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.

  • Letter
  • Published:

Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia

Nature Genetics volume 30, pages 86–91 (2002)Cite this article

Abstract

Developmental dyslexia is defined as a specific and significant impairment in reading ability that cannot be explained by deficits in intelligence, learning opportunity, motivation or sensory acuity. It is one of the most frequently diagnosed disorders in childhood, representing a major educational and social problem1. It is well established that dyslexia is a significantly heritable trait2 with a neurobiological basis3. The etiological mechanisms remain elusive, however, despite being the focus of intensive multidisciplinary research3. All attempts to map quantitative-trait loci (QTLs) influencing dyslexia susceptibility have targeted specific chromosomal regions, so that inferences regarding genetic etiology have been made on the basis of very limited information4. Here we present the first two complete QTL-based genome-wide scans for this trait, in large samples of families from the United Kingdom and United States. Using single-point analysis, linkage to marker D18S53 was independently identified as being one of the most significant results of the genome in each scan (P≤0.0004 for single word–reading ability in each family sample). Multipoint analysis gave increased evidence of 18p11.2 linkage for single-word reading, yielding top empirical P values of 0.00001 (UK) and 0.0004 (US). Measures related to phonological and orthographic processing also showed linkage at this locus. We replicated linkage to 18p11.2 in a third independent sample of families (from the UK), in which the strongest evidence came from a phoneme-awareness measure (most significant P value=0.00004). A combined analysis of all UK families confirmed that this newly discovered 18p QTL is probably a general risk factor for dyslexia, influencing several reading-related processes. This is the first report of QTL-based genome-wide scanning for a human cognitive trait.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Relationship between VC lod scores and pointwise significance of linkage for different measures in each genome-screen sample.
Figure 2: A new QTL on 18p influences dyslexia.

Similar content being viewed by others

References

  1. Brown, B.S. in Dyslexia: An Appraisal of Current Knowledge (eds Benton, A.L. & Pearl, D.) v–vii (Oxford University Press, Oxford, 1978).

    Google Scholar 

  2. DeFries, J.C., Fulker, D.W. & LaBuda, M.C. Evidence for a genetic aetiology in reading disability of twins. Nature 329, 537–539 (1987).

    Article  CAS  PubMed  Google Scholar 

  3. Habib, M. The neurological basis of developmental dyslexia. An overview and working hypothesis. Brain 123, 2373–2399 (2000).

    Article  PubMed  Google Scholar 

  4. Fisher, S.E. & Smith, S.D. in Dyslexia: Theory and Good Practice (ed. Fawcett, A.J.) 39–64 (Whurr, London, 2001).

    Google Scholar 

  5. Cardon, L.R. et al. Quantitative trait locus for reading disability on chromosome 6. Science 266, 276–279 (1994).

    Article  CAS  PubMed  Google Scholar 

  6. Cardon, L.R. et al. Quantitative trait locus for reading disability: correction. Science 268, 1553 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Fisher, S.E. et al. A quantitative trait locus on chromosome 6p influences different aspects of developmental dyslexia. Am. J. Hum. Genet. 64, 146–156 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gayán, J. et al. Quantitative trait locus for specific language and reading deficits on chromosome 6p. Am. J. Hum. Genet. 64, 157–164 (1999).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Grigorenko, E.L. et al. Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15. Am. J. Hum. Genet. 60, 27–39 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Field, L.L. & Kaplan, B.J. Absence of linkage of phonological coding dyslexia to chromosome 6p23–p21.3 in a large family data set. Am. J. Hum. Genet. 63, 1448–1456 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Schulte-Körne, G. et al. Evidence for linkage of spelling disability to chromosome 15. Am. J. Hum. Genet. 63, 279–282 (1998).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Morris, D.W. et al. Family-based association mapping provides evidence for a gene for reading disability on chromosome 15q. Hum. Mol. Genet. 9, 843–848 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Fagerheim, T. et al. A new gene (DYX3) for dyslexia is located on chromosome 2. J. Med. Genet. 36, 664–669 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Fisher, S.E., Stein, J.F. & Monaco, A.P. A genome-wide search strategy for identifying quantitative trait loci involved in reading and spelling disability (developmental dyslexia). Eur. Child Adolesc. Psych. 8, 47–51 (1999).

    Article  Google Scholar 

  15. Marlow, A.J. et al. Investigation of quantitative measures related to reading disability in a large sample of sib-pairs from the UK. Behav. Genet. 31, 219–230 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Olson, R.K., Forsberg, H. & Wise, B. in The Varieties of Orthographic Knowledge Vol I: Theoretical and Developmental Issues (ed. Berninger, V.W.) 27–71 (Kluwer Academic, Dordrecht, 1994).

    Book  Google Scholar 

  17. Gayán, J. & Olson, R.K. Genetic and environmental influences on orthographic and phonological skills in children with reading disabilities. Dev. Neuropsych. 20 487–511 (2001).

    Article  Google Scholar 

  18. Amos, C.I. Robust variance-components approach for assessing genetic linkage in pedigrees. Am. J. Hum. Genet. 54, 535–543 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Allison, D.B. et al. Testing the robustness of the likelihood-ratio test in a variance-component quantitative-trait loci-mapping procedure. Am. J. Hum. Genet. 65, 531–544 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lander, E. & Kruglyak, L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genet. 11, 241–247 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Haseman, J.K. & Elston, R.C. The investigation of linkage between a quantitative trait and a marker locus. Behav. Genet. 2, 3–19 (1972).

    Article  CAS  PubMed  Google Scholar 

  22. Kruglyak, L. & Lander, E.S. Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am. J. Hum. Genet. 57, 439–454 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Flannery, K.A., Liederman, J., Daly, L. & Schultz, J. Male prevalence for reading disability is found in a large sample of black and white children free from ascertainment bias. J. Int. Neuropsychol. Soc. 6, 433–442 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Olson, R.K., Datta, H., Gayán, J. & DeFries, J.C. in Converging Methods for Understanding Reading and Dyslexia (eds Klein, R.M. & McMullen, P.A.) 133–151 (MIT Press, Cambridge, MA, 1999).

    Google Scholar 

  25. Pennington, B.F. Using genetics to dissect cognition. Am. J. Hum. Genet. 60, 13–16 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Dib, C. et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152–154 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Pratt, S.C., Daly, M.J. & Kruglyak, L. Exact multipoint quantitative-trait linkage analysis in pedigrees by variance components. Am. J. Hum. Genet. 66, 1153–1157 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lessem, J.M. & Cherny, S.C. DeFries–Fulker multiple regression of sibship QTL data: a SAS macro. Bioinformatics 17, 371–372 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are very grateful to all the families who participated in this study. We thank J. Walter, P. Southcott, S. Fowler and C. Clisby for collection of the UK families; K. Taylor for assistance with handling the UK phenotype data; H. Rees, J. Smith and P. Kelley for assistance with genotyping; and D. Weeks and S. Cherny for advice on statistical analyses. Collection of the UK families and all genotyping were funded by the Wellcome Trust. The US study was supported in part by grants from the National Institute of Child Health and Human Development and the National Institute of Mental Health. L.R.C. was funded in part by an NIH grant. I.L.M is funded by the British Council and NSERC (Canada). C.F. was a Wellcome Trust Prize Student. A.P.M. is a Wellcome Trust Principal Research Fellow.

Author information

Author notes

  1. Simon E. Fisher and Clyde Francks: These authors contributed equally to this work.

Authors and Affiliations

  1. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK

    Simon E. Fisher, Clyde Francks, Angela J. Marlow, I. Laurence MacPhie, Dianne F. Newbury, Lon R. Cardon, Yumiko Ishikawa-Brush & Anthony P. Monaco

  2. Department of Physiology, University of Oxford, Parks Road, Oxford, OX1 3PT, UK

    Alex J. Richardson, Joel B. Talcott & John F. Stein

  3. Institute for Behavioral Genetics, University of Colorado, Boulder, 80309-0447, Colorado, USA

    Javier Gayán, Richard K. Olson & John C. DeFries

  4. Department of Psychology, University of Denver, Denver, 80208, Colorado, USA

    Bruce F. Pennington

  5. Center for Human Molecular Genetics, University of Nebraska Medical Center, Omaha, 68198-5455, Nebraska, USA

    Shelley D. Smith

Authors
  1. Simon E. Fisher
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Clyde Francks
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Angela J. Marlow
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. I. Laurence MacPhie
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dianne F. Newbury
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lon R. Cardon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yumiko Ishikawa-Brush
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alex J. Richardson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Joel B. Talcott
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Javier Gayán
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Richard K. Olson
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Bruce F. Pennington
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Shelley D. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. John C. DeFries
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. John F. Stein
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Anthony P. Monaco
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anthony P. Monaco.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fisher, S., Francks, C., Marlow, A. et al. Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia. Nat Genet 30, 86–91 (2002). https://doi.org/10.1038/ng792

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng792

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing