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Quantitative genome scan and Ordered-Subsets Analysis of autism endophenotypes support language QTLs

Molecular Psychiatry volume 10, pages 747–757 (2005)Cite this article

Abstract

Autism is a neurodevelopmental syndrome with early childhood onset and deficits in three behavioral and cognitive dimensions: language, social skills and repetitive or restrictive behaviors. We hypothesized that using these endophenotypes would provide more power to detect linkage than the diagnosis of autism. Previously, we reported results for a nonparametric quantitative trait locus (QTL) genome scan in 152 families with autism, which revealed a linkage peak related to spoken language on 7q35. Here, we present the results of a nonparametric QTL scan of autism endophenotypes in 291 multiplex families, including the original 152. The strongest evidence for an ‘age at first word’ QTL was on chromosomes 3q at 147 cM (Z=3.10, P<0.001), and 17q at 93 cM (Z=2.84, P=0.002), both represent novel susceptibility loci for autism endophenotypes. There was also support for a previously identified autism peak on chromosome 17 at 43 cM (Z=2.22, P=0.013) with ‘age at first phrase’. The 7q35 language peak was attenuated (Z=2.05, P=0.02) compared with the original finding. To explore the possibility of increased heterogeneity resulting from the addition of 135 families to the sample, we conducted an Ordered-Subsets Analysis on chromosome 7; these results suggest that the 132 autism families with the earliest average age at first word are responsible for the QTL on 7q35. This locus on 7q35 may harbor a gene contributing variability in spoken language that is not uniquely related to language delay in autism.

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References

  1. Yeargin-Allsopp M, Rice C, Karapurkar T, Doernberg N, Boyle C, Murphy C . Prevalence of autism in a US metropolitan area. JAMA 2003; 289: 49–55.

    Article  PubMed  Google Scholar 

  2. Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995; 25: 63–77.

    Article  CAS  PubMed  Google Scholar 

  3. Smalley SL, Asarnow RF, Spence A . Autism and genetics. Arch Gen Psychiatry 1988; 45: 953–961.

    Article  CAS  PubMed  Google Scholar 

  4. Wassink TH, Piven J, Patil SR . Chromosomal abnormalities in a clinic sample of individuals with autistic disorder. Psychiatr Genet 2001; 11: 57–63.

    Article  CAS  PubMed  Google Scholar 

  5. 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 

  6. Lamb JA, Moore J, Bailey A, Monaco AP . Autism: recent molecular genetic advances. Hum Mol Genet 2000; 9 (6): 861–868.

    Article  CAS  PubMed  Google Scholar 

  7. IMGSAC. 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.

  8. IMGSAC. A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet 2001; 69: 570–581.

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Philippe A, Martinez M, Guilloud-Bataille M, Gillberg C, Råstam 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 

  11. 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 

  12. Veenstra-VanderWeele J, Cook EH . Molecular genetics of autism spectrum disorder. Mol Psychiatry 2004; 9: 819–832.

    Article  CAS  PubMed  Google Scholar 

  13. Bryson SE, Smith IM . Epidemiology of autism: prevalence, associated characteristics, and implications for research and service delivery. Ment Retard Dev Disabilities Res Rev 1998; 4: 97–103.

    Article  Google Scholar 

  14. Stoltenberg SF, Burmeister M . Recent progress in psychiatric genetics-some hope but no hype. Hum Mol Genet 2000; 9: 927–935.

    Article  CAS  PubMed  Google Scholar 

  15. Piven J, Palmer P, Landa R, Santangelo S, Jacobi D, Childress D . Personality and language characteristics in parents from multiple-incidence autism families. Am J Med Genet 1997; 74: 398–411.

    Article  CAS  PubMed  Google Scholar 

  16. Gottesman I, Gould TD . The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003; 160: 636–645.

    Article  PubMed  Google Scholar 

  17. Gottesman I, Shields J . Schizophrenia and Genetics: A Twin Study Vantage Point. New York: Academic Press, 1972.

    Google Scholar 

  18. Bradford Y, Haines J, Hutcheson H, Gardiner M, Braun T, Sheffield V et al. Incorporating language phenotypes strengthens evidence of linkage to autism. Am J Med Genet 2001; 105: 539–547.

    Article  CAS  PubMed  Google Scholar 

  19. Buxbaum JD, Silverman JM, Smith CJ, Kilifarski M, Reichert J, Hollander E et al. Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity. Am J Hum Genet 2001; 68: 1514–1520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Shao Y, Cuccaro ML, Hauser ER, Raiford KL, Menold MM, Wolpert CM et al. Fine mapping of autistic disorder to chromosome 15q11–q13 by use of phenotypic subtypes. Am J Hum Genet 2003; 72: 539–548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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 

  22. Lord C, Rutter M, 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 1994; 24: 659–685.

    Article  CAS  PubMed  Google Scholar 

  23. Alarcón M, Cantor RM, Liu J, Gilliam TC, Consortium A, Geschwind DH . Evidence for a language QTL on chromosome 7q in multiplex autism families. Am J Hum Genet 2002; 70: 60–71.

    Article  PubMed  Google Scholar 

  24. Hauser ER, Watanabe RM, Duren WL, Bass MP, Langefeld CD, Boehnke M . Ordered subset analysis in genetic linkage mapping of complex traits. Genet Epidemiol 2004; 27: 53–63.

    Article  PubMed  Google Scholar 

  25. Scott WK, Hauser ER, Schmechel DE, Welsh-Bohmer KA, Small GW, Roses AD et al. Ordered-subsets linkage analysis detects novel Alzheimer disease loci on chromosomes 2q34 and 15q22. Am J Hum Genet 2003; 73: 1041–1051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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 

  27. 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 

  28. Aita VM, Christiano AM, Gilliam TC . Mapping complex traits in diseases of the hair and skin. Exp Dermatol 1999; 8: 439–452.

    Article  CAS  PubMed  Google Scholar 

  29. O'Connell JR, Weeks DE . PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998; 63: 259–266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kruglyak L, Lander ES . Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am J Hum Genet 1995; 57: 439–454.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 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 

  32. Conover WJ . Practical Nonparametric Statistics, 2nd edn. John Wiley and Sons Inc: New York, 1980.

    Google Scholar 

  33. 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 

  34. Ashley-Koch A, Wolpert CM, Menold MM, Zaeem L, Basu S, Donnelly SL et al. Genetic studies of autistic disorder and chromosome 7. Genomics 1999; 61: 227–236.

    Article  CAS  PubMed  Google Scholar 

  35. 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 

  36. Kaminen N, Hannula-Jouppi K, Kestila M, Lahermo P, Muller K, Kaaranen M et al. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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 

  38. Consortium S . A genomewide scan identifies two novel loci involved in specific language impairment. Am J Hum Genet 2002; 70: 384–398.

    Article  Google Scholar 

  39. 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.

    Article  CAS  PubMed  Google Scholar 

  40. Fisher SE, Francks C, McCracken JT, McGough JJ, Marlow AJ, MacPhie IL et al. A genomewide scan for loci involved in attention-deficit/hyperactivity disorder. Am J Hum Genet 2002; 70: 1183–1196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Stein CM, Schick JH, Gerry Taylor H, Shriberg LD, Millard C, Kundtz-Kluge A et al. Pleiotropic effects of a chromosome 3 locus on speech-sound disorder and reading. Am J Hum Genet 2004; 74: 283–297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lai CS, Fisher SE, Hurst JA, Levy ER, Hodgson S, Fox M et al. The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder [see comments]. Am J Hum Genet 2000; 67: 357–368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fisher SE, Vargha-Khadem F, Watkins KE, Monaco AP, Pembrey ME . Localisation of a gene implicated in a severe speech and language disorder [published erratum appears in Nat Genet 1998 Mar;18(3):298]. Nat Genet 1998; 18: 168–170.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We gratefully acknowledge the contributions of the AGRE families who participated in this study and have made the resource possible. In addition, we thank the AGRE Consortium (see Appendix A) for their oversight of the resource. This project was supported by NIMH Grant R01 MH 64547 (to DHG), the UCLA Center for Autism Research and Treatment and the Cure Autism Now foundation (to AGRE). TCG also acknowledges support from the generous contribution of Dr Judith P Sulzberger.

Author information

Authors and Affiliations

  1. Department of Neurology, UCLA School of Medicine, Center for Neurobehavioral Genetics and Neuropsychiatric Research Institute, Los Angeles, CA, USA

    M Alarcón & D H Geschwind

  2. Department of Genetics and Development, Columbia Genome Center, New York, NY, USA

    A L Yonan & T C Gilliam

  3. Department of Psychiatry, Columbia University, New York, NY, USA

    T C Gilliam

  4. Departments of Human Genetics and Pediatrics, UCLA School of Medicine, Los Angeles, CA, USA

    R M Cantor

Authors
  1. M Alarcón
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  2. A L Yonan
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  3. T C Gilliam
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  4. R M Cantor
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  5. D H Geschwind
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Corresponding authors

Correspondence to M Alarcón or D H Geschwind.

Additional information

Electronic-Database Information

Autism Genetic Research Exchange, http://agre.org/

Cure Autism Now, http://canfoundation.org/

Genome Database, The, http://gdbwww.gdb.org/

Human Biological Database Interchange, http://www.hbdi.org/

Marshfield Medical Research Foundation, The, http://research.marshfieldclinic.org/genetics/

Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/omim/ (for Autism Disorder (MIM 209850))

Appendix A

Appendix A

AGRE ConsortiumDaniel H Geschwind, University of California at Los Angeles, Los Angeles; Maja Bucan, University of Pennsylvania, Philadelphia; W Ted Brown, New York State Institute for Basic Research in Developmental Disabilities, Long Island; Joseph D Buxbaum, Mt Sinai School of Medicine, New York; Rita M Cantor, University of California, Los Angeles; John N Constantino, Washington University School of Medicine, St Louis; T Conrad Gilliam, Columbia Genome Center, New York; Clara Lajonchere, Cure Autism Now, Los Angeles; David H Ledbetter, Emory University, Atlanta; Christa Lese-Martin, Emory University, Atlanta; Janet Miller, Cure Austism Now, Los Angeles; Stanley F Nelson, University of California at Los Angeles School of Medicine, Los Angeles; Gerard D Schellenberg, University of Washington and Veterans Affairs Medical Center, Seattle; Carole Samango-Sprouse, Children's National Medical Center, Baltimore; Sarah J Spence, University of California, Los Angeles; Rudolph E Tanzi, Massachusetts General Hospital, Boston.

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Alarcón, M., Yonan, A., Gilliam, T. et al. Quantitative genome scan and Ordered-Subsets Analysis of autism endophenotypes support language QTLs. Mol Psychiatry 10, 747–757 (2005). https://doi.org/10.1038/sj.mp.4001666

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