Hum Hered 2004;57:10–20

Examination of Potential Overlap in Autism and Language Loci on Chromosomes 2, 7, and 13 in Two Independent Samples Ascertained for Specific Language Impairment

Bartlett C.W.a · Flax J.F.a · Logue M.W.b · Smith B.J.d · Vieland V.J.b,c · Tallal P.a · Brzustowicz L.M.a,d,e
aCenter for Molecular and Behavioral Neuroscience, Rutgers University, Newark, N.J.; bProgram in Public Health Genetics, Coll Public Health, and cDepartment of Psychiatry, College of Medicine, University of Iowa, Iowa City, Iowa; dDepartment of Genetics, Rutgers University, and eDepartment of Psychiatry, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, N.J., USA
email Corresponding Author

 goto top of outline Key Words

  • Autism
  • Language impairment
  • Multiple data sets
  • Heterogeneity
  • Linkage analysis

 goto top of outline Abstract

Specific language impairment is a neurodevelopmental disorder characterized by impairments essentially restricted to the domain of language and language learning skills. This contrasts with autism, which is a pervasive developmental disorder defined by multiple impairments in language, social reciprocity, narrow interests and/or repetitive behaviors. Genetic linkage studies and family data suggest that the two disorders may have genetic components in common. Two samples, from Canada and the US, selected for specific language impairment were genotyped at loci where such common genes are likely to reside. Significant evidence for linkage was previously observed at chromosome 13q21 in our Canadian sample (HLOD 3.56) and was confirmed in our US sample (HLOD 2.61). Using the posterior probability of linkage (PPL) to combine evidence for linkage across the two samples yielded a PPL over 92%. Two additional loci on chromosome 2 and 7 showed weak evidence for linkage. However, a marker in the cystic fibrosis transmembrane conductance regulator (7q31) showed evidence for association to SLI, confirming results from another group (O’Brien et al. 2003). Our results indicate that using samples selected for components of the autism phenotype may be a useful adjunct to autism genetics.

Copyright © 2004 S. Karger AG, Basel

 goto top of outline References
  1. Tomblin JB, Records NL, Buckwalter P, Zhang X, Smith E, O’Brien M: Prevalence of specific language impairment in kindergarten children. J Speech Lang Hear Res 1997;40:1245–1260.
  2. Stothard SE, Snowling MJ, Bishop DV, Chipchase BB, Kaplan CA: Language-impaired preschoolers: a follow-up into adolescence. J Speech Lang Hear Res 1998;41:407–418.
  3. Snowling MJ, Adams JW, Bishop DV, Stothard SE: Educational attainments of school leavers with a preschool history of speech-language impairments. Int J Lang Commun Dis 2001;36:173–183.
  4. Snowling M, Bishop DV, Stothard SE: Is preschool language impairment a risk factor for dyslexia in adolescence? Child Psychol Psychiatry Allied Disciplines 2000;41:587–600.
  5. Catts HW, Fey ME, Tomblin JB, Zhang X: A longitudinal investigation of reading outcomes in children with language impairments. J Speech Lang Hear Res 2002;45:1142–1157.
  6. Nasir J, Cohen W, Cowie H, Maclean A, Watson J, Seckl J, O’Hare A: Genetics of specific language impairment. Prostaglandins Leukot Essent Fatty Acids 2000;63:101–107.
  7. Stromswold K: Genetics of spoken language disorders. Hum Biol 1998;70:297–324.
  8. Stromswold K: The cognitive neuroscience of language acquisition; in Gazzaniga M (ed): The new cognitive neurosciences. Cambridge, MA, MIT Press, 2000, pp 909–932.
  9. Stromswold K: The heritability of language: A review and metaanalysis of twin adoption and linkage studies. Language 2001;77:647–723.
  10. The SLI Consortium: A genomewide scan identifies two novel loci involved in specific language impairment. Am J Hum Genet 2002;70:384–398.
  11. Bartlett CW, Flax JF, Logue MW, Vieland VJ, Bassett AS, Tallal P, Brzustowicz LM: A major susceptibility locus for specific language impairment is located on 13q21. Am J Hum Genet 2002;71:45–55.
  12. Fombonne E: The epidemiology of autism: a review. Psychol Med 1999;29:769–786.
  13. Badner JA, Gershon ES: Regional meta-analysis of published data supports linkage of autism with markers on chromosome 7. Mol Psychiatry 2002;7:56–66.
  14. Folstein SE, Rosen-Sheidley B: Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet 2001;2:943–955.
  15. Narayan S, Moyes B, Wolff S: Family characteristics of autistic children: a further report. J Autism Dev Disord 1990;20:523–535.
  16. Landa R, Folstein SE, Isaacs C: Spontaneous narrative-discourse performance of parents of autistic individuals. J Speech Hear Res 1991;34:1339–1345.
  17. Landa R, Piven J, Wzorek MM, Gayle JO, Chase GA, Folstein SE: Social language use in parents of autistic individuals. Psychol Med 1992;22:245–254.
  18. Bailey A, Palferman S, Heavey L, Le Couteur A: Autism: the phenotype in relatives. J Autism Devel Disord 1998;28:369–392.
  19. Szatmari P, MacLean JE, Jones MB, Bryson SE, Zwaigenbaum L, Bartolucci G, Mahoney WJ, Tuff L: The familial aggregation of the lesser variant in biological and nonbiological relatives of PDD probands: a family history study. J Child Psychol Psychiatry 2000;41:579–586.
  20. Pickles A, Starr E, Kazak S, Bolton P, Papanikolaou K, Bailey A, Goodman R, Rutter M: Variable expression of the autism broader phenotype: findings from extended pedigrees. J Child Psychol Psychiatry 2000;41:491–502.

    External Resources

  21. Folstein S, Rutter M: Infantile autism: a genetic study of 21 twin pairs. J Child Psychol Psychiatry Allied Disciplines 1977;18:297–321.
  22. Shriberg LD, Tomblin JB, McSweeny JL: Prevalence of speech delay in 6-year-old children and comorbidity with language impairment. J Speech Lang Hear Res 1999;42:1461–1481.
  23. Fombonne E, Bolton P, Prior J, Jordan H, Rutter M: Family study of autism: Cognitive patterns and levels in parents and siblings. J Child Psychol Psychiatry Allied Disciplines 1997;38:667–683.
  24. Freeman BJ, Ritvo ER, Mason-Brothers A, Pingree C, Yokota A, Jenson WR, McMahon WM, Petersen PB, Mo A, Schroth P: Psychometric assessment of first-degree relatives of 62 autistic probands in Utah. Am J Psychiatry 1989;146:361–364.
  25. Szatmari P, Jones MB, Tuff L, Bartolucci G, Fisman S, Mahoney W: Lack of cognitive impairments in first-degree relatives of children with pervasive developmental disorders. J Am Acad Child Adolesc Psychiatry 1993;32:1264–1273.
  26. Kjelgaard MM, Tager-Flusberg H: An investigation of language impairment in autism: Implications for genetic subgroups. Lang Cogn Processes 2001;16:287–308.

    External Resources

  27. 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.

    External Resources

  28. International Molecular Genetic Study of Autism Consortium: A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet 2001;69:570–581.
  29. Philippe A, Martinez M, Guilloud-Bataille M, Gillberg C, Rastam M, Sponheim E, Coleman M, Zappella M, Aschauer H, Van Maldergem L, Penet C, Feingold J, Brice A, Leboyer M, van Malldergerme L: Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study. [Erratum appears in Hum Mol Genet 1999 Jul;8(7):1353 Note: van Malldergerme L corrected to Van Maldergem L]. Hum Mol Genet 1999;8:805–812.

    External Resources

  30. Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J, Kalaydjieva L, McCague P, Dimiceli S, Pitts T, Nguyen L, Yang J, Harper C, Thorpe D, Vermeer S, Young H, Hebert J, et al: A genomic screen of autism: evidence for a multilocus etiology. Am J Hum Genet 1999;65:493–507.
  31. Collaborative Linkage Study of Autism: An autosomal genomic screen for autism. Am J Med Genet 2001;105:609–615.
  32. Liu J, Nyholt DR, Magnussen P, Parano E, Pavone P, Geschwind D, Lord C, Iversen P, Hoh J, Ott J, Gilliam TC, The Autism Genetic Resource Exchange C: A genomewide screen for autism susceptibility loci. Am J Hum Genet 2001;69:327–340.
  33. Shao Y, Wolpert CM, Raiford KL, Menold MM, Donnelly SL, Ravan SA, Bass MP, McClain C, von Wendt L, Vance JM, Abramson RH, Wright HH, Ashley-Koch A, Gilbert JR, DeLong RG, Cuccaro ML, Pericak-Vance MA: Genomic screen and follow-up analysis for autistic disorder. Am J Med Genet 2002;114:99–105.
  34. Steele MM, Al-Adeimi M, Siu VM, Fan YS: Brief report: A case of autism with interstitial deletion of chromosome 13. J Autism Dev Disord 2001;31:231–234.

    External Resources

  35. Gallagher L, Becker K, Kearney G, Dunlop A, Stallings R, Green A, Fitzgerald M, GIll M: Brief report: A case of autism associated with del(2)(q32.1q32.2 or (q32.2q32.3). J Autism Dev Disord 2003;33:105–108.
  36. Buxbaum JD, Silverman JM, Smith CJ, Kilifarski M, Reichert J, Hollander E, Lawlor BA, Fitzgerald M, Greenberg DA, Davis KL: Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity. [Erratum appears in Am J Hum Genet 2001 Aug;69(2):470]. Am J Hum Genet 2001;68:1514–1520.
  37. Collaborative Linkage Study of Autism: Incorporating language phenotypes strengthens evidence of linkage to autism. Am J Med Genet 2001;105:539–547.

    External Resources

  38. International Molecular Genetic Study of Autism Consortium: Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q. Hum Mol Genet 2001;10:973–982.

    External Resources

  39. Shao Y, Raiford KL, Wolpert CM, Cope HA, Ravan SA, Ashley-Koch AA, Abramson RK, Wright HH, DeLong RG, Gilbert JR, Cuccaro ML, Pericak-Vance MA: Phenotypic homogeneity provides increased support for linkage on chromosome 2 in autistic disorder. Am J Hum Genet 2002;70:1058–1061.
  40. Ashley-Koch A, Wolpert CM, Menold MM, Zaeem L, Basu S, Donnelly SL, Ravan SA, Powell CM, Qumsiyeh MB, Aylsworth AS, Vance JM, Gilbert JR, Wright HH, Abramson RK, DeLong GR, Cuccaro ML, Pericak-Vance MA: Genetic studies of autistic disorder and chromosome 7. Genomics 1999;61:227–236.

    External Resources

  41. Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP: A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 2001;413:519–523.
  42. Gauthier J, Joober R, Mottron L, Laurent S, Fuchs M, De Kimpe V, Rouleau GA: Mutation screening of FOXP2 in individuals diagnosed with autistic disorder. Am J Med Genet A 2003;118A:172–175.
  43. Newbury DF, Bonora E, Lamb JA, Fisher SE, Lai CS, Baird G, Jannoun L, Slonims V, Stott CM, Merricks MJ, Bolton PF, Bailey AJ, Monaco AP, International Molecular Genetic Study of Autism C: FOXP2 is not a major susceptibility gene for autism or specific language impairment. Am J Hum Genet 2002;70:1318–1327.
  44. Wassink TH, Piven J, Vieland VJ, Pietila J, Goedken RJ, Folstein SE, Sheffield VC: Evaluation of FOXP2 as an autism susceptibility gene. Am J Med Genet 2002;114:566–569.
  45. O’Brien EK, Zhang X, Nishimura C, Tomblin JB, Murray JC: Association of specific language impairment (SLI) to the region of 7q31. Am J Hum Genet 2003;72:1536–1543.
  46. Meaburn E, Dale PS, Craig IW, Plomin R: Language-impaired children: No sign of the FOXP2 mutation. Neuroreport 2002;13:1075–1077.
  47. Newbury DF, Bonora E, Lamb JA, Fisher SE, Lai CSL, Baird G, Jannoun L, Slonims V, Stott CM, Merricks MJ, Bolton PF, Bailey AJ, Monaco AP: FOXP2 is not a major susceptibility gene for autism or specific language impairment. Am J Hum Genet 2002;70:1318–1327.
  48. Kaminen M, Hannula-Jouppi K, Kestila M, Lahermo P, Muller K, Kaaranen M, Myllyluoma B, Voutilainen A, Lyytinen H, Nopola-Hemmi J, Kere J: A genome scan for developmental dyslexia confirms linkage to chromosome 2p11 and suggests a new locus on 7q32. J Med Genet 2003;40:340–345.
  49. Alarcon M, Cantor RM, Liu J, Gilliam TC, Geschwind DH, Consortium AGRE: Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families. Am J Hum Genet 2002;70:60–71.
  50. Vieland VJ, Wang K, Huang J: 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 2001;51:199–208.
  51. Vieland VJ: Bayesian linkage analysis, or: how I learned to stop worrying and love the posterior probability of linkage. Am J Hum Genet 1998;63:947–954.
  52. Wang K, Huang J, Vieland VJ: The consistency of the posterior probability of linkage. Ann Hum Genet 2000;64:533–553.
  53. Greenberg DA, Hodge SE, Vieland VJ, Spence MA: Power, mode of inheritance, and type I error in LOD scores and affecteds-only methods: reply to Kruglyak. Am J Hum Genet 1998;62:202–204.
  54. 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.
  55. Brzustowicz LM, Honer WG, Chow EW, Hogan J, Hodgkinson K, Bassett AS: Use of a quantitative trait to map a locus associated with severity of positive symptoms in familial schizophrenia to chromosome 6p. Am J Hum Genet 1997;61:1388–1396.
  56. Gasparini P, Dognini M, Bonizzato A, Pignatti PF, Morral N, Estivill X: A tetranucleotide repeat polymorphism in the cystic fibrosis gene. Hum Genet 1991;86:625.
  57. Rozen S, Skaletsky HJ: Primer3 on the WWW for general users and for biologist programmers; in Krawetz S, Misener S (eds): Bioinformatics Methods and Protocols: Methods in Molecular Biology. Totowa, NJ, Humana Press, 2000, pp. 365–386.
  58. Cottingham RW, Jr., Idury RM, Schaffer AA: Faster sequential genetic linkage computations. Am J Hum Genet 1993;53:252–263.
  59. Schaffer AA, Gupta SK, Shriram K, Cottingham Jr RW: Avoiding recomputation in linkage analysis. Hum Hered 1994;44:225–237.
  60. 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;63:861–689.
  61. Sobel E, Lange K: Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am J Hum Genet 1996;58:1323–1337.
  62. Smith CAB: Testing for heterogeneity of recombination fraction values in human genetics. Ann Hum Genet 1963;27:175–182.
  63. Logue MW: Complications of an unknown genetic model in the presence of heterogeneity for linkage analysis [Ph. D. Dissertation]. Ph D thesis, The University of Iowa, Iowa City, 2001.
  64. Logue MW, Vieland VJ, Goedken RJ, Crowe RR: Bayesian Analysis of a Previously Published Genome Screen for Panic Disorder Reveals New and Compelling Evidence for Linkage to Chromosome 7. Am J Med Genet, Neuropsychiatr Genet. In press.
  65. Elston RC: An approximation for the prior probability of autosomal linkage. Cytogenet Cell Genet 1975;14:290–292.
  66. Morton NE: Significance levels in complex inheritance. [Erratum appears in Am J Hum Genet 1998 Oct;63(4):1252]. Am J Hum Genet 1998;62:690–697.
  67. Martin ER, Monks SA, Warren LL, Kaplan NL: A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am J Hum Genet 2000;67:146–154.
  68. Martin ER, Bass MP, Kaplan NL: Correcting for a potential bias in the pedigree disequilibrium test. Am J Hum Genet 2001;68:1065–1067.
  69. Gordon D, Heath SC, Liu X, Ott J: A transmission/disequilibrium test that allows for genotyping errors in the analysis of single-nucleotide polymorphism data. Am J Hum Genet 2001;69:371–380.
  70. Wassink TH, Piven J, Vieland VJ, Huang J, Swiderski RE, Pietila J, Braun T, Beck G, Folstein SE, Haines JL, Sheffield VC: Evidence supporting WNT2 as an autism susceptibility gene. Am J Med Genet 2001;105:406–413.
  71. Vieland VJ, Logue M: HLODs, trait models, and ascertainment: implications of admixture for parameter estimation and linkage detection. Hum Hered 2002;53:23–35.
  72. Pal DK, Greenberg DA: Evaluating genetic heterogeneity in complex disease. Hum Hered 2002;53:216–226.
  73. Huang J, Vieland VJ: Comparison of ‘model-free’ and ‘model-based’ linkage statistics in the presence of locus heterogeneity: single data set and multiple data set applications. Hum Hered 2001;51:217–225.
  74. Hodge SE, Vieland VJ, Greenberg DA: HLODs remain powerful tools for detection of linkage in the presence of genetic heterogeneity. Am J Hum Genet 2002;70:556–559.
  75. Greenberg DA, Abreu PC: Determining trait locus position from multipoint analysis: accuracy and power of three different statistics. Genet Epidemiol 2001;21:299–314.
  76. Terwilliger JD: On the resolution and feasibility of genome scanning approaches; in Rao DC, Province MA (eds): Genetic Dissection of Complex Traits. New York, Academic Press, 2000, pp 351–391.

 goto top of outline Author Contacts

Christopher W. Bartlett
Rutgers University, Department of Genetics, Nelson Biological Laboratories, Room B314
604 Allison Rd
Piscataway, NJ 08854-8095 (USA)
Tel. +1 732 445 1638, Fax +1 732 445 1636, E-Mail

 goto top of outline Article Information

Received: June 10, 2003
Accepted after revision: August 25, 2003
Number of Print Pages : 11
Number of Figures : 0, Number of Tables : 4, Number of References : 76

 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)
Founded 1950 as Acta Genetica et Statistica Medica by Gunnar Dahlberg; Continued by M. Hauge (1965–1983)

Vol. 57, No. 1, Year 2004 (Cover Date: Released April 2004)

Journal Editor: J. Ott, New York, N.Y.
ISSN: 0001–5652 (print), 1423–0062 (Online)

For additional information:

Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.