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. 2014 Apr;13(4):418-29.
doi: 10.1111/gbb.12127. Epub 2014 Mar 24.

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

R Nudel  1 , 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
Affiliations

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

R Nudel et al. Genes Brain Behav. 2014 Apr.

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.

Keywords: ALSPAC; GWAS; imprinting; neurodevelopmental disorder; specific language impairment.

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Figures

Figure 1
Figure 1
Results of the child trend association analysis. (a) Manhattan plot for the child trend association analysis. (b) QQ plot for the child trend association analysis with 95% confidence intervals.
Figure 2
Figure 2
Results of the paternal parent-of-origin effects association analysis. (a) Manhattan plot for the paternal parent-of-origin effects association analysis. (b) QQ plot for the paternal parent-of-origin effects association analysis with 95% confidence intervals.
Figure 3
Figure 3
Results of the maternal parent-of-origin effects association analysis. (a) Manhattan plot for the maternal parent-of-origin effects association analysis. (b) QQ plot for the maternal parent-of-origin effects association analysis with 95% confidence intervals.
Figure 4
Figure 4
Regional association plots for top associations. (a) SNPs around the association peak on 14q12. (b) SNPs around the association peak on 5p13.
See this image and copyright information in PMC

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