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

TitleGenome-Wide Association and Exome Sequencing Study of Language Disorder in an Isolated Population.
Publication TypeJournal Article
Year of Publication2016
AuthorsKornilov, SA, Rakhlin, N, Koposov, R, Lee, M, Yrigollen, C, Çağlayan, AOkay, Magnuson, JS, Mane, S, Chang, JT, Grigorenko, EL
Date Published2016 04
KeywordsAdolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Exome, Genome-Wide Association Study, Humans, Language Disorders, Middle Aged, Polymorphism, Single Nucleotide, Russia, Sequence Analysis, DNA, Young Adult

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.

Alternate JournalPediatrics
PubMed ID27016271
PubMed Central IDPMC4811310
Grant ListP50 HD052120 / HD / NICHD NIH HHS / United States
R01 DC007665 / DC / NIDCD NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
UM1 HG006504 / HG / NHGRI NIH HHS / United States