1. Genome-wide association analyses of child genotype effects and parent-of-origin effects in specific language impairment.
- Author
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Nudel R, Simpson NH, Baird G, O'Hare A, Conti-Ramsden G, Bolton PF, Hennessy ER, Ring SM, Davey Smith G, Francks C, Paracchini S, Monaco AP, Fisher SE, and Newbury DF
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adult, Apoptosis Regulatory Proteins, Child, Chromosomes, Human genetics, Female, Genome-Wide Association Study, Guanine Nucleotide Exchange Factors genetics, Humans, Male, Polymorphism, Single Nucleotide, Quantitative Trait Loci, RNA-Binding Proteins genetics, Receptors, Prostaglandin E, EP4 Subtype genetics, Tumor Suppressor Proteins genetics, Apraxias genetics, Genomic Imprinting, Genotype, RNA-Binding Proteins metabolism
- 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 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., (© 2014 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)
- Published
- 2014
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