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

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Ron Nudel, Nuala H Simpson, Gillian Baird, Anne O'Hare, Gina Conti-Ramsden, Patrick F Bolton, Elizabeth R Hennessy, Susan M Ring, George Davey Smith, Clyde Francks, Silvia Paracchini, Anthony P Monaco, Simon E Fisher, Dianne F Newbury, The SLI Consortium

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Abstract

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 = 3.74 × 10-8 ) and suggestive maternal parent-of-origin-effects on chromosome 5p13 (P = 1.16 × 10-7 ). A subsequent targeted association of six single-nucleotide-polymorphisms (SNPs) on chromosome 5 in 313 language-impaired individuals 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 sum, 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.

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Original languageEnglish
Pages (from-to)418–429
JournalGenes, Brain and Behavior
Volume13
Issue number4
Early online date24 Mar 2014
DOIs
Publication statusPublished - Apr 2014

    Research areas

  • ALSPAC, GWAS, Imprinting, Neurodevelopmental disorder, Specific language impairment

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