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

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.

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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.

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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.

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Correspondence to Anthony P. Monaco.

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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

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