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

Content Provider	Europe PMC
Author	Kornilov, Sergey A. Rakhlin, Natalia Koposov, Roman Lee, Maria Yrigollen, Carolyn Caglayan, Ahmet Okay Magnuson, James S. Mane, Shrikant Chang, Joseph T. Grigorenko, Elena L.
Copyright Year	2016
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.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC4811310&blobtype=pdf
Page Count	13
ISSN	00314005
Volume Number	137
DOI	10.1542/peds.2015-2469
PubMed Central reference number	PMC4811310
Issue Number	4
PubMed reference number	27016271
Journal	Pediatrics
e-ISSN	10984275
Language	English
Publisher	American Academy of Pediatrics
Publisher Date	2016-03-25
Publisher Place	USA
Access Restriction	Open
Rights License	Copyright © 2016 by the American Academy of Pediatrics
Content Type	Text
Resource Type	Article
Subject	Pediatrics, Perinatology and Child Health