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

R. Nudel, N. H. Simpson, G. Baird, A. O'Hare, G. Conti-Ramsden, P. F. Bolton, E. R. Hennessy, S. M. Ring, G. Davey Smith, C. Francks, S. Paracchini, A. P. Monaco, S. E. Fisher, D. F. Newbury*, SLI Consortium

*Corresponding author for this work

Research output: Contribution to journalArticle

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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=3.74x10(-8)) and suggestive maternal parent-of-origin effects on chromosome 5p13 (P=1.16x10(-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.

Original languageEnglish
Pages (from-to)418-429
Number of pages12
JournalGenes, Brain, and Behavior
Volume13
Issue number4
Early online date24 Mar 2014
DOIs
Publication statusPublished - Apr 2014

Keywords

  • ALSPAC
  • GWAS
  • imprinting
  • neurodevelopmental disorder
  • specific language impairment
  • attention-deficit/hyperactivity disorder
  • nucleotide exchange factor
  • RHO-GTPASES
  • communication checklist
  • hyperactivity disorder
  • developmental dyslexia
  • susceptibility locus
  • suggestive linkage
  • mental-retardation
  • reading-disability

Cite this

Nudel, R., Simpson, N. H., Baird, G., O'Hare, A., Conti-Ramsden, G., Bolton, P. F., ... SLI Consortium (2014). Genome- wide association analyses of child genotype effects and parent- of- origin effects in specific language impairment. Genes, Brain, and Behavior, 13(4), 418-429. https://doi.org/10.1111/gbb.12127

Genome- wide association analyses of child genotype effects and parent- of- origin effects in specific language impairment. / Nudel, R.; Simpson, N. H.; Baird, G.; O'Hare, A.; Conti-Ramsden, G.; Bolton, P. F.; Hennessy, E. R.; Ring, S. M.; Smith, G. Davey; Francks, C.; Paracchini, S.; Monaco, A. P.; Fisher, S. E.; Newbury, D. F.; SLI Consortium.

In: Genes, Brain, and Behavior, Vol. 13, No. 4, 04.2014, p. 418-429.

Research output: Contribution to journalArticle

Nudel, R, Simpson, NH, Baird, G, O'Hare, A, Conti-Ramsden, G, Bolton, PF, Hennessy, ER, Ring, SM, Smith, GD, Francks, C, Paracchini, S, Monaco, AP, Fisher, SE, Newbury, DF & SLI Consortium 2014, 'Genome- wide association analyses of child genotype effects and parent- of- origin effects in specific language impairment', Genes, Brain, and Behavior, vol. 13, no. 4, pp. 418-429. https://doi.org/10.1111/gbb.12127
Nudel, R. ; Simpson, N. H. ; Baird, G. ; O'Hare, A. ; Conti-Ramsden, G. ; Bolton, P. F. ; Hennessy, E. R. ; Ring, S. M. ; Smith, G. Davey ; Francks, C. ; Paracchini, S. ; Monaco, A. P. ; Fisher, S. E. ; Newbury, D. F. ; SLI Consortium. / Genome- wide association analyses of child genotype effects and parent- of- origin effects in specific language impairment. In: Genes, Brain, and Behavior. 2014 ; Vol. 13, No. 4. pp. 418-429.
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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=3.74x10(-8)) and suggestive maternal parent-of-origin effects on chromosome 5p13 (P=1.16x10(-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.",
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AU - Conti-Ramsden, G.

AU - Bolton, P. F.

AU - Hennessy, E. R.

AU - Ring, S. M.

AU - Smith, G. Davey

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AU - Fisher, S. E.

AU - Newbury, D. F.

AU - SLI Consortium

N1 - Funded by •Medical Research Council. Grant Numbers: G1000569/1, MR/J003719/1, G0800523/86473 •University of Oxford Nuffield Department of Medicine Prize Studentship •Max Planck Society •Wellcome Trust. Grant Numbers: 060774, 076566, 090532/Z/09/Z, 092731 •National Institute of Health Research (UK) Senior Investigator award •Biomedical Research Centre in Mental Health

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N2 - 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=3.74x10(-8)) and suggestive maternal parent-of-origin effects on chromosome 5p13 (P=1.16x10(-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.

AB - 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=3.74x10(-8)) and suggestive maternal parent-of-origin effects on chromosome 5p13 (P=1.16x10(-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.

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KW - GWAS

KW - imprinting

KW - neurodevelopmental disorder

KW - specific language impairment

KW - attention-deficit/hyperactivity disorder

KW - nucleotide exchange factor

KW - RHO-GTPASES

KW - communication checklist

KW - hyperactivity disorder

KW - developmental dyslexia

KW - susceptibility locus

KW - suggestive linkage

KW - mental-retardation

KW - reading-disability

U2 - 10.1111/gbb.12127

DO - 10.1111/gbb.12127

M3 - Article

VL - 13

SP - 418

EP - 429

JO - Genes, Brain, and Behavior

JF - Genes, Brain, and Behavior

SN - 1601-1848

IS - 4

ER -