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

Nudel, Ron; Simpson, Nuala H.; Baird, Gillian; O’Hare, Anne; Conti-Ramsden, Gina; Bolton, Patrick F.; Hennessy, Elizabeth R.; The SLli consortium,; Ring, Susan M; Smith, George Davey; Francks, Clyde; Paracchini, Silvia; Monaco, Anthony P.; Fisher, Simon E.; Newbury, Dianne F.

doi:10.1111/gbb.12127

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

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Francks, Clyde
Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society;
Donders Institute for Brain, Cognition and Behaviour, External Organizations;
Imaging Genomics, MPI for Psycholinguistics, Max Planck Society;

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Fisher, Simon E.
Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society;
Donders Institute for Brain, Cognition and Behaviour, External Organizations;

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Citation

Nudel, R., Simpson, N. H., Baird, G., O’Hare, A., Conti-Ramsden, G., Bolton, P. F., et al. (2014). Genome-wide association analyses of child genotype effects and parent-of origin effects in specific language impairment. Genes, Brain and Behavior, 13, 418-429. doi:10.1111/gbb.12127.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0015-822E-4

Abstract

Specific language impairment (SLI) is a neurodevelopmental disorder that affects
linguistic abilities when development is otherwise normal. We report the results of a genomewide 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.