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.

Evidence for linkage on 21q and 7q in a subset of autism characterized by developmental regression

Abstract

Autism is a pervasive developmental disorder with a strong genetic component. While candidate regions of the genome have been identified, location of genes conferring susceptibility to autism has been hindered by the heterogeneity within this clinically defined disorder, and the likely contribution of many genes of weak effect. Subsetting samples on the basis of distinct, nondiagnostic clinical features has been recommended to decrease sample heterogeneity. In this study, linkage analysis was performed on a subset of families in the database of the Autism Genetic Resource Exchange (AGRE). This set of autism-affected relative pairs (n=34) was also concordant for a history of developmental regression as measured by the Autism Diagnostic Interview—Revised (ADI-R). In this sample, a maximum multipoint LOD score of 3.4 under the dominant mode of inheritance and an NPL score of 3.0 (P=1.3 × 10−3) were observed on chromosome 21 near D21S1437. On chromosome 7 near D7S483 a LOD score of 2.0 under the dominant mode of inheritance and an NPL score of 3.7 (P=7.9 × 10−5) were observed. Genetic elements in these regions of 21q and 7q are likely to confer susceptibility to autism or modify the disease presentation in a subgroup of children characterized by a history of developmental regression.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 3
Figure 4

References

  1. American Psychiatric Associaiton. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Association: Washington, DC, 2000.

  2. Folstein SE, Rosen-Sheidley B . Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet 2001; 2: 943–955.

    Article  CAS  PubMed  Google Scholar 

  3. Lamb JA, Moore J, Bailey A, Monaco AP . Autism: recent molecular genetic advances. Hum Mol Genet 2000; 9: 861–868.

    Article  CAS  PubMed  Google Scholar 

  4. Auranen M, Vanhala R, Varilo T, Ayers K, Kempas E, Ylisaukko-Oja T et al. A genomewide screen for autism-spectrum disorders: evidence for a major susceptibility locus on chromosome 3q25–27. Am J Hum Genet 2002; 71: 777–790.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Gutknecht L . Full-genome scans with autistic disorder: a review. Behav Genet 2001; 31: 113–123.

    Article  CAS  PubMed  Google Scholar 

  6. IMGSAC, T.I.M.G.S.o.A.C. A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet 2001; 69: 570–581.

  7. Liu J, Nyholt DR, Magnussen P, Parano E, Pavone P, Geschwind D et al. A genomewide screen for autism susceptibility loci. Am J Hum Genet 2001; 69: 327–340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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 

  9. 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 

  10. Yonan AL, Alarcon M, Cheng R, Magnusson PK, Spence SJ, Palmer AA et al. A genomewide screen of 345 families for autism-susceptibility loci. Am J Hum Genet 2003; 73: 886–897.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Silverman JM, Smith CJ, Schmeidler J, Hollander E, Lawlor BA, Fitzgerald M et al. Symptom domains in autism and related conditions: evidence for familiality. Am J Med Genet 2002; 114: 64–73.

    Article  PubMed  Google Scholar 

  12. Lord C, Pickles A, McLennan J, Rutter M, Bregman J, Folstein S et al. Diagnosing autism: analyses of data from the Autism Diagnostic Interview. J Autism Dev Disord 1997; 27: 501–517.

    Article  CAS  PubMed  Google Scholar 

  13. Lord C, Risi S, Lambrecht L, Cook Jr EH, Leventhal BL, DiLavore PC et al. The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord 2000; 30: 205–223.

    Article  CAS  PubMed  Google Scholar 

  14. Shao Y, Raiford KL, Wolpert CM, Cope HA, Ravan SA, Ashley-Koch AA et al. Phenotypic homogeneity provides increased support for linkage on chromosome 2 in autistic disorder. Am J Hum Genet 2002; 70: 1058–1061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Buxbaum JD, Silverman J, Keddache M, Smith CJ, Hollander E, Ramoz N et al. 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 2004; 9: 144–150.

    Article  CAS  PubMed  Google Scholar 

  16. Molloy C, Morrow A, Meinzen-Derr J, Dawson G, Bernier R, Dunn M et al. Familial autoimmune thyroid disease as a risk factor for regression in children with autism spectrum disorder: A CPEA study. J Aut Dev Disord 2005, in press.

  17. Goldberg W, Osann K, Filipek P, Laulhere T, Jarvis K, Modahl C et al. Language and other regression: assessment and timing. J Aut Dev Disord 2003; 33: 607–616.

    Article  Google Scholar 

  18. Lord C, Shulman C, DiLavore P . Regression and word loss in autistic spectrum disorders. J Child Psychol Psychiatry 2004; 45: 936–955.

    Article  PubMed  Google Scholar 

  19. Burack JA, Volkmar FR . Development of low- and high-functioning autistic children. J Child Psychol Psychiatry 1992; 33: 607–616.

    Article  CAS  PubMed  Google Scholar 

  20. Kobayashi R, Murata T . Setback phenomenon in autism and long-term prognosis. Acta Psychiatr Scand 1998; 98: 296–303.

    Article  CAS  PubMed  Google Scholar 

  21. Brown J, Prelock PA . Brief report: the impact of regression on language development in autism. J Autism Dev Disord 1995; 25: 305–309.

    Article  CAS  PubMed  Google Scholar 

  22. Siperstein R, Volkmar F . Parental reporting of regression in autism. J Aut Dev Disord 2004; 34: 731–734.

    Article  Google Scholar 

  23. Geschwind DH, Sowinski J, Lord C, Iversen P, Shestack J, Jones P et al. The autism genetic resource exchange: a resource for the study of autism and related neuropsychiatric conditions. Am J Hum Genet 2001; 69: 463–466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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 

  25. Greenberg DA, Abreu P, Hodge SE . The power to detect linkage in complex disease by means of simple LOD-score analyses. Am J Hum Genet 1998; 63: 870–879.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sham P . Statistics in Human Genetics. John Wiley & Sons: New York, 1998.

    Google Scholar 

  27. Broman KW, Murray JC, Sheffield VC, White RL, Weber JL . Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am J Hum Genet 1998; 63: 861–869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Terwilliger JD, Speer M, Ott J . Chromosome-based method for rapid computer simulation in human genetic linkage analysis. Genet Epidemiol 1993; 10: 217–224.

    Article  CAS  PubMed  Google Scholar 

  29. Terwilliger JD, Ott J . Handbook of Human Genetic Linkage. Johns Hopkins University Press: Baltimore, 1994.

    Google Scholar 

  30. Abreu PC, Greenberg DA, Hodge SE . Direct power comparisons between simple LOD scores and NPL scores for linkage analysis in complex diseases. Am J Hum Genet 1999; 65: 847–857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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 

  32. Shao Y, Wolpert CM, Raiford KL, Menold MM, Donnelly SL, Ravan SA et al. Genomic screen and follow-up analysis for autistic disorder. Am J Med Genet 2002; 114: 99–105.

    Article  PubMed  Google Scholar 

  33. Tomko RP, Johansson CB, Totrov M, Abagyan R, Frisen J, Philipson L . Expression of the adenovirus receptor and its interaction with the fiber knob. Exp Cell Res 2000; 255: 47–55.

    Article  CAS  PubMed  Google Scholar 

  34. Yoshida Y, Matsuda S, Ikematsu N, Kawamura-Tsuzuku J, Inazawa J, Umemori H et al. ANA, a novel member of Tob/BTG1 family, is expressed in the ventricular zone of the developing central nervous system. Oncogene 1998; 16: 2687–2693.

    Article  CAS  PubMed  Google Scholar 

  35. Guehenneux F, Duret L, Callanan MB, Bouhas R, Hayette S, Berthet C et al. Cloning of the mouse BTG3 gene and definition of a new gene family (the BTG family) involved in the negative control of the cell cycle. Leukemia 1997; 11: 370–375.

    Article  CAS  PubMed  Google Scholar 

  36. Corrente G, Guardavaccaro D, Tirone F . PC3 potentiates NGF-induced differentiation and protects neurons from apoptosis. Neuroreport 2002; 13: 417–422.

    Article  CAS  PubMed  Google Scholar 

  37. Fatemi S, Stary JM, Halt AR, Realmuto GR . Dysregulation of Reelin and Bcl-2 proteins in autistic cerebellum. J Autism Dev Disord 2001; 31: 529–535.

    Article  CAS  PubMed  Google Scholar 

  38. Araghi-Niknam M, Fatemi SH . Levels of Bcl-2 and P53 are altered in superior frontal and cerebellar cortices of autistic subjects. Cell Mol Neurobiol 2003; 23: 945–952.

    Article  CAS  PubMed  Google Scholar 

  39. Levitt P, Eagleson KL, Powell EM . Regulation of neocortical interneuron development and the implications for neurodevelopmental disorders. Trends Neurosci 2004; 27: 400–406.

    Article  CAS  PubMed  Google Scholar 

  40. James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr 2004; 80: 1611–1617.

    Article  CAS  PubMed  Google Scholar 

  41. Chauhan A, Chauhan V, Brown WT, Cohen I . Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin—the antioxidant proteins. Life Sci 2004; 75: 2539–2549.

    Article  CAS  PubMed  Google Scholar 

  42. Bergelson JM . Receptors mediating adenovirus attachment and internalization. Biochem Pharmacol 1999; 57: 975–979.

    Article  CAS  PubMed  Google Scholar 

  43. Chess S . Follow-up report on autism in congenital rubella. J Autism Child Schizophr 1977; 7: 69–81.

    Article  CAS  PubMed  Google Scholar 

  44. Shi L, Fatemi SH, Sidwell RW, Patterson PH . Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci 2003; 23: 297–302.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Fatemi SH, Earle J, Kanodia R, Kist D, Emamian ES, Patterson PH et al. Prenatal viral infection leads to pyramidal cell atrophy and macrocephaly in adulthood: implications for genesis of autism and schizophrenia. Cell Mol Neurobiol 2002; 22: 25–33.

    Article  PubMed  Google Scholar 

  46. Alenius M, Bohm S . Identification of a novel neural cell adhesion molecule-related gene with a potential role in selective axonal projection. J Biol Chem 1997; 272: 26083–26086.

    Article  CAS  PubMed  Google Scholar 

  47. Paoloni-Giacobino A, Chen H, Antonarakis SE . Cloning of a novel human neural cell adhesion molecule gene (NCAM2) that maps to chromosome region 21q21 and is potentially involved in Down syndrome. Genomics 1997; 43: 43–51.

    Article  CAS  PubMed  Google Scholar 

  48. Bailey A, Luthert P, Dean A, Harding B, Janota I, Montgomery M et al. A clinicopathological study of autism. Brain 1998; 121 (Part 5): 889–905.

    Article  PubMed  Google Scholar 

  49. Storey JD, Tibshirani R . Statistical significance for genomewide studies. Proc Natl Acad Sci USA 2003; 100: 9440–9445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kent L, Evans J, Paul M, Sharp M . Comorbidity of autistic spectrum disorders in children with Down syndrome. Dev Med Child Neurol 1999; 41: 153–158.

    Article  CAS  PubMed  Google Scholar 

  51. Hickey FJ, Patterson B . Occurrence of language regression and EEG abnormalities in children with Down syndrome and autism spectrum disorder. Presented at the International Meeting for Autism Research, May 5–7, 2005, Boston.

Download references

Acknowledgements

We acknowledge support from the Autism Genetic Resource Exchange (AGRE) and Cure Autism Now. We gratefully acknowledge the resources provided by the AGRE consortium and the participating AGRE families. The Autism Genetic Resource Exchange (AGRE) is a program of Cure Autism Now and is supported, in part, by grant MH64547 from the National Institute of Mental Health to Daniel H Geschuind (PI). We gratefully acknowledge the thoughtful review of this manuscript by Ardythe L Morrow, PhD and the contribution of Li Jin, PhD in the preliminary discussion of these analyses.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to C A Molloy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Molloy, C., Keddache, M. & Martin, L. Evidence for linkage on 21q and 7q in a subset of autism characterized by developmental regression. Mol Psychiatry 10, 741–746 (2005). https://doi.org/10.1038/sj.mp.4001691

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001691

Keywords

This article is cited by

Search

Quick links