期刊
GENES BRAIN AND BEHAVIOR
卷 13, 期 4, 页码 418-429出版社
WILEY
DOI: 10.1111/gbb.12127
关键词
ALSPAC; GWAS; imprinting; neurodevelopmental disorder; specific language impairment
资金
- Medical Research Council [G1000569/1, MR/J003719/1, G0800523/86473]
- University of Oxford Nuffield Department of Medicine Prize Studentship
- Max Planck Society
- Wellcome Trust [060774, 076566, 092731]
- National Institute of Health Research (UK)
- Biomedical Research Centre in Mental Health at the South London & Maudsley NHS Trust Hospital, London
- MRC [MC_UU_12013/1, MR/J003719/1, G1000569, G0800523] Funding Source: UKRI
- Medical Research Council [MR/J003719/1, G9817803B, MC_UU_12013/1, G1000569, G0800523, MC_PC_15018] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10268] Funding Source: researchfish
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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