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Quantitative trait locus association scan of early reading disability and ability using pooled DNA and 100K SNP microarrays in a sample of 5760 children

Abstract

Quantitative genetic research suggests that reading disability is the quantitative extreme of the same genetic and environmental factors responsible for normal variation in reading ability. This finding warrants a quantitative trait locus (QTL) strategy that compares low versus high extremes of the normal distribution of reading in the search for QTLs associated with variation throughout the distribution. A low reading ability group (N=755) and a high reading group (N=747) were selected from a representative UK sample of 7-year-olds assessed on two measures of reading that we have shown to be highly heritable and highly genetically correlated. The low and high reading ability groups were each divided into 10 independent DNA pools and the 20 pools were assayed on 100 K single nucleotide polymorphism (SNP) microarrays to screen for the largest allele frequency differences between the low and high reading ability groups. Seventy five of these nominated SNPs were individually genotyped in an independent sample of low (N=452) and high (N=452) reading ability children selected from a second sample of 4258 7-year-olds. Nine of the seventy-five SNPs were nominally significant (P<0.05) in the predicted direction. These 9 SNPs and 14 other SNPs showing low versus high allele frequency differences in the predicted direction were genotyped in the rest of the second sample to test the QTL hypothesis. Ten SNPs yielded nominally significant linear associations in the expected direction across the distribution of reading ability. However, none of these SNP associations accounted for more than 0.5% of the variance of reading ability, despite 99% power to detect them. We conclude that QTL effect sizes, even for highly heritable common disorders and quantitative traits such as early reading disability and ability, might be much smaller than previously considered.

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Acknowledgements

We are indebted to the parents of the twins in the Twins Early Development Study (TEDS) for making the study possible. We thank Charles Curtis for constructing the DNA pools used in this study. TEDS is supported by a programme grant from the UK Medical Research Council (Grant no. G0500079); the association scan of reading disability and ability is supported by a grant from the US National Institute of Child Health and Human Development (Grant no. HD49861). The study was approved by the Institute of Psychiatry/South London and Maudsley Research Ethics Committee and appropriate informed consent was obtained from the parents and teachers of the children.

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Correspondence to E L Meaburn.

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Meaburn, E., Harlaar, N., Craig, I. et al. Quantitative trait locus association scan of early reading disability and ability using pooled DNA and 100K SNP microarrays in a sample of 5760 children. Mol Psychiatry 13, 729–740 (2008). https://doi.org/10.1038/sj.mp.4002063

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Keywords

  • dyslexia
  • learning disability
  • DNA pooling
  • quantitative trait
  • allelic association
  • twins

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