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: R Nudel, N H Simpson, G Baird, A O'Hare, G Conti-Ramsden, P F Bolton, E R Hennessy, SLI Consortium, S M Ring, G Davey Smith, C Francks, S Paracchini, A P Monaco, S E Fisher, D F Newbury
• Journal: Genes, brain, and behavior (Genes Brain Behav) Vol. 13 Issue 4 Pg. 418-29 (Apr 2014) ISSN: 1601-183X [Electronic] England
• PMID: 24571439 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.

Chemical References

• ARHGEF19 protein, human
• Adaptor Proteins, Signal Transducing
• Apoptosis Regulatory Proteins
• DAB2 protein, human
• Guanine Nucleotide Exchange Factors
• NOP9 protein, human
• PTGER4 protein, human
• RNA-Binding Proteins
• Receptors, Prostaglandin E, EP4 Subtype
• Tumor Suppressor Proteins

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Adult
• Apoptosis Regulatory Proteins
• Apraxias (genetics)
• Child
• Chromosomes, Human (genetics)
• Female
• Genome-Wide Association Study
• Genomic Imprinting
• Genotype
• Guanine Nucleotide Exchange Factors (genetics)
• Humans
• Male
• Polymorphism, Single Nucleotide
• Quantitative Trait Loci
• RNA-Binding Proteins (genetics, metabolism)
• Receptors, Prostaglandin E, EP4 Subtype (genetics)
• Tumor Suppressor Proteins (genetics)