title: Genome-Wide Association and Exome Sequencing Study of Language Disorder in an Isolated Population.
abstract: 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).
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Child 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;
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Kornilov
authors.affiliation: Child Study Center, School of Medicine, Yale University, New Haven, Connecticut; Department of Communication Sciences and Disorders, Wayne State University, Detroit, Michigan;
authors.forename: Natalia
authors.initials: N
authors.lastname: Rakhlin
authors.affiliation: Regional Centre for Child and Youth Mental Health and Child Welfare, UiT The Arctic University of Norway, Tromsø, Norway;
authors.forename: Roman
authors.initials: R
authors.lastname: Koposov
authors.affiliation: Child Study Center, School of Medicine, Yale University, New Haven, Connecticut;
authors.forename: Maria
authors.initials: M
authors.lastname: Lee
authors.affiliation: The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania;
authors.forename: Carolyn
authors.initials: C
authors.lastname: Yrigollen
authors.affiliation: Child Study Center, School of Medicine, Yale University, New Haven, Connecticut; Department of Medical Genetics, Istanbul Bilim University, Istanbul, Turkey; and.
authors.forename: Ahmet Okay
authors.initials: AO
authors.lastname: Caglayan
authors.affiliation: Department of Psychology, University of Connecticut, Storrs, Connecticut; Haskins Laboratories, New Haven, Connecticut;
authors.forename: James S
authors.initials: JS
authors.lastname: Magnuson
authors.affiliation: Child Study Center, School of Medicine, Yale University, New Haven, Connecticut;
authors.forename: Shrikant
authors.initials: S
authors.lastname: Mane
authors.affiliation: Child Study Center, School of Medicine, Yale University, New Haven, Connecticut;
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Chang
authors.affiliation: Child 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.
authors.forename: Elena L
authors.initials: EL
authors.lastname: Grigorenko
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D059472:Exome / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D007806:Language Disorders / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012426:Russia / Q000453:epidemiology; D017422:Sequence Analysis, DNA / Q000379:methods*; D055815:Young Adult