Genetic advances in autism: heterogeneity and convergence on shared pathways

Current Opinion in Genetics and Development

Volumn 19, Issue 3, 2009, Pages 271-278

  Bill, Brent R ^a   Geschwind, Daniel H ^a,b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

FRAGILE X MENTAL RETARDATION PROTEIN; NEUREXIN; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN KINASE B; SCATTER FACTOR; TUBERIN;

ASPERGER SYNDROME; AUTISM; BEHAVIOR GENETICS; CHROMOSOME ABERRATION; CHROMOSOME VARIANT; GENE DELETION; GENE LOCUS; GENETIC ASSOCIATION; GENETIC EPISTASIS; GENETIC SUSCEPTIBILITY; GENETIC VARIABILITY; HUMAN; MACROCEPHALY; PATHOGENESIS; PHENOTYPE; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; SOCIAL INTERACTION; TUBEROUS SCLEROSIS;

AUTISTIC DISORDER; EPIGENESIS, GENETIC; GENE REGULATORY NETWORKS; GENETIC HETEROGENEITY; GENETIC PREDISPOSITION TO DISEASE; HUMANS; MODELS, GENETIC; SIGNAL TRANSDUCTION;

EID: 67651010456     PISSN: 0959437X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.gde.2009.04.004     Document Type: Review

References (49)

1. Association A.P. Diagnostic and Statistical Manual of Mental Disorders. edn 4 (1994), American Psychiatric Association, Washington, DC
2. Ronald A., Happe F., Bolton P., Butcher L.M., Price T.S., Wheelwright S., Baron-Cohen S., and Plomin R. Genetic heterogeneity between the three components of the autism spectrum: a twin study. J Am Acad Child Adolesc Psychiatry 45 (2006) 691-699. This study demonstrates independent inheritance, with up to 90% heritability, of the three core deficits of ASD in both typically and atypically developing twins.
3. Lauritsen M.B., Pedersen C.B., and Mortensen P.B. The incidence and prevalence of pervasive developmental disorders: a Danish population-based study. Psychol Med 34 (2004) 1339-1346
4. Prevalence of autism spectrum disorders - autism and developmental disabilities monitoring network, 14 sites, United States, 2002. MMWR Surveill Summ 56 (2007) 12-28
5. 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 (1998) 571-578
6. Szatmari P., Paterson A.D., Zwaigenbaum L., Roberts W., Brian J., Liu X.Q., Vincent J.B., Skaug J.L., Thompson A.P., Senman L., et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 39 (2007) 319-328. The Autism Genome Project Consortium performed SNP and CNV analysis of 1181 families, the largest analysis of its kind for ASD, demonstrating a suggestive linkage peak on chromosome 11p12-13 for all families and CNVs within autism susceptibility candidate loci.
7. Geschwind D.H., Sowinski J., Lord C., Iversen P., Shestack J., Jones P., Ducat L., and Spence S.J. The autism genetic resource exchange: a resource for the study of autism and related neuropsychiatric conditions. Am J Hum Genet 69 (2001) 463-466
8. A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. International Molecular Genetic Study of Autism Consortium. Am J Hum Genet 69 (2001) 570-581
9. Stone J.L., Merriman B., Cantor R.M., Yonan A.L., Gilliam T.C., Geschwind D.H., and Nelson S.F. Evidence for sex-specific risk alleles in autism spectrum disorder. Am J Hum Genet 75 (2004) 1117-1123
10. Cantor R.M., Kono N., Duvall J.A., Alvarez-Retuerto A., Stone J.L., Alarcon M., Nelson S.F., and Geschwind D.H. Replication of autism linkage: fine-mapping peak at 17q21. Am J Hum Genet 76 (2005) 1050-1056
11. Yonan A.L., Alarcon M., Cheng R., Magnusson P.K., Spence S.J., Palmer A.A., Grunn A., Juo S.H., Terwilliger J.D., Liu J., et al. A genomewide screen of 345 families for autism-susceptibility loci. Am J Hum Genet 73 (2003) 886-897
12. Abrahams B.S., and Geschwind D.H. Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 9 (2008) 341-355
13. Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS, Salyakina D, Imielinski M, Bradfield JP, Sleiman PM, et al: Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 2009, doi:10.1038/nature07999. This is the first significant genome-wide association study for ASD with replication. It implicates a much more important role for cell adhesion molecule polymorphisms in ASD.
14. Lord C., Rutter M., Goode S., Heemsbergen J., Jordan H., Mawhood L., and Schopler E. Autism diagnostic observation schedule: a standardized observation of communicative and social behavior. J Autism Dev Disord 19 (1989) 185-212
15. Lord C., Rutter M., and 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 24 (1994) 659-685
16. Alarcon M., Yonan A.L., Gilliam T.C., Cantor R.M., and Geschwind D.H. Quantitative genome scan and Ordered-Subsets Analysis of autism endophenotypes support language QTLs. Mol Psychiatry 10 (2005) 747-757
17. Gottesman I.I., and Gould T.D. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160 (2003) 636-645
18. Liu X.Q., Paterson A.D., and Szatmari P. Genome-wide linkage analyses of quantitative and categorical autism subphenotypes. Biol Psychiatry 64 (2008) 561-570
19. Duvall J.A., Lu A., Cantor R.M., Todd R.D., Constantino J.N., and Geschwind D.H. A quantitative trait locus analysis of social responsiveness in multiplex autism families. Am J Psychiatry 164 (2007) 656-662
20. Alarcon M., Cantor R.M., Liu J., Gilliam T.C., and Geschwind D.H. Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families. Am J Hum Genet 70 (2002) 60-71
21. Alarcon M., Abrahams B.S., Stone J.L., Duvall J.A., Perederiy J.V., Bomar J.M., Sebat J., Wigler M., Martin C.L., Ledbetter D.H., et al. Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet 82 (2008) 150-159. This study associates CNTNAP2, a gene expressed within the language circuit of the brain, with a language endophenotype in ASD trios.
22. Strauss K.A., Puffenberger E.G., Huentelman M.J., Gottlieb S., Dobrin S.E., Parod J.M., Stephan D.A., and Morton D.H. Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med 354 (2006) 1370-1377
23. Vernes S.C., Newbury D.F., Abrahams B.S., Winchester L., Nicod J., Groszer M., Alarcon M., Oliver P.L., Davies K.E., Geschwind D.H., et al. A functional genetic link between distinct developmental language disorders. N Engl J Med 359 (2008) 2337-2345. This study identifies CNTNAP2 as part of a genetic pathway for language, by demonstrating regulation by FOXP2 and genetic association with Specific Language Impairment.
24. Sebat J., Lakshmi B., Malhotra D., Troge J., Lese-Martin C., Walsh T., Yamrom B., Yoon S., Krasnitz A., Kendall J., et al. Strong association of de novo copy number mutations with autism. Science 316 (2007) 445-449. Utilizing ROMA-mediated comparative genomic hybridization, they performed a large-scale screen for chromosomal structural variants for 264 families. This paper is the first one to identify CNVs as a major contributor to the etiology of ASD.
25. Marshall C.R., Noor A., Vincent J.B., Lionel A.C., Feuk L., Skaug J., Shago M., Moessner R., Pinto D., Ren Y., et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82 (2008) 477-488
26. Morrow E.M., Yoo S.Y., Flavell S.W., Kim T.K., Lin Y., Hill R.S., Mukaddes N.M., Balkhy S., Gascon G., Hashmi A., et al. Identifying autism loci and genes by tracing recent shared ancestry. Science 321 (2008) 218-223. This study demonstrates that ASD can be caused by a heterogeneous set of rare private mutations utilizing homozygosity mapping.
27. Weiss L.A., Shen Y., Korn J.M., Arking D.E., Miller D.T., Fossdal R., Saemundsen E., Stefansson H., Ferreira M.A., Green T., et al. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 358 (2008) 667-675
28. Kumar R.A., KaraMohamed S., Sudi J., Conrad D.F., Brune C., Badner J.A., Gilliam T.C., Nowak N.J., Cook Jr. E.H., Dobyns W.B., et al. Recurrent 16p11.2 microdeletions in autism. Hum Mol Genet 17 (2008) 628-638
29. Durand C.M., Betancur C., Boeckers T.M., Bockmann J., Chaste P., Fauchereau F., Nygren G., Rastam M., Gillberg I.C., Anckarsater H., et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 39 (2007) 25-27
30. Veltman M.W., Craig E.E., and Bolton P.F. Autism spectrum disorders in Prader-Willi and Angelman syndromes: a systematic review. Psychiatr Genet 15 (2005) 243-254
31. Croen L.A., Najjar D.V., Fireman B., and Grether J.K. Maternal and paternal age and risk of autism spectrum disorders. Arch Pediatr Adolesc Med 161 (2007) 334-340
32. Lupski J.R. Genomic rearrangements and sporadic disease. Nat Genet 39 (2007) S43-47
33. Iossifov I., Zheng T., Baron M., Gilliam T.C., and Rzhetsky A. Genetic-linkage mapping of complex hereditary disorders to a whole-genome molecular-interaction network. Genome Res 18 (2008) 1150-1162. Utilizing a unique computational approach to overlay interaction analysis and linkage analysis, this paper identifies 24 new autism susceptibility candidate genes in silica. Duplicating this analysis for bipolar and schizophrenic populations, they demonstrate a large overlap in the candidate genes between the three disorders blurring the lines between neurodevelopmental and psychiatric disorders.
34. Campbell D.B., Sutcliffe J.S., Ebert P.J., Militerni R., Bravaccio C., Trillo S., Elia M., Schneider C., Melmed R., Sacco R., et al. A genetic variant that disrupts MET transcription is associated with autism. Proc Natl Acad Sci U S A 103 (2006) 16834-16839. Identifies an association between the C allele of the MET promoter with ASD based on a candidate gene approach.
35. Campbell D.B., Li C., Sutcliffe J.S., Persico A.M., and Levitt P. Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder. Autism Res 1 (2008) 159-168
36. Nishimura Y., Martin C.L., Vazquez-Lopez A., Spence S.J., Alvarez-Retuerto A.I., Sigman M., Steindler C., Pellegrini S., Schanen N.C., Warren S.T., et al. Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways. Hum Mol Genet 16 (2007) 1682-1698
37. Lintas C., Sacco R., Garbett K., Mirnics K., Militerni R., Bravaccio C., Curatolo P., Manzi B., Schneider C., Melmed R., et al. Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression. Mol Psychiatry (2008) doi:10.1038/mp.2008.21, available online
38. Fombonne E. The epidemiology of autism: a review. Psychol Med 29 (1999) 769-786
39. Knickmeyer R.C., and Baron-Cohen S. Fetal testosterone and sex differences in typical social development and in autism. J Child Neurol 21 (2006) 825-845
40. Limperopoulos C., Bassan H., Sullivan N.R., Soul J.S., Robertson Jr. R.L., Moore M., Ringer S.A., Volpe J.J., and du Plessis A.J. Positive screening for autism in ex-preterm infants: prevalence and risk factors. Pediatrics 121 (2008) 758-765
41. Vargas D.L., Nascimbene C., Krishnan C., Zimmerman A.W., and Pardo C.A. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 57 (2005) 67-81
42. Herbert M.R., Russo J.P., Yang S., Roohi J., Blaxill M., Kahler S.G., Cremer L., and Hatchwell E. Autism and environmental genomics. Neurotoxicology 27 (2006) 671-684
43. Geschwind D.H. Autism: many genes, common pathways?. Cell 135 (2008) 391-395
44. Geschwind D.H., and Levitt P. Autism spectrum disorders: developmental disconnection syndromes. Curr Opin Neurobiol 17 (2007) 103-111
45. Courchesne E., Pierce K., Schumann C.M., Redcay E., Buckwalter J.A., Kennedy D.P., and Morgan J. Mapping early brain development in autism. Neuron 56 (2007) 399-413
46. Chiu S., Wegelin J.A., Blank J., Jenkins M., Day J., Hessl D., Tassone F., and Hagerman R. Early acceleration of head circumference in children with fragile x syndrome and autism. J Dev Behav Pediatr 28 (2007) 31-35
47. Butler M.G., Dasouki M.J., Zhou X.P., Talebizadeh Z., Brown M., Takahashi T.N., Miles J.H., Wang C.H., Stratton R., Pilarski R., et al. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet 42 (2005) 318-321
48. Sudhof T.C. Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455 (2008) 903-911
49. Ferland R.J., Eyaid W., Collura R.V., Tully L.D., Hill R.S., Al-Nouri D., Al-Rumayyan A., Topcu M., Gascon G., Bodell A., et al. Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat Genet 36 (2004) 1008-1013