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

Simon E. Fisher, Clyde Francks, Angela J. Marlow, I. Laurence MacPhie, Dianne F. Newbury, Lon R. Cardon, Yumiko Ishikawa-Brush, Alex J. Richardson, Joel B. Talcott, Javier Gayán, Richard K. Olson, Bruce F. Pennington, Shelley D. Smith, John C. DeFries, John F. Stein, Anthony P. Monaco

Research output: Contribution to journalArticle

215 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)86-91
Number of pages6
JournalNature Genetics
Volume30
Issue number1
DOIs
StatePublished - Jan 2002

ASJC Scopus subject areas

  • Genetics

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    Fisher, S. E., Francks, C., Marlow, A. J., MacPhie, I. L., Newbury, D. F., Cardon, L. R., Ishikawa-Brush, Y., Richardson, A. J., Talcott, J. B., Gayán, J., Olson, R. K., Pennington, B. F., Smith, S. D., DeFries, J. C., Stein, J. F., & Monaco, A. P. (2002). Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia. Nature Genetics, 30(1), 86-91. https://doi.org/10.1038/ng792