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Pediatrics. 2016 Apr;137(4). pii: e20152469. doi: 10.1542/peds.2015-2469. Epub 2016 Mar 25.

Genome-Wide Association and Exome Sequencing Study of Language Disorder in an Isolated Population.

Author information

  • 1Child Study Center, School of Medicine, Yale University, New Haven, Connecticut; Department of Psychology, University of Connecticut, Storrs, Connecticut; Haskins Laboratories, New Haven, Connecticut; Department of Psychology, Moscow State University, Moscow, Russia; Department of Psychology, Saint Petersburg State University, Saint Petersburg, Russia;
  • 2Child Study Center, School of Medicine, Yale University, New Haven, Connecticut; Department of Communication Sciences and Disorders, Wayne State University, Detroit, Michigan;
  • 3Regional Centre for Child and Youth Mental Health and Child Welfare, UiT The Arctic University of Norway, Tromsø, Norway;
  • 4Child Study Center, School of Medicine, Yale University, New Haven, Connecticut;
  • 5The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania;
  • 6Child Study Center, School of Medicine, Yale University, New Haven, Connecticut; Department of Medical Genetics, Istanbul Bilim University, Istanbul, Turkey; and.
  • 7Department of Psychology, University of Connecticut, Storrs, Connecticut; Haskins Laboratories, New Haven, Connecticut;
  • 8Child Study Center, School of Medicine, Yale University, New Haven, Connecticut; Haskins Laboratories, New Haven, Connecticut; Department of Psychology, Saint Petersburg State University, Saint Petersburg, Russia; Moscow State University for Psychology and Education, Moscow, Russia elena.grigorenko@yale.edu.

Abstract

BACKGROUND AND OBJECTIVE:

Developmental language disorder (DLD) is a highly prevalent neurodevelopmental disorder associated with negative outcomes in different domains; the etiology of DLD is unknown. To investigate the genetic underpinnings of DLD, we performed genome-wide association and whole exome sequencing studies in a geographically isolated population with a substantially elevated prevalence of the disorder (ie, the AZ sample).

METHODS:

DNA samples were collected from 359 individuals for the genome-wide association study and from 12 severely affected individuals for whole exome sequencing. Multifaceted phenotypes, representing major domains of expressive language functioning, were derived from collected speech samples.

RESULTS:

Gene-based analyses revealed a significant association between SETBP1 and complexity of linguistic output (P = 5.47 × 10(-7)). The analysis of exome variants revealed coding sequence variants in 14 genes, most of which play a role in neural development. Targeted enrichment analysis implicated myocyte enhancer factor-2 (MEF2)-regulated genes in DLD in the AZ population. The main findings were successfully replicated in an independent cohort of children at risk for related disorders (n = 372).

CONCLUSIONS:

MEF2-regulated pathways were identified as potential candidate pathways in the etiology of DLD. Several genes (including the candidate SETBP1 and other MEF2-related genes) seem to jointly influence certain, but not all, facets of the DLD phenotype. Even when genetic and environmental diversity is reduced, DLD is best conceptualized as etiologically complex. Future research should establish whether the signals detected in the AZ population can be replicated in other samples and languages and provide further characterization of the identified pathway.

PMID:
27016271
PMCID:
PMC4811310
[Available on 2017-04-01]
DOI:
10.1542/peds.2015-2469
[PubMed - in process]
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