
  85. Li J., Tabor H. K., Nguyen L., Gleason C., Lotspeich L. J., Spiker D., et al. (2001) Lack of Association Between HoxA1, HoxB1, Reelin and WNT-2 Gene Variants and Autism in 110 Multiplex Families. Paper presented at American Society of Human Genetics, San Diego, CA.Google Scholar
  86. Li J., Tabor H. K., Nguyen L., Gleason C., Lotspeich L. J., Spiker D., et al. (2002) Lack of association between HoxA1 and HoxB1 gene variants and autism in 110 multiplex families. Am. J. Med. Genet. 114, 24–30.PubMedCrossRefGoogle Scholar
  87. Liu J., Nyholt D. R., Magnussen P., Parano E., Pavone P., Geschwind D., et al. (2001) A genomewide screen for autism susceptibility loci. Am. J. Hum. Genet. 69, 327–340.PubMedCrossRefGoogle Scholar
  88. Lockyer L. and Rutter M. (1969) A five to fifteen year follow up study of infantile psychosis: III. Psychological Aspects. Br. J. Psychiatry 115, 865–882.PubMedGoogle Scholar
  89. Lotspeich L. J. and Ciaranello R. D. (1993) The neurobiology and genetics of infantile autism. Int. Rev. Neurobiol. 35, 87–129.PubMedGoogle Scholar
  90. Maddox L. O., Menold M. M., Bass M. P., Rogala A. R., Pericak-Vance M. A., Vance J. M., and Gilbert J. R. (1999) Autistic disorder and chromosome 15q11–q13: construction and analysis of a BAC/PAC contig. Genomics 62, 325–331.PubMedCrossRefGoogle Scholar
  91. Maestrini E., Lai C., Marlow A., Matthews N., Wallace S., Bailey A., Cook E. H., Weeks D. E., Monaco A. P., and IMGSAC (1999) Serotonin transporter (5-HTT) and gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families. Am. J. Med. Genet. 88, 492–496.PubMedCrossRefGoogle Scholar
  92. Martin E. R., Lai E. H., Gilbert J. R., Rogala A. R., Afshari A. J., Riley J., et al. (2000a) SNPing away at complex diseases: analysis of single-nucleotide polymorphisms around APOE in Alzheimer Disease. Am. J. Hum. Genet. 67, 383–394.PubMedCrossRefGoogle Scholar
  93. Martin E. R., Menold M. M., Wolpert C. M., Bass M. P., Donnelly S. L., Ravan S. A., et al. (2000b) Analysis of linkage disequilibrium in gamma-aminobutyric acid receptor subunit genes in autistic disorder. Am. J. Med. Genet. 96, 43–48.PubMedCrossRefGoogle Scholar
  94. Mbarek O., Marouillat S., Martineau J., Barthelemy C., Muh J. P., and Andres C. (1999) Association study of the NF1 gene and autistic disorder. Am. J. Med. Genet. 88, 729–732.PubMedCrossRefGoogle Scholar
  95. McCoy P. A., Shao Y., Martin E. R., Delong G. R., Cuccaro M. L., Gilbert J. R., and Pericak-Vance M. A. (2001) Association studies of genetic risk factors for autistic disorder on chromosome 7. Paper presented at American Society of Human Genetics, San Diego, CA.Google Scholar
  96. McCoy P. A., Shao Y., Wolpert C. M., Donnelly S. L., Ashley-Koch A., Abel H. L., et al. (2002) No association between the WNT2 gene and autistic disorder. Am. J. Med. Genet. 114, 106–109.PubMedCrossRefGoogle Scholar
  97. McDougle C. J., Brodkin E. S., Naylor S. T., Carlson D. C., Cohen D. J., and Price L. H. (1998) Sertraline in adults with pervasive developmental disorders: a prospective open-label investigation. J. Clin. Psychopharmacol. 18, 62–66.PubMedCrossRefGoogle Scholar
  98. Medical Research Council (2001) MRC Review of Autism Research. Epidemiology and Causes. December 2001. (Report available at http://www.mrc.ac.uk/).Google Scholar
  99. Menold M. M., Shao Y., Martin E. R., Wolpert C. M., Raiford K. L., Abel H. L., et al. (2001) Association Analysis of Autistic Disorder and SNPs in the chromosome 15 GABAA receptor subunit genes. Paper presented at American Society of Human Genetics, San Diego, CA.Google Scholar
  100. Miles J. H., Hadden L. L., Takahashi T. N., and Hillman R. E. (2000) Head circumference is an independent clinical finding associated with autism. Am. J. Med. Genet. 95, 339–350.PubMedCrossRefGoogle Scholar
  101. Miles J. H. and Hillman R. E. (2000) Value of a clinical morphology examination in autism. Am. J. Med. Genet. 91, 245–253.PubMedCrossRefGoogle Scholar
  102. Moffatt M. F., Traherne J. A., Abecasis G. R., and Cookson W. O. (2000) Single nucleotide polymorphism and linkage disequilibrium within the TCR alpha/delta locus. Hum. Mol. Genet. 9, 1011–1019.PubMedCrossRefGoogle Scholar
  103. Newbury D. F., Bonora E., Lamb J. A., Fisher S. E., Lai C. S. L., Baird G., et al. (2002) FOXP2 is not a major susceptibility gene for autism or Specific Language Impairment(SLI). Am. J. Hum. Genet., 70(5), 1318–1327.PubMedCrossRefGoogle Scholar
  104. Nurmi E. L., Amin T., Bradford Y., Jacobs M. M., Haines J. L., Sutcliffe J. S., and the Collaborative Linkage Study of Autism (2001a) Linkage disequilibrium mapping and haplotype analysis in the 15q11–q13 autism candidate region reveals suggestive association at ATP10C and OCA2 in the CLSA families. Paper presented at American Society of Human Genetics, San Diego, CA.Google Scholar
  105. Nurmi E. L., Bradford Y., Chen Y., Hall J., Arnone B., Gardiner M. B., et al. (2001b) Linkage disequilibrium at the angelman syndrome gene ube3a in autism families. Genomics 77, 105–113.PubMedCrossRefGoogle Scholar
  106. Oberle I., Rousseau F., Heitz D., Kretz C., Devys D., Hanauer A., et al. (1991) Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science 252, 1097–1102.PubMedCrossRefGoogle Scholar
  107. Ogura Y., Bonen D. K., Inohara N., Nicolae D. L., Chen F. F., Ramos R., et al. (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411, 603–606.PubMedCrossRefGoogle Scholar
  108. Page T. (2000) Metabolic approaches to the treatment of autism spectrum disorders. J. Autism Dev. Disord. 30, 463–469.PubMedCrossRefGoogle Scholar
  109. Peltola H., Patja A., Leinikki P., Valle M., Davidkin I., and Paunio M. (1998) No evidence for measles, mumps, and rubella vaccine-associated inflammatory bowel disease or autism in a 14-year prospective study. Lancet 351, 1327–1328.PubMedCrossRefGoogle Scholar
  110. Pericak-Vance M. A., Shao Y., Raiford K., Wolpert C. M., Wright H. H., Abramson R. K., et al. (2001) Linkage and association analysis of chromosome 3 in autistic disorder. Paper presented at American Society of Human Genetics, San Diego, CA.Google Scholar
  111. Persico A. M., D’Agruma L., Maiorano N., Totaro A., Militerni R., Bravaccio C., et al. (2001) Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol. Psychiatry 6, 150–159.PubMedCrossRefGoogle Scholar
  112. Persico A. M., Militerni R., Bravaccio C., Schneider C., Melmed R., Conciatori M., et al. (2000a) Lack of association between serotonin transporter gene promoter variants and autistic disorder in two ethnically distinct samples. Am. J. Med. Genet. 96, 123–127.PubMedCrossRefGoogle Scholar
  113. Persico A. M., Militerni R., Bravaccio C., Schneider C., Melmed R., Trillo S., et al. (2000b) Adenosine deaminase alleles and autistic disorder: case-control and family-based association studies. Am. J. Med. Genet. 96, 784–790.PubMedCrossRefGoogle Scholar
  114. Petit E., Herault J., Martineau J., Perrot A., Barthelemy C., Hameury L., et al. (1995) Association study with two markers of a human homeogene in infantile autism. J. Med. Genet. 32, 269–274.PubMedGoogle Scholar
  115. Philippe A., Martinez M., Guilloud-Bataille M., Gillberg C., Rastam M., Sponheim E., et al. (1999) Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study [published erratum appears in Hum. Mol. Genet. 1999 Jul;8(7):1353]. Hum. Mol. Genet. 8, 805–812.PubMedCrossRefGoogle Scholar
  116. Pickles A., Bolton P., Macdonald H., Bailey A., Le Couteur A., Sim C. H., and 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. Am. J. Hum. Genet. 57, 717–726.PubMedGoogle Scholar
  117. Pickles A., Starr E., Kazak S., Bolton P., Papanikolaou K., Bailey A., et al. (2000) Variable expression of the autism broader phenotype: findings from extended pedigrees. J. Child. Psychol. Psychiatry 41, 491–502.PubMedCrossRefGoogle Scholar
  118. Plank S. M., Copeland-Yates S. A., Sossey-Alaoui K., Bell J. M., Schroer R. J., Skinner C., and Michaelis R. C. (2001) Lack of association of the (AAAT)6 allele of the GXAlu tetranucleotide repeat in intron 27b of the NF1 gene with autism. Am. J. Med. Genet. 105, 404–405.PubMedCrossRefGoogle Scholar
  119. Posey D. J. and McDougle C. J. (2000) The pharmacotherapy of target symptoms associated with autistic disorder and other pervasive developmental disorders. Harv. Rev. Psychiatry 8, 45–63.PubMedCrossRefGoogle Scholar
  120. Pritchard J. K. and Przeworski M. (2001) Linkage disequilibrium in humans: models and data. Am. J. Hum. Genet. 69, 1–14.PubMedCrossRefGoogle Scholar
  121. Purcell A. E., Jeon O. H., Zimmerman A. W., Blue M. E., and Pevsner J. (2001) Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology 57, 1618–1628.PubMedGoogle Scholar
  122. Rapin I. (1995) Autistic regression and disintegrative disorder: how important the role of epilepsy? Semin. Pediatr. Neurol. 2, 278–285.PubMedCrossRefGoogle Scholar
  123. Rapin I. (1997) Autism. N. Engl. J. Med. 337, 97–104.PubMedCrossRefGoogle Scholar
  124. Repetto G. M., White L. M., Bader P. J., Johnson D., and Knoll J. H. (1998) Interstitial duplications of chromosome region 15q11q13: clinical and molecular characterization. Am. J. Med. Genet. 79, 82–89.PubMedCrossRefGoogle Scholar
  125. Rineer S., Finucane B., and Simon E. W. (1998) Autistic symptoms among children and young adults with isodicentric chromosome 15. Am. J. Med. Genet. 81, 428–433.PubMedCrossRefGoogle Scholar
  126. Rioux J. D., Daly M. J., Silverberg M. S., Lindblad K., Steinhart H., Cohen Z., et al. (2001) Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat. Genet. 29, 223–228.PubMedCrossRefGoogle Scholar
  127. Risch N., Spiker D., Lotspeich L., Nouri N., Hinds D., Hallmayer J., et al. (1999) A genomic screen of autism: evidence for a multilocus etiology. Am. J. Hum. Genet. 65, 493–507.PubMedCrossRefGoogle Scholar
  128. Roberts S. B., MacLean C. J., Neale M. C., Eaves L. J., and Kendler K. S. (1999) Replication of linkage studies of complex traits: an examination of variation in location estimates. Am. J. Hum. Genet. 65, 876–884.PubMedCrossRefGoogle Scholar
  129. Roses A. D. (2000) Pharmacogenetics and the practice of medicine. Nature 405, 857–865.PubMedCrossRefGoogle Scholar
  130. Rutter M. (1970) Autistic children: infancy to adulthood. Semin. Psychiatry 2, 435–350.PubMedGoogle Scholar
  131. Rutter M., Bailey A., Bolton P., and Le Couteur A. (1994) Autism and known medical conditions: myth and substance. J. Child. Psychol. Psychiatry 35, 311–322.PubMedCrossRefGoogle Scholar
  132. Salmon B., Hallmayer J., Rogers T., Kalaydjieva L., Petersen P. B., Nicholas P., et al. (1999) Absence of linkage and linkage disequilibrium to chromosome 15q11–q13 markers in 139 multiplex families with autism. Am. J. Med. Genet. 88, 551–556.PubMedCrossRefGoogle Scholar
  133. Schain R. J. and Freedman D. X. (1961) Studies on 5-hydroxyindole metabolism in autistic and other mentally retarded children. J. Pediatr. 58, 315–320.PubMedCrossRefGoogle Scholar
  134. Schroer R. J., Phelan M. C., Michaelis R. C., Crawford E. C., Skinner S. A., Cuccaro M., et al. (1998) Autism and maternally derived aberrations of chromosome 15q. Am. J. Med. Genet. 76, 327–336.PubMedCrossRefGoogle Scholar
  135. Service S., Ophoff R., and Freimer N. (2001) The genome-wide distribution of background linkage disequilibrium in a population isolate. Hum. Mol. Genet. 10, 545–551.PubMedCrossRefGoogle Scholar
  136. Shao Y., Scott W. K., Raiford K. L., Wolpert C. M., Ashley-Koch A., Cuccaro M. L., et al. (2001) Loci on Chromosomes 7 and 2 Interact to Increase Linkage Evidence in Autistic Disorder. Paper presented at American Society of Human Genetics, San Diego, CA.Google Scholar
  137. Shao Y., Wolpert C. M., Raiford K. L., Menold M. M., Donnelly S. L., Raven S. A., et al. (2002) Genomic screen and follow-up analysis for autistic disorder. Am. J. Med. Genet. 114, 99–105.PubMedCrossRefGoogle Scholar
  138. Shinnar S., Rapin I., Arnold S., Tuchman R. F., Shulman L., Ballaban-Gil K., et al. (2001) Language regression in childhood. Pediatr. Neurol. 24, 183–189.PubMedCrossRefGoogle Scholar
  139. Skuse D. H. (2000) Imprinting, the X-chromosome, and the male brain: explaining sex differences in the liability to autism. Pediatr. Res. 47, 9–16.PubMedCrossRefGoogle Scholar
  140. Skuse D. H., James R. S., Bishop D. V., Coppin B., Dalton P., Aamodt-Leeper G., et al. (1997) Evidence from Turner’s syndrome of an imprinted X-linked locus affecting cognitive function. Nature 387, 705–708.PubMedCrossRefGoogle Scholar
  141. Smalley S. L. (1998) Autism and tuberous sclerosis. J. Autism Dev. Disord. 28, 407–414.PubMedCrossRefGoogle Scholar
  142. Smalley S. L., Tanguay P. E., Smith M., and Gutierrez G. (1992) Autism and tuberous sclerosis. J. Autism Dev. Disord. 22, 339–355.PubMedCrossRefGoogle Scholar
  143. Smith M., Escamilla J. R., Filipek P., Bocian M. E., Modahl C., Flodman P., and Spence M. A. (2001) Deletion of chromosome 2q37.3: report of a case and of candidate genes for autism and osteodystrophy. Paper presented at American Society of Human Genetics, San Diego, CA.Google Scholar
  144. Spiker D., Lotspeich L. J., Dimiceli S., Myers R. M., and Risch N. (2002) Behavioral phenotypic variation in autism multiplex families: evidence for a continuous severity gradient. Am. J. Med. Genet. 114, 129–136.PubMedCrossRefGoogle Scholar
  145. Steffenberg S., Gillberg C., Hellgre L., Anderen L., Gillberg I., Jackobsson G., and Bohman M. (1989) A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J. Child Psychol. Psychiatry 30, 405–416.CrossRefGoogle Scholar
  146. Steffenburg S., Gillberg C. L., Steffenburg U., and Kyllerman M. (1996) Autism in Angelman syndrome: a population-based study. Pediatr. Neurol. 14, 131–136.PubMedCrossRefGoogle Scholar
  147. Stoltenberg S. F. and Burmeister M. (2000) Recent progress in psychiatric genetics-some hope but no hype. Hum. Mol. Genet. 9, 927–935.PubMedCrossRefGoogle Scholar
  148. Swillen A., Hellemans H., Steyaert J., and Fryns J. P. (1996) Autism and genetics: high incidence of specific genetic syndromes in 21 autistic adolescents and adults living in two residential homes in Belgium. Am. J. Med. Genet. 67, 315–316.PubMedCrossRefGoogle Scholar
  149. Szatmari P. (1999) Heterogeneity and the genetics of autism. J. Psychiatry Neurosci. 24, 159–165.PubMedGoogle Scholar
  150. Szatmari P., Jones M. B., Zwaigenbaum L., and MacLean J. E. (1998) Genetics of autism: overview and new directions. J. Autism Dev. Disord. 28, 351–368.PubMedCrossRefGoogle Scholar
  151. Tager-Flusberg H. and Folstein S. E. (1999) Evidence for variation in the language phenotype for autism: implications for genetic subgroups. Paper presented at The VIIth World Congress of Psychiatric Genetics, Monterey, CA.Google Scholar
  152. Taillon-Miller P., Bauer-Sardina I., Saccone N. L., Putzel J., Laitinen T., Cao A., et al. (2000) Juxtaposed regions of extensive and minimal linkage disequilibrium in human Xq25 and Xq28. Nat. Genet. 25, 324–328.PubMedCrossRefGoogle Scholar
  153. Tarantino L. M. and Bucan M. (2000) Dissection of behavior and psychiatric disorders using the mouse as a model. Hum. Mol. Genet. 9, 953–965.PubMedCrossRefGoogle Scholar
  154. Taylor B., Miller E., Farrington C. P., Petropoulos M. C., Favot-Mayaud I., Li J., and Waight P. A. (1999) Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. Lancet 353, 2026–2029.PubMedCrossRefGoogle Scholar
  155. The SLI Consortium (SLIC) (2002) Agenome-wide scan identifies two novel loci involved in Specific Language Impairment (SLI). Am. J. Human Genet. 70, 384–398.CrossRefGoogle Scholar
  156. Thomas N. S., Sharp A. J., Browne C. E., Skuse D., Hardie C., and Dennis N. R. (1999) Xp deletions associated with autism in three females. Hum. Genet. 104, 43–48.PubMedCrossRefGoogle Scholar
  157. Tuchman R. F. and Rapin I. (1997) Regression in pervasive developmental disorders: seizures and epileptiform electroencephalogram correlates. Pediatrics 99, 560–566.PubMedCrossRefGoogle Scholar
  158. Veenstra-VanderWeele J., Gonen D., Leventhal B. L., and Cook E. H., Jr. (1999) Mutation screening of the UBE3A / E6-AP gene in autistic disorder. Mol. Psychiatry 4, 64–67.PubMedCrossRefGoogle Scholar
  159. Venter J. C., Adams M. D., Myers E. W., Li P. W., Mural R. J., Sutton G. G., et al. (2001) The sequence of the human genome. Science 291, 1304–1351.PubMedCrossRefGoogle Scholar
  160. Verkerk A. J., Pieretti M., Sutcliffe J. S., Fu Y. H., Kuhl D. P., Pizzuti A., et al. (1991) Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905–914.PubMedCrossRefGoogle Scholar
  161. Vincent J. B., Herbrick J. A., Gurling H. M., Bolton P. F., Roberts W., and Scherer S. W. (2000) Identification of a novel gene on chromosome 7q31 that is interrupted by a translocation breakpoint in an autistic individual. Am. J. Hum. Genet. 67, 510–514.PubMedCrossRefGoogle Scholar
  162. Volkmar F. R. and Nelson D. S. (1990) Seizure disorders in autism. J. Am. Acad. Child. Adolesc. Psychiatry 29, 127–129.PubMedCrossRefGoogle Scholar
  163. Vourc’h P., Bienvenu T., Beldjord C., Chelly J., Barthelemy C., Muh J. P., and Andres C. (2001) No mutations in the coding region of the Rett syndrome gene MECP2 in 59 autistic patients. Eur. J. Hum. Genet. 9, 556–558.PubMedCrossRefGoogle Scholar
  164. Wakefield A. J., Murch S. H., Anthony A., Linnell J., Casson D. M., Malik M., et al. (1998) Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 351, 637–641.PubMedCrossRefGoogle Scholar
  165. Warburton P., Baird G., Chen W., Morris K., Jacobs B. W., Hodgson S., and Docherty Z. (2000) Support for linkage of autism and specific language impairment to 7q3 from two chromosome rearrangements involving band 7q31. Am. J. Med. Genet. 96, 228–234.PubMedCrossRefGoogle Scholar
  166. Wassink T. H., Piven J., and Patil S. R. (2001a) Chromosomal abnormalities in a clinic sample of individuals with autistic disorder. Psychiatry Genet. 11, 57–63.CrossRefGoogle Scholar
  167. Wassink T. H., Piven J., Vieland V. J., Huang J., Swiderski R. E., Pietila J., et al. (2001b) Evidence supporting WNT2 as an autism susceptibility gene. Am. J. Med. Genet. 105, 406–413.PubMedCrossRefGoogle Scholar
  168. Williams P. G. and Hersh J. H. (1998) Brief report: the association of neurofibromatosis type 1 and autism. J. Autism Dev. Disord. 28, 567–571.PubMedCrossRefGoogle Scholar
  169. Wolpert C. M., Menold M. M., Bass M. P., Qumsiyeh M. B., Donnelly S. L., Ravan S. A., et al. (2000) Three probands with autistic disorder and isodicentric chromosome 15. Am. J. Med. Genet. 96, 365–372.PubMedCrossRefGoogle Scholar
  170. Xu J., Meyers D. A., Ober C., Blumenthal M. N., Mellen B., Barnes K. C., et al. (2001) Genomewide screen and identification of gene-gene interactions for asthma-susceptibility loci in three U.S. populations: collaborative study on the genetics of asthma. Am. J. Hum. Genet. 68, 1437–1446.PubMedCrossRefGoogle Scholar
  171. Zavattari P., Deidda E., Whalen M., Lampis R., Mulargia A., Loddo M., et al. (2000) Major factors influencing linkage disequilibrium by analysis of different chromosome regions in distinct populations: demography, chromosome recombination frequency and selection. Hum. Mol. Genet. 9, 2947–2957.PubMedCrossRefGoogle Scholar
  172. Zhang H., Zhang C., Robitaille S., Grayson D. R., Guidotti A. R., Macciardi F., and Leggo J. (2000) The Reln gene as a candidate locus for autism spectrum disorders. Paper presented at American Society for Human Genetics, Philadelphia, PA.Google Scholar
  173. Zhong N., Ye L., Ju W., Brown W. T., Tsiouris J., and Cohen I. (1999) 5-HTTLPR variants not associated with autistic spectrum disorders. Neurogenetics 2, 129–131.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2002

Authors and Affiliations

  • Janine A. Lamb
    • 1
  • Jeremy R. Parr
    • 2
  • Anthony J. Bailey
    • 2
  • Anthony P. Monaco
    • 1
  1. 1.Wellcome Trust Centre for Human GeneticsHeadington, OxfordUK
  2. 2.Centre for Social, Genetic and Developmental Psychiatry and Department of Child and Adolescent PsychiatryInstitute of PsychiatryLondonUK

Personalised recommendations