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Autism: the quest for the genes

  • Nuala H. Sykes (a1) and Janine A. Lamb (a2)

Autism, at its most extreme, is a severe neurodevelopmental disorder, and recent studies have indicated that autism spectrum disorders are considerably more common than previously supposed. However, although one of the most heritable neuropsychiatric syndromes, autism has so far eluded attempts to discover its genetic origins in the majority of cases. Several whole-genome scans for autism-susceptibility loci have identified specific chromosomal regions, but the results have been inconclusive and fine mapping and association studies have failed to identify the underlying genes. Recent advances in knowledge from the Human Genome and HapMap Projects, and progress in technology and bioinformatic resources, have aided study design and made data generation more efficient and cost-effective. Broadening horizons about the landscape of structural genetic variation and the field of epigenetics are indicating new possible mechanisms underlying autism aetiology, while endophenotypes are being used in an attempt to break down the complexity of the syndrome and refine genetic data. Although the genetic variants underlying idiopathic autism have proven elusive so far, the future for this field looks promising.

Corresponding author
*Corresponding author: Janine A. Lamb, Centre for Integrated Genomic Medical Research (CIGMR), Stopford Building, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK. Tel: +44 (0)161 275 1619; Fax: +44 (0)161 275 1617; E-mail:
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3 K. Jarbrink and M. Knapp (2001) The economic impact of autism in Britain. Autism 5, 7-22

4 G. Baird (2006) Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: the Special Needs and Autism Project (SNAP). Lancet 368, 210-215

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

8 S. Folstein and M. Rutter (1977) Infantile autism: a genetic study of 21 twin pairs. J Child Psychol Psychiatry 18, 297-321

10 S. Steffenburg (1989) A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry 30, 405-416

12 M. Rutter (1999) Genetics and child psychiatry: II Empirical research findings. J Child Psychol Psychiatry 40, 19-55

14 N. Risch (1999) A genomic screen of autism: evidence for a multilocus etiology. Am J Hum Genet 65, 493-507

16 N. Juul-Dam , J. Townsend and E. Courchesne (2001) Prenatal, perinatal, and neonatal factors in autism, pervasive developmental disorder-not otherwise specified, and the general population. Pediatrics 107, E63

17 K. Miyazaki , N. Narita and M. Narita (2005) Maternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring: implication for pathogenesis of autism. Int J Dev Neurosci 23, 287-297

18 K. Stromland (1994) Autism in thalidomide embryopathy: a population study. Dev Med Child Neurol 36, 351-356

19 P.H. Patterson (2002) Maternal infection: window on neuroimmune interactions in fetal brain development and mental illness. Curr Opin Neurobiol 12, 115-118

20 L. Smeeth (2004) MMR vaccination and pervasive developmental disorders: a case-control study. Lancet 364, 963-969

21 T. Uchiyama , M. Kurosawa and Y. Inaba (2007) MMR-vaccine and regression in autism spectrum disorders: negative results presented from Japan. J Autism Dev Disord 37, 210-217

22International Molecular Genetic Study of Autism Consortium (IMGSAC) (2001) A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet 69, 570-581

23International Molecular Genetic Study of Autism Consortium (IMGSAC) (1998) 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 7, 571-578

24 J.A. Lamb (2005) Analysis of IMGSAC autism susceptibility loci: evidence for sex limited and parent of origin specific effects. J Med Genet 42, 132-137

26 A. Philippe (1999) Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study. Hum Mol Genet 8, 805-812

27 J.D. Buxbaum (2001) Evidence for a susceptibility gene for autism on chromosome 2 and for ge netic heterogeneity. Am J Hum Genet 68, 1514-1520

28 J. Liu (2001) A genomewide screen for autism susceptibility loci. Am J Hum Genet 69, 327-340

29 A.L. Yonan (2003) A genomewide screen of 345 families for autism-susceptibility loci. Am J Hum Genet 73, 886-897

30 J.D. Buxbaum (2004) Linkage analysis for autism in a subset families with obsessive-compulsive behaviors: evidence for an autism susceptibility gene on chromosome 1 and further support for susceptibility genes on chromosome 6 and 19. Mol Psychiatry 9, 144-150

31 Y. Shao (2002) Genomic screen and follow-up analysis for autistic disorder. Am J Med Genet 114, 99-105

32 M. Auranen (2002) A genomewide screen for autism-spectrum disorders: evidence for a major susceptibility locus on chromosome 3q25-27. Am J Hum Genet 71, 777-790

33 R.M. Cantor (2005) Replication of autism linkage: fine-mapping peak at 17q21. Am J Hum Genet 76, 1050-1056

34 G.D. Schellenberg (2006) Evidence for multiple loci from a genome scan of autism kindreds. Mol Psychiatry 11, 1049–60, 979

35 J.L. McCauley (2005) Genome-wide and Ordered-Subset linkage analyses provide support for autism loci on 17q and 19p with evidence of phenotypic and interlocus genetic correlates. BMC Med Genet 6, 1

37 Y. Shao (2002) Phenotypic homogeneity provides increased support for linkage on chromosome 2 in autistic disorder. Am J Hum Genet 70, 1058-1061

38 J.A. Badner and E.S. Gershon (2002) Regional meta-analysis of published data supports linkage of autism with markers on chromosome 7. Mol Psychiatry 7, 56-66

40 T.A. Trikalinos (2006) A heterogeneity-based genome search meta-analysis for autism-spectrum disorders. Mol Psychiatry 11, 29-36

41 J.L. Stone (2004) Evidence for sex-specific risk alleles in autism spectrum disorder. Am J Hum Genet 75, 1117-1123

42 E.H. Cook and B.L. Leventhal (1996) The serotonin system in autism. Curr Opin Pediatr 8, 348-354

43 K.S. Lam , M.G. Aman and L.E. Arnold (2006) Neurochemical correlates of autistic disorder: a review of the literature. Res Dev Disabil 27, 254-289

44The Autism Genome Project (AGP) Consortium (2007) Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 39, 319-328

45 C.W. Bartlett and V.J. Vieland (2007) Accumulating quantitative trait linkage evidence across multiple datasets using the posterior probability of linkage. Genet Epidemiol 31, 91-102

46 V.J. Vieland , K. Wang and J. Huang (2001) Power to detect linkage based on multiple sets of data in the presence of locus heterogeneity: comparative evaluation of model-based linkage methods for affected sib pair data. Hum Hered 51, 199-208

47 C.S. Carlson (2004) Mapping complex disease loci in whole-genome association studies. Nature 429, 446-452

49 N. Ramoz (2004) Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism. Am J Psychiatry 161, 662-669

50 R. Segurado (2005) Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31. Am J Psychiatry 162, 2182-2184

52 R. Rabionet (2006) Lack of association between autism and SLC25A12. Am J Psychiatry 163, 929-931

53 A.M. Persico (2001) Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol Psychiatry 6, 150-159

54 D.A. Skaar (2005) Analysis of the RELN gene as a genetic risk factor for autism. Mol Psychiatry 10, 563-571

56 E. Bonora (2003) Analysis of reelin as a candidate gene for autism. Mol Psychiatry 8, 885-892

58 M.O. Krebs (2002) Absence of association between a polymorphic GGC repeat in the 5 untranslated region of the reelin gene and autism. Mol Psychiatry 7, 801-804

59 H. Zhang (2002) Reelin gene alleles and susceptibility to autism spectrum disorders. Mol Psychiatry 7, 1012-1017

60 A.M. Persico , P. Levitt and A.F. Pimenta (2006) Polymorphic GGC repeat differentially regulates human reelin gene expression levels. J Neural Transm 113, 1373-1382

61 S.H. Fatemi (2005) Reelin signaling is impaired in autism. Biol Psychiatry 57, 777-787

64 J. Conroy (2004) Serotonin transporter gene and autism: a haplotype analysis in an Irish autistic population. Mol Psychiatry 9, 587-593

65 B. Devlin (2005) Autism and the serotonin transporter: the long and short of it. Mol Psychiatry 10, 1110-1116

66 S.M. Klauck (1997) Serotonin transporter (5-HTT) gene variants associated with autism? Hum Mol Genet 6, 2233-2238

67 N. Yirmiya (2001) Evidence for an association with the serotonin transporter promoter region polymorphism and autism. Am J Med Genet 105, 381-386

68 E. Maestrini (1999) Serotonin transporter (5-HTT) and gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families. The International Molecular Genetic Study of Autism Consortium. Am J Med Genet 88, 492-496

69 A.M. Persico (2000) Lack of association between serotonin transporter gene promoter variants and autistic disorder in two ethnically distinct samples. Am J Med Genet 96, 123-127

70 N. Ramoz (2006) Lack of evidence for association of the serotonin transporter gene SLC6A4 with autism. Biol Psychiatry 60, 186-191

71 N. Zhong (1999) 5-HTTLPR variants not associated with autistic spectrum disorders. Neurogenetics 2, 129-131

72 C.W. Brune (2006) 5-HTTLPR Genotype-Specific Phenotype in Children and Adolescents With Autism. Am J Psychiatry 163, 2148-2156

73 J.S. Sutcliffe (2005) Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. Am J Hum Genet 77, 265-279

74 K.T. Zondervan and L.R. Cardon (2004) The complex interplay among factors that influence allelic association. Nat Rev Genet 5, 89-100

75 T.A. Trikalinos (2004) Establishment of genetic associations for complex diseases is independent of early study findings. Eur J Hum Genet 12, 762-769

76 S. Zollner and J.K. Pritchard (2007) Overcoming the winner's curse: estimating penetrance parameters from case-control data. Am J Hum Genet 80, 605-615

77 S. Jamain (2003) Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 34, 27-29

78 C.M. Durand (2007) Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 39, 25-27

79International Human Genome Sequencing Consortium (2004) Finishing the euchromatic sequence of the human genome. Nature 431, 931-945

80The International HapMap Consortium (2003) The International HapMap Project. Nature 426, 789-796

81 J.B. Fan , M.S. Chee and K.L. Gunderson (2006) Highly parallel genomic assays. Nat Rev Genet 7, 632-644

82 J.A. Todd (2007) Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 39, 857-864

83The Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661-678

84 L. Feuk , A.R. Carson and S.W. Scherer (2006) Structural variation in the human genome. Nat Rev Genet 7, 85-97

85 E.E. Eichler (2007) Completing the map of human genetic variation. Nature 447, 161-165

86 R. Redon (2006) Global variation in copy number in the human genome. Nature 444, 444-454

87 K.K. Wong (2007) A comprehensive analysis of common copy-number variations in the human genome. Am J Hum Genet 80, 91-104

89 S.J. Rogers , S. Hepburn and E. Wehner (2003) Parent reports of sensory symptoms in toddlers with autism and those with other developmental disorders. J Autism Dev Disord 33, 631-642

90 J. Feng (2006) High frequency of neurexin 1beta signal peptide structural variants in patients with autism. Neurosci Lett 409, 10-13

91 J. Sebat (2007) Strong association of de novo copy number mutations with autism. Science 316, 445-449

92 F. Eckhardt (2006) DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet 38, 1378-1385

94 C. Badcock and B. Crespi (2006) Imbalanced genomic imprinting in brain development: an evolutionary basis for the aetiology of autism. J Evol Biol 19, 1007-1032

95 D.H. Skuse (2000) Imprinting, the X-chromosome, and the male brain: explaining sex differences in the liability to autism. Pediatr Res 47, 9-16

97 M. Girard (2001) Parental origin of de novo MECP2 mutations in Rett syndrome. Eur J Hum Genet 9, 231-236

98 R. Trappe (2001) MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin. Am J Hum Genet 68, 1093-1101

99 Y. Nishimura (2007) Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways. Hum Mol Genet 16, 1682-1698

100 M.A. Junaid and R.K. Pullarkat (2001) Proteomic approach for the elucidation of biological defects in autism. J Autism Dev Disord 31, 557-560

103 F. Happe , A. Ronald and R. Plomin (2006) Time to give up on a single explanation for autism. Nat Neurosci 9, 1218-1220

104 M. Alarcon (2002) Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families. Am J Hum Genet 70, 60-71

107 M.G. Butler (2005) Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet 42, 318-321

S. Baron-Cohen (2006) The hyper-systemizing, assortative mating theory of autism. Prog Neuropsychopharmacol Biol Psychiatry 30, 865-872

V.K. Rakyan and S. Beck (2006) Epigenetic variation and inheritance in mammals. Curr Opin Genet Dev 16, 573-577

L.J. Palmer and L.R. Cardon (2005) Shaking the tree: mapping complex disease genes with linkage disequilibrium. Lancet 366, 1223-1234

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