Genome-wide association analyses of child genotype effects and parent-of-origin effects in specific language impairment
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.
Citation
Nudel , R , Simpson , N H , Baird , G , O'Hare , A , Conti-Ramsden , G , Bolton , P F , Hennessy , E R , Ring , S M , Smith , G D , Francks , C , Paracchini , S , Monaco , A P , Fisher , S E , Newbury , D F & The SLI Consortium 2014 , ' Genome-wide association analyses of child genotype effects and parent-of-origin effects in specific language impairment ' , Genes, Brain and Behavior , vol. 13 , no. 4 , pp. 418–429 . https://doi.org/10.1111/gbb.12127
Publication
Genes, Brain and Behavior
Status
Peer reviewed
ISSN
1601-1848Type
Journal article
Description
Dianne Newbury is an MRC Career Development Fellow and a Junior Research Fellow at St John’s College, University of Oxford. The work of the Newbury lab is funded by the Medical Research Council [G1000569/1 and MR/J003719/1]. Ron Nudel is funded by a University of Oxford Nuffield Department of Medicine Prize Studentship. The genotyping of samples was funded by the Max Planck Society. Silvia Paracchini is a Royal Society University Research Fellow. The analyses of the ALSPAC cohort were supported by a grant from the Medical Research Council [G0800523/86473]. The collection of the SLIC samples was supported by the Wellcome Trust (060774 and 076566). Patrick Bolton is supported by a National Institute of Health Research (UK) Senior Investigator award and the Biomedical Research Centre in Mental Health at the South London & Maudsley NHS Trust Hospital, London. The work of the Wellcome Trust Centre in Oxford is supported by the Wellcome Trust [090532/Z/09/Z].Collections
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