title: Investigating the effects of copy number variants on reading and language performance.
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.
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Wundtlaan 1, 6525 XD Nijmegen, The Netherlands ; Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gialluisi
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Alessia
authors.initials: A
authors.lastname: Visconti
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, Boulder, CO USA ; Department of Psychology and Neuroscience, University of Colorado, Boulder, CO USA.
authors.forename: Erik G
authors.initials: EG
authors.lastname: Willcutt
authors.affiliation: Munroe Meyer Institute, University of Nebraska Medical Center, Omaha, NE USA.
authors.forename: Shelley D
authors.initials: SD
authors.lastname: Smith
authors.affiliation: Department of Psychology, University of Denver, Denver, CO USA.
authors.forename: Bruce F
authors.initials: BF
authors.lastname: Pennington
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Mario
authors.initials: M
authors.lastname: Falchi
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, Boulder, CO USA ; Department of Psychology and Neuroscience, University of Colorado, Boulder, CO USA.
authors.forename: John C
authors.initials: JC
authors.lastname: DeFries
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, Boulder, CO USA ; Department of Psychology and Neuroscience, University of Colorado, Boulder, CO USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Olson
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Wundtlaan 1, 6525 XD Nijmegen, The Netherlands ; Donders Institute for Brain Cognition and Behaviour, Nijmegen, The Netherlands.
authors.forename: Clyde
authors.initials: C
authors.lastname: Francks
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Wundtlaan 1, 6525 XD Nijmegen, The Netherlands ; Donders Institute for Brain Cognition and Behaviour, Nijmegen, The Netherlands.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Fisher
keywords: CLDRC; Copy number variants; Developmental dyslexia; Family-based GWAS; Language; Meta-analysis; Reading; Reading disability