Genome- wide association analyses of child genotype effects and parent- of- origin effects in specific language impairment

R. Nudel, N. H. Simpson, G. Baird, A. O'Hare, G. Conti-Ramsden, P. F. Bolton, E. R. Hennessy, S. M. Ring, G. Davey Smith, C. Francks, S. Paracchini, A. P. Monaco, S. E. Fisher, D. F. Newbury*, SLI Consortium

*Corresponding author for this work

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Specific language impairment (SLI) is a neurodevelopmental disorder that affects linguistic abilities when development is otherwise normal. We report the results of a genome-wide association study of SLI which included parent-of-origin effects and child genotype effects and used 278 families of language-impaired children. The child genotype effects analysis did not identify significant associations. We found genome-wide significant paternal parent-of-origin effects on chromosome 14q12 (P=3.74x10(-8)) and suggestive maternal parent-of-origin effects on chromosome 5p13 (P=1.16x10(-7)). A subsequent targeted association of six single-nucleotide-polymorphisms (SNPs) on chromosome 5 in 313 language-impaired individuals and their mothers from the ALSPAC cohort replicated the maternal effects, albeit in the opposite direction (P=0.001); as fathers' genotypes were not available in the ALSPAC study, the replication analysis did not include paternal parent-of-origin effects. The paternally-associated SNP on chromosome 14 yields a non-synonymous coding change within the NOP9 gene. This gene encodes an RNA-binding protein that has been reported to be significantly dysregulated in individuals with schizophrenia. The region of maternal association on chromosome 5 falls between the PTGER4 and DAB2 genes, in a region previously implicated in autism and ADHD. The top SNP in this association locus is a potential expression QTL of ARHGEF19 (also called WGEF) on chromosome 1. Members of this protein family have been implicated in intellectual disability. In summary, this study implicates parent-of-origin effects in language impairment, and adds an interesting new dimension to the emerging picture of shared genetic etiology across various neurodevelopmental disorders.

Original languageEnglish
Pages (from-to)418-429
Number of pages12
JournalGenes, Brain, and Behavior
Issue number4
Early online date24 Mar 2014
Publication statusPublished - Apr 2014

Bibliographical note

Funded by
•Medical Research Council. Grant Numbers: G1000569/1, MR/J003719/1, G0800523/86473
•University of Oxford Nuffield Department of Medicine Prize Studentship
•Max Planck Society
•Wellcome Trust. Grant Numbers: 060774, 076566, 090532/Z/09/Z, 092731
•National Institute of Health Research (UK) Senior Investigator award
•Biomedical Research Centre in Mental Health


  • GWAS
  • imprinting
  • neurodevelopmental disorder
  • specific language impairment
  • attention-deficit/hyperactivity disorder
  • nucleotide exchange factor
  • communication checklist
  • hyperactivity disorder
  • developmental dyslexia
  • susceptibility locus
  • suggestive linkage
  • mental-retardation
  • reading-disability


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