Investigating the effects of copy number variants on reading and language performance

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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Article number17
JournalJournal of Neurodevelopmental Disorders
Volume8
Issue number1
DOIs
StatePublished - Jan 1 2016

Fingerprint

Reading
Language
Contactins
alpha Catenin
Genome
Ligand-Gated Ion Channels
Dyslexia
Zinc Fingers
Cell Adhesion Molecules
Attention Deficit Disorder with Hyperactivity
Autistic Disorder
Siblings
Proteins
Genes
Datasets

Keywords

  • CLDRC
  • Copy number variants
  • Developmental dyslexia
  • Family-based GWAS
  • Language
  • Meta-analysis
  • Reading
  • Reading disability

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cognitive Neuroscience

Cite this

Investigating the effects of copy number variants on reading and language performance. / Gialluisi, Alessandro; Visconti, Alessia; Willcutt, Erik G.; Smith, Shelley D.; Pennington, Bruce F.; Falchi, Mario; DeFries, John C.; Olson, Richard K.; Francks, Clyde; Fisher, Simon E.

In: Journal of Neurodevelopmental Disorders, Vol. 8, No. 1, 17, 01.01.2016.

Research output: Contribution to journalArticle

Gialluisi, A, Visconti, A, Willcutt, EG, Smith, SD, Pennington, BF, Falchi, M, DeFries, JC, Olson, RK, Francks, C & Fisher, SE 2016, 'Investigating the effects of copy number variants on reading and language performance', Journal of Neurodevelopmental Disorders, vol. 8, no. 1, 17. https://doi.org/10.1186/s11689-016-9147-8
Gialluisi, Alessandro ; Visconti, Alessia ; Willcutt, Erik G. ; Smith, Shelley D. ; Pennington, Bruce F. ; Falchi, Mario ; DeFries, John C. ; Olson, Richard K. ; Francks, Clyde ; Fisher, Simon E. / Investigating the effects of copy number variants on reading and language performance. In: Journal of Neurodevelopmental Disorders. 2016 ; Vol. 8, No. 1.
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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.",
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AU - Smith, Shelley D.

AU - Pennington, Bruce F.

AU - Falchi, Mario

AU - DeFries, John C.

AU - Olson, Richard K.

AU - Francks, Clyde

AU - Fisher, Simon E.

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N2 - 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.

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KW - CLDRC

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