Publication Date

5-15-2016

Document Type

Article

Organizational Units

College of Arts Humanities and Social Sciences, Psychology

Keywords

Reading disability, Developmental dyslexia, Language, Reading, Copy number variants

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 (~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~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~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~10−2–10−4) within a frequent deletion ~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.

Copyright Date

5-15-2016

Copyright Statement / License for Reuse

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

Rights Holder

Alessandro Gialluisi, Alessia Visconti, Erik G. Willcutt, Shelley D. Smith, Bruce F. Pennington, Mario Falchi, John C. DeFries, Richard K. Olson, Clyde Francks, and Simon E. Fisher

Provenance

Received from CHORUS

File Format

application/pdf

Language

English (eng)

Extent

15 pgs

File Size

1.0 MB

Publication Statement

Copyright is held by the authors. User is responsible for all copyright compliance. This article was originally published as:

Gialluisi, A., Visconti, A., Willcutt, E. G., Smith, S. D., Pennington, B. F., Falchi, M., . . ., & Fisher, S. E. (2016). Investigating the effects of copy number variants on reading and language performance. Journal of Neurodevelopmental Disorders, 8(1), 15-30. https://doi.org/10.1186/s11689-016-9147-8

Publication Title

Journal of Neurodevelopmental Disorders

Volume

8

Issue

1

First Page

15

Last Page

30

ISSN

1866-1955

PubMed ID

27186239

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