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Reading disability, developmental dyslexia, language, reading, copy number variants, family-based GWAS, meta-analysis, CLDRC
Abstract:
Background: Reading and language skills have overlapping genetic bases,
most of which are still unknown. Part of the missing heritability may be
caused by copy number variants (CNVs).
Methods: In a dataset of children recruited for a history of reading
disability (RD, also known as dyslexia) or attention deficit
hyperactivity disorder (ADHD) and their siblings, we investigated the
effects of CNVs on reading and language performance. First, we called
CNVs with PennCNV using signal intensity data from Illumina OmniExpress
arrays (similar to 723,000 probes). Then, we computed the correlation
between measures of CNV genomic burden and the first principal component
(PC) score derived from several continuous reading and language traits,
both before and after adjustment for performance IQ. Finally, we
screened the genome, probe-by-probe, for association with the PC scores,
through two complementary analyses: we tested a binary CNV state
assigned for the location of each probe (i.e., CNV+ or CNV-), and we
analyzed continuous probe intensity data using FamCNV.
Results: No significant correlation was found between measures of CNV
burden and PC scores, and no genome-wide significant associations were
detected in probe-by-probe screening. Nominally significant associations
were detected (p similar to 10(-2)-10(-3)) within CNTN4 (contactin 4)
and CTNNA3 (catenin alpha 3). These genes encode cell adhesion molecules
with a likely role in neuronal development, and they have been
previously implicated in autism and other neurodevelopmental disorders.
A further, targeted assessment of candidate CNV regions revealed
associations with the PC score (p similar to 0.026-0.045) within CHRNA7
(cholinergic nicotinic receptor alpha 7), which encodes a ligand-gated
ion channel and has also been implicated in neurodevelopmental
conditions and language impairment. FamCNV analysis detected a region of
association (p similar to 10(-2)-10(-4)) within a frequent deletion
similar to 6 kb downstream of ZNF737 (zinc finger protein 737,
uncharacterized protein), which was also observed in the association
analysis using CNV calls.
Conclusions: These data suggest that CNVs do not underlie a substantial
proportion of variance in reading and language skills. Analysis of
additional, larger datasets is warranted to further assess the potential
effects that we found and to increase the power to detect CNV effects on
reading and language.
