title: 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 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.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: R
authors.initials: R
authors.lastname: Nudel
authors.forename: N H
authors.initials: NH
authors.lastname: Simpson
authors.forename: G
authors.initials: G
authors.lastname: Baird
authors.forename: A
authors.initials: A
authors.lastname: O'Hare
authors.forename: G
authors.initials: G
authors.lastname: Conti-Ramsden
authors.forename: P F
authors.initials: PF
authors.lastname: Bolton
authors.forename: E R
authors.initials: ER
authors.lastname: Hennessy
authors.forename: S M
authors.initials: SM
authors.lastname: Ring
authors.forename: G
authors.initials: G
authors.lastname: Davey Smith
authors.forename: C
authors.initials: C
authors.lastname: Francks
authors.forename: S
authors.initials: S
authors.lastname: Paracchini
authors.forename: A P
authors.initials: AP
authors.lastname: Monaco
authors.forename: S E
authors.initials: SE
authors.lastname: Fisher
authors.forename: D F
authors.initials: DF
authors.lastname: Newbury
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D051017:Apoptosis Regulatory Proteins; D001072:Apraxias / Q000235:genetics*; D002648:Child; D002877:Chromosomes, Human / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D018392:Genomic Imprinting; D005838:Genotype; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C000588578:ARHGEF19 protein, human; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C102885:DAB2 protein, human; D020662:Guanine Nucleotide Exchange Factors; C000594119:NOP9 protein, human; C545650:PTGER4 protein, human; D016601:RNA-Binding Proteins; D058309:Receptors, Prostaglandin E, EP4 Subtype; D025521:Tumor Suppressor Proteins
keywords: ALSPAC; GWAS; imprinting; neurodevelopmental disorder; specific language impairment